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These patients require rapid extrication, advanced resuscitation, and transport by a dedicated RTF component; they cannot be attended to solely by tactical medics.Recently, RTF has become a “buzz word” that first responder departments use to demonstrate their effectiveness in tactical events. However, the role and implementation of such teams varies markedly from agency to agency. In practice, interoperability must continue to be emphasized by both command and ground-level units, and it must be practiced on a recurring basis to prevent confusion of operational objectives. On the day of the San Bernardino shooting only three fire agencies in the county had active RTF programs in place. Communication between these units was extremely strained by existing systems and the varied understanding of RTF concepts. Ensuring cohesive and coherent medical education across agencies will not only provide law enforcement with understanding of medical priorities, but also familiarize EMS with the tactical priorities of their law enforcement partners.As many law enforcement agencies begin to deploy their own medical assets, it is critical that EMS medical directors recognize the tactical medical resource as separate from but augmenting the overall medical profile. This position falls outside the realm of the medical branch of the incident command system because of its integration with operational teams. Thus, a law enforcement medical coordinator may provide a conduit to both EMS and fire assets as well as providing operational input to the incident commander. The LEMC would then provide the commander with critical information that may be overlooked by the traditional medical branch of the ICS. First, the ability to conduct an in-depth, plant grow table medical-threat assessment using operational data gathered by law enforcement and combined with EMS resources will provide on-scene commanders with a much better perspective on potential threats and limitations to operational plans.

Secondly, this position will provide improved integration between the tactical elements of the response and the force protection and rescue elements of the task force. Creating a LEMC position ensures proper allocation of both human and medical assets. Because SWAT medics operate within the law enforcement branch and not the medical branch, there is potential for duplication of efforts and general disorganization. This occurred in San Bernardino. Despite the traffic management by the SBPD, local resources pouring into the area of the shooting caused an obstacle to staged EMS assets. Medical resources were also being dispatched in duplicate with their respective law enforcement teams. Consolidated coordination of these assets would improve law enforcement support as well as integration for agencies less experienced with the RTF model. Ideally this position would be filled by an active or former tactical medical provider – preferably a physician with knowledge of both the tactical and EMS functions. The benefits include continuous evaluation of the medical threat from law enforcement assets in the hot zone as well as EMS and fire in the warm/cold zone. Additionally, the LEMC would oversee resource need and distribution among the operational teams. Designating one individual streamlines the process and enables the SWAT medic to focus solely on providing emergent aid within the hot zone, while knowing that coordination is being managed by a professional who understands the scene, its evolution, and their needs. Further, because of the uncertain nature of these operations, agencies must be prepared for extended operations.This possibility was understood by several teams present at the IRC event because they had recently been involved in the manhunt for Christopher Dorner, the disgraced Los Angeles Police Department officer who went on a shooting spree throughout Southern California. As the duration of that event extended several hours teams began to lack the basic necessities such as food and water, and experienced a shortage of personnel needed for the rotation system in order to sustain a high operational tempo.

Though the logistics branch of the ICS is theoretically tasked with procurement of supplies for an operation, law enforcement team health remains under the purview of the tactical medic. Therefore, a LEMC would be the ideal person to ensure proper allotment of resources regardless of the duration of operations.Law enforcement and fire departments have adapted quickly to minimize the loss of life in high-threat incidents through improved integration and education. Training for these scenarios is more often practiced as isolated events and less frequently combined. As a result, medical directors often outfit their teams in relation to the perceived threat, with PPE and medical equipment designed to protect from handguns and treat the “preventable causes of death.” Despite this traditional mindset, it has been repeatedly demonstrated that modern terrorists coordinate complex attacks, using multiple detonations to “drive” response and inflict maximal damage. Although many of the victims of the San Bernardino terrorist event were shot numerous times, it has been well documented that there were unexploded IEDs in the immediate vicinity of both survivors and rescuers. In the face of multiple, armed attackers using high-powered rifles and multiple explosive devices, the typically-issued PPE is inadequate and the available medical supplies could quickly be exhausted, particularly when treating individuals with blast injuries. Further, as active-shooter incidents have evolved, the push to incorporate Tactical Emergency Casualty Care guidelines by first-responder agencies has accordingly focused on ballistic injuries. This approach emphasizes the need for hemorrhage control but overlooks both the likelihood of encountering victims with multiple amputations and the complications of blast injury not seen by a penetrating injury. Medical directors and medical assets should update their education programs to re-emphasize treatment of blast vs. ballistic injury. In addition, focused, mass-casualty management will help agencies and designated LEMCs as to the care and coordination necessary for adequate resource planning.

In light of the threats now faced by our society, merely supplying one tourniquet, one chest seal and one dressing may no longer be sufficient. We recommend that ALL responders carry tourniquets,hydroponic table while SWAT team members should carry several. In addition, designated law enforcement medical elements should wear the same PPE as their colleagues on patrol. The development of a portable medical kit for active shooter/suspected terrorist events should be encouraged. Should extra equipment become necessary, this kit should contain multiple tourniquets, triage tape, combination dressing/ bandages and large quantities of gauze for hemostasis/wound packing. Contrary to conventional thinking, establishment of an airway is not of primary concern in these types of events, eliminating the need for multiple advanced airway kits. Most public buildings follow standard security practices, and medical directors and tactical medics should accordingly make basic changes in their response profiles. When the sprinklers were activated in the IRC building, medical assets were unprepared for operations in a wet environment. Moving forward, medical directors should educate and plan for the electrical shock hazards and biological hazards posed to responders in that environment. Rescue equipment should include waterproof triage tags , and teams should have the tools to circumvent difficulties with building access as part of the rescue plan. In the current environment, all tactical teams must have such access. Finally, agency training can no longer accept notional acknowledgment to the presence of IEDs. The actual procedures for IED, complicated, active shooter incident events should now be the standard, practiced scenario.Additionally, the complex and critical nature of injuries seen in these events and the challenge of accessing patients wounded by explosions, demonstrate the necessity for bystander care at the scene of the incident. Municipal and county agencies should consider training communities in TECC First Care Provider guidelines.Similarly, as the community has accepted the placement of automated external defibrillators in high-traffic areas, trauma/MCI equipment stations should also be pre-positioned in such areas and co-located with the AED.Stresses from these critical incidents may be reversed or halted through adaptive responses. Recognition that PTS is a likely outcome to mass casualty events should stimulate medical directors and team medics to create mechanisms for early recognition and practice of adaptive responses both for the individual and the collective. While individual stress is the focus of therapy, shared trauma or group stress remains a possible outcome. This shared trauma may unconsciously change processes within the group, affecting operational capabilities.Restricting access by non-essential personnel to victims remains the most basic process for decreasing stress in all groups. Additionally, there is a marked difference to the responses expected by responding patrol units and organized SWAT units. While specialized teams may have the infrastructure to address PTS, including their own medical assets, individuals involved in the initial response may find it difficult to participate in departmental programs because they fear stigmatization.

Avoidance of formal services may isolate and cause development of maladaptive responses that incur significantly higher risk for long-term pathology.Formal gatherings of team members and peer groups should be initiated very early to begin discussion of what has been witnessed and to prevent isolation by those most affected. However, support services must remain flexible and available to individuals reaching out to medical directors and team medics. Moreover, these gatherings must be protected from rules of discovery; fostering unguarded discussion/ conversation is crucial to this process, and fear of retribution may destroy this process. Finally, team medics may themselves need assistance following a crisis. It is imperative that medical directors or medical coordinators, as well as team leaders, allow for small-group or peer discussions in the aftermath of a critical event.As part of their standard training, each participant received a standardized irritant exposure and completed a training evolution.They were then required to complete a series of tasks to simulate control and apprehension of a combative criminal suspect. This training sequence lasted approximately 1½-2 minutes. Military trainees wearing protective gas masks were placed in an enclosed structure that was then saturated with CS gas. Gas masks were removed and each trainee was exposed to the tear gas for approximately 10 seconds. They were then required to perform a series of training tasks and safely exit the multi-story structure. This training sequence also lasted approximately 1½-2 minutes. After irritant exposure and completion of their training sequence, all subjects proceeded to a decontamination area and were allowed to irrigate their eyes and skin ad lib with water. Participants were randomized to a control group and intervention group. The intervention group was provided a cup containing a unit “dose” of 15cc of Johnson’s® baby shampoo and instructed to apply it liberally to their head, neck, and face. Repeat shampoo “doses” were available ad lib to this group. Irrigation was provided by a garden hose for police trainees exposed to OC and by a custom-made, multi-station irrigation device for military trainees exposed to CS. This device was constructed of two PVC pipes supported horizontally three feet off the ground and connected to a fire hydrant. Water flow was adjusted to produce an approximately 48-inch column of water from each of 20 holes drilled in each PVC pipe at offset angles. Oleoresin capsicum or “pepper spray” is an oil-based extract from pepper plants of the genus Capsicum. The chemically active ingredient is capsaicin, a fat-soluble phenol. OC causes its effect by stimulating type C unmyelinated nerve fibers that cause the release of substance P along with other neuropeptides, causing neurogenic inflammation and vasodilation.These neuropeptides also produce protective reactions of mucus secretion and coughing.Clinically this results in a painful burning sensation of the skin and mucous membranes, blepharospasm , and shortness of breath. Although OC causes a prominent subjective sense of dyspnea due to mucosal irritation, research has shown no objective change in respiratory function.OC has been estimated to be 90% effective in stopping aggressive behavior.A prior review of ED visits for OC exposure found the most common symptoms to be burning, erythema and local irritation to exposed areas.“Tear gas” is a lay term used to describe a group of irritant chemicals that cause lacrimation. The most commonly used agent by law enforcement is CS. CS is actually a crystalline solid, not a gas, making the term “tear gas” a misnomer; it is insoluble in water and has a small solubility in alcohols.It is aerosolized by multiple techniques including dissolving it in an organic solvent, micro-pulverization into a powder or in use with a thermal grenade that produces hot gases.

The pre-implementation time period used for comparison was November 1, 2014, to May 1, 2015. The post-implementation time period was November 1, 2015, to May 1, 2016. We defined TTVS documented as the time from quick registration to first vital sign documented in the electronic medical record. The pilot phase was initiated in May 2014 for eight hours/day, five days/week, excluding weekends. This was extended to 16 hours/day, seven days/week in November 2014, which was the study period. During the implementation period, a vital signs station was created and a personal care assistant was assigned to the waiting area with the designated job of obtaining vital signs on all patients upon arrival to the ED and prior to leaving the waiting area. PCAs are part of the ED team and perform duties under the supervision of doctors and nurses. They assist with numerous tasks. This vital sign station was directly adjacent to the quick registration desk. After patient arrival and sign-in, a quick registration including name, date of birth, and chief complaint was completed. Subsequently, patients were directed to a PCA with a portable vital signs machine and a computer on wheels with access to the EMR. The PCA’s sole task was to obtain vital signs on all patients before they left the waiting area and then enter this information in the EMR. Patients who arrived via EMS had vital signs entered by the ED triage nurse and were also included in this analysis. PCAs were also empowered to obtain vital signs on patients who were waiting in line for registration.The implementation of DTR has had countless benefits, including faster turnaround times, improved door-to- doctor times, and decreased LWBS rates.3 By reducing ED crowding, decision-making time can be reduced as well as reducing over-use of the laboratory and computed tomography.9 However, our experience has shown that an unintended consequence of DTR is both a delay and inconsistency in obtaining initial vital signs. In this study, we demonstrated that the implementation of a vital sign station at ambulatory registration reduced the TTVS, an unintended consequence of DTR, by a mean time of nearly six minutes. When we coupled a vital signs station with our already existing quick registration process,vertical rack the department experienced no delays in overall throughput. Although this now adds a few minutes to the quick registration, we found that the overall benefits far outweigh this short delay.

For EDs that have some form of quick registration and DTR process and experience similar delays in obtaining vital signs, we believe that creating a vital sign station in the waiting room is a feasible and effective solution that could be implemented by any ED. Our ED has two portals of entry: an ambulance entrance, where the patient is immediately triaged and has his vital signs obtained by a nurse who then enters them in the patient chart; and a quick registration desk in the waiting room where all ambulatory patients must sign in prior to being brought to the treatment area. At the quick registration desk, brief demographic information and chief complaint is obtained, which allows the patient to be entered into the EMR and receive a medical record number. After undergoing a quick registration, there are three subsequent pathways for the patient: 1) taken directly into the treatment area by a nurse, PCA, or pavilion coordinator ; 2) taken to a triage station for formal nursing triage, 3) queued in the waiting room for either the next available DTR or formal triage availability. At our institution the pavilion coordinator is an ED greeter who helps the nursing staff facilitate our DTR process. Quick registration with chief complaint and vital sign assessment is markedly different from formal triage, in that formal triage requires nursing resources and a significant amount of time. Quick registration only requires patient demographics and chief complaint, whereas traditional formal triage includes expanded history-taking and a medical assessment including allergies, medications, surgical history, etc. which can lead to a delay in initial clinical assessment in treatment areas. There are many potential benefits to this new process besides the decrease in TTVS. Obtaining earlier vital signs enhances patient safety since it allows for earlier recognition of potentially abnormal vital signs and therefore prompt treatment and intervention. This is especially true in the patient who may appear stable. Second, patient satisfaction is improved since they recognize that they are being taken care of from the moment they walk into the ED. Implementation may be limited due to PCA competing priorities and unanticipated staffing needs within the department. While there were no extra personnel costs as staffing did not increase to fill the vital signs station, we did decrease the availability of existing PCAs in the clinical arena. Annually over 400,000 people suffer non-traumatic out-of hospital cardiac arrest in the United States.This represents the third leading cause of death in industrial nations and accounts for eight times as many deaths as motor vehicle collisions.

There have been steady, albeit modest, improvements in the survival of patients with OHCA over the past decade.Other improvements including higher rates of bystander CPR, dispatch directed CPR, deployment of automatic external defibrillators in the community, and improved CPR quality have also contributed to increasing survival rates.Recently the American Heart Association and other subject matter experts have advocated for the development of regional systems of cardiac arrest care with designation of cardiac arrest centers.A cardiac arrest center is a hospital that provides evidence-based practice in resuscitation and post-resuscitation care, including 24/7 percutaneous coronary intervention capability and targeted temperature management , as well as an adequate annual volume of OHCA cases and a commitment to performance improvement and bench marking. There is a similar precedent in the establishment of ST-segment elevation myocardial infarction centers over the past decade to improve outcomes in that time-dependent disease.Observational studies suggest a benefit of regionalization; therefore, the establishment of regional care systems may optimize access to and delivery of care for patients with OHCA. A prospective study demonstrated improved outcomes in patients with OHCA transported to a cardiac arrest center compared to non-cardiac arrest centers.There have been numerous observational studies with differing hospital characteristics as well as a number of studies that compared outcomes before and after the implementation of regionalized systems of care,microgreen flood table all suggesting an association between improved survival and routing of select patients to cardiac arrest centers. A regionalized cardiac arrest system involves a systematic approach to the care of the OHCA patients across a geographic area. This would include consistency in prehospital care, selective transport to designated cardiac arrest centers, consistent policies on the post-resuscitation care, and participation in a regional performance improvement process to address any potential disparities in care. Currently, most cardiac arrest centers in the U.S. are self-designated academic centers.The extent to which regionalization of cardiac arrest care has been established is not well quantified.

Two studies describing established regional cardiac arrest care systems demonstrated improved patient outcomes with regionalization.This survey of local EMS agencies in California was intended to determine the current practices regarding the treatment and routing of OHCA patients and the extent to which EMS systems have regionalized care across California. The State of California has a population of 39 million, and EMS care is regulated by the California EMS Authority. Oversight of local care is provided by 33 LEMSA. These government agencies establish uniform policies and procedures for a countywide or region-wide system of first responders and EMS providers. While all LEMSA must have an EMS plan that conforms to California EMS Authority mandates, policies and protocols vary among them.We surveyed all 33 California LEMSA on three topics: 1) local policy regarding routing of OHCA patients to designated cardiac arrest centers; 2) specific interventions for post-resuscitation care available in those centers; and 3) access to data on OHCA treatment and outcome measures. We also requested system metrics on frequency of OHCA and patient outcomes. Of note, our survey inquired about the policies and protocols pertaining to all OHCA patients, not only those who achieved ROSC. We developed a 37-question survey in three sections: field treatment and routing policies ; specialty centers ; and system data. Prior to dissemination, the survey was reviewed by several LEMSA administrators and subsequently edited for clarity. The survey was distributed by email to the California LEMSA administrators and medical directors in August 2016, available online via Qualtrics software. Reminders were sent until all LEMSA completed the survey. We clarified incomplete or inconsistent survey responses by email and/or phone. The primary objective was to describe management of OHCA throughout California in terms of current treatment guidelines and specifically to determine the extent to which systems have regionalized care. Responses were submitted by either the LEMSA director or representative and downloaded or input into Excel for analysis. The findings of this study will be shared with the EMS Medical Directors Association of California ,an advisory body to the California EMS Authority comprised of all EMS medical directors of the 33 LEMSAs, who meet quarterly to advise the state on issues pertaining to prehospital scope of practice and quality of care. This study was submitted to the Institutional Review Board at the University of California at San Francisco and was deemed to not involve human subjects as to require continuous IRB review.

All 33 California LEMSA participated in the survey for a response rate of 100%. Table 1 provides a summary of LEMSA routing policies. Two LEMSA reported a fully developed regional cardiac arrest care system with specific clinical protocols to direct patients to cardiac arrest centers, a role in influencing hospital policies about post-cardiac arrest care, and participate in a regional performance-improvement process. The Los Angeles regional cardiac arrest system has been described previously.In LA, all OHCA with ROSC and those transported with presumed cardiac etiology are routed to designated centers, which double as STEMI and cardiac arrest centers. All have 24/7 PCI capability, written internal protocols for TTM, and take part in a regional performance-improvement process. Alameda County operates a similar system, routing all OHCA patients with ROSC at any time to cardiac arrest centers. A large number of LEMSA , comprising a population of 14 million, have specific protocols to direct all OHCA patients with ROSC to designated PCI-capable hospitals. They have a limited role or no role in influencing hospital policies about post cardiac arrest care and do not have a regional performance-improvement process. There was inconsistency among agencies regarding the protocols and reporting required from these hospitals. Nearly all LEMSA have a termination of resuscitation protocol for OHCA. Eight LEMSA have policies and protocols that direct the use of TTM during post-resuscitation care, requiring hospitals to have a written TTM protocol, and five have a memorandum of understanding to enforce the requirement and allow them a role in determining the inclusion and exclusion criteria.Seven LEMSA have policies that require receiving hospitals to have a written protocol for emergent PCI after OHCA. Of these, four have memoranda of understanding with the hospitals and three have a role in determining inclusion and exclusion criteria. The use of PCI for patients with persistent cardiac arrest was rare. Fifteen agencies reported that this occurred in their system, but none reported more than 3-5 patients. Eleven LEMSA have hospitals with extracorporeal membrane oxygenation capability, but it was rarely used for this indication and there were no LEMSA with specific routing or regional policies for its use. Mechanical CPR devices were optional for 18 local EMS agencies. One agency required the use of mechanical CPR devices during transport and another required them for all OHCA patients. The majority of LEMSA report collecting process measures for system quality improvement, with EMS response time the most commonly measured , followed by the time to CPR , the time to defibrillation , and the rate of dispatcher-assisted CPR. However, the measurements of in-hospital outcomes were significantly lower with survival to hospital discharge the most commonly measured. The frequency of reported treatment and outcome measures are listed in Table 2. We present the current policies for treatment and routing of all OHCA patients throughout California with a 100% survey response rate.

Ascertainment of HIV infected patients by this registry has been shown to be at least 95% complete. The HIV registry contains information on patient demographics , HIV transmission risk group , dates of known HIV infection, and AIDS diagnoses. KPNC also maintains complete and historical electronic databases on hospital admission/discharge/transfer data, prescription dispensing, outpatient visits, and laboratory tests results, including CD4 T-cell counts and HIV-1 RNA levels. Mortality information including date and cause of death are obtained from hospitalization records, membership files, California death certificates, and Social Security Administration databases. Mortality data were complete through December 31, 2007. Antiretroviral medication prescription data were obtained from KPNC pharmacy databases. Approximately 97% of members fill their prescriptions at KPNC pharmacies, including patients whose prescriptions are obtained through the Ryan White AIDS Drug Assistance Program. ARV medication data included date of first fill, dosage, and days supply, as well as data on all refills. Patients were classified as: currently receiving combination-ARV , current dual NNRTI/NRTI ARV use, past ARV use, or never users.Psychiatric diagnoses were assigned by providers.Psychiatric diagnoses selected for this study were the most common and serious psychiatric disorders diagnosed among health plan members including schizophrenic disorders , major depressive disorder, bipolar affective disorder, neurotic disorders , hysteria, phobic disorders, obsessive-compulsive disorder, anorexianervosa, and bulimia. We examined the impact of having one or more of these psychiatric disorders in aggregate, as in prior HIV studies.Within the health plan,rolling benches canada psychiatry can be accessed directly by patients. Mild cases of depression and anxiety may be addressed in primary care with medication but moderate to severe cases are referred to psychiatry.

Treatment in psychiatry includes assessment, psychotherapy and medication management. Patients diagnosed with a psychiatric disorder generally return to psychiatry for individual and/or group psychotherapy and/or medication evaluations. Our measure of psychiatric treatment was whether or not a patient had visits to a psychiatric clinic after a psychiatric diagnosis,obtained from automated databases.A diagnosis of ICD-9 substance dependence or abuse can be made by the patient’s clinician in primary care, SU disorder treatment, or psychiatry as a primary or secondary diagnosis.Diagnostic categories include all alcoholic psychoses, drug psychoses, alcohol dependence syndrome, drug dependence , alcohol abuse, cannabis abuse, hallucinogen abuse, barbiturate abuse, sedative/tranquilizer abuse, opioid abuse, cocaine abuse, and amphetamine abuse; as well as multiple substance abuse and unspecified substance abuse. In our analyses we classified patients as having one or more diagnoses of substance abuse and/or dependence versus no diagnosis.KPNC provides comprehensive outpatient SU treatment available to all members of the health plan. Services include both day hospital and traditional outpatient programs,both of which include eight weeks of individual and group therapy, education, relapse prevention, family therapy, with aftercare visits once a week for ten months. In addition to these primary services, ambulatory detoxification and residential services are available, as needed. A small proportion of patients engage in residential SU treatment, conducted by contractual agreement with outside institutions. These data are available in the KPNC referrals and claims databases. As with psychiatric treatment, in the current study SU treatment initiation was measured as having one or more visits to an outpatient program or a stay in a residential SU treatment unit following diagnosis.Analyses focused on diagnoses of psychiatric disorders with and without co-occurring SU diagnoses as the primary predictors of interest. The distribution of demographic, clinical and behavioral characteristics was compared between patients with and without a major psychiatric diagnosis; statistical significance was assessed using the w2 test.

The distribution of cause of death was examined by psychiatric diagnostic status ; statistical significance was assessed using the w2 test or Fisher’s exact test where table cells were sparsely populated. Cox proportional hazards regression was used to obtain point and interval estimates of mortality relative hazards associated with psychiatric diagnosis/treatment status and SU problems diagnosis/treatment status, with each of these two time dependent covariates measured at three levels: no diagnosis, diagnosis with treatment, diagnosis without treatment. With the goal of examining the joint effects of these two covariates on mortality, results are expressed as hazard ratios for combi nations of psychiatric diagnosis/treatment and SU diagnosis/treatment levels, with no diagnosis of either comorbidity as the referent. These estimates were adjusted for an a priori chosen set of available covariates, including age at entry into study, race/ethnicity, gender, HIV transmission risk group, CD4 T-cell counts and HIV RNA levels and ARV treatment modeled as time-dependent covariates, year of known HIV infection, AIDS diagnosis prior to entry into study, and evidence of hepatitis C viral infection. Initial modeling results demonstrated a significant interaction be tween psychiatric and SU diagnosis/treatment status in Cox regression models. Therefore, relative hazard estimates of interest were obtained via appropriate linear combinations of parameter estimates from a fully saturated model. Although a significant minority of patients remained ARV naı¨ve throughout the study follow-up,flood table we wanted to estimate adherence to combination highly active antiretroviral therapy stratified by psychiatric diagnosis and SU diagnosis status for study participants who did receive HAART. Adherence was measured using electronic pharmacy dispensing refill records; the “days supply of HAART medication was divided by the “total time elapsed between first day of HAART initiation and last day of HAART medication supply’’ over the first 12 and 24 months of study follow-up. Mean and standard deviaition of adherence were then estimated by diagnostic status category.

All data analyses were conducted using SAS software, version 9.1.The distributions of demographic and HIV-related clinical and behavioral characteristics by psychiatric diagnosis status are presented in Table 1. The results of w2 tests indicate significant differences in most characteristics between those patients with and without a psychiatric diagnosis. However it can be seen that the categories of these characteristics were still very similar in distribution in both groups. Finding significant results for very small differences in distributions is likely the consequence of having a very large sample size in this study. The majority of patients were white, male, 30–49 years of age at baseline, and belonged to the men who have sex with men HIV transmission risk group. CD4 T lymphocyte cell counts measured at or near time of study entry were comparable in both patients with and without a psychiatric diagnosis. Similar results were observed for HIV RNA levels. Of the 2472 patients with a psychiatric diagnosis, 83.9% had one or more psychiatry department visits. The proportion of patients with any ARV therapy experience at baseline was similar across psychiatric disorder status, with on average 35% of all patients having no ARV experience. Throughout study follow-up, approximately 25% of all patients remained ARV naı¨ve. Among those who were receiving HAART during study follow-up, mean adherence was estimated as 82.4% among patients with a psychiatric diagnosis at 12 months after initiation of HAART and 83.7% among patients with no psychiatric diagnoses; similar mean adherence was observed at 24 months. Patients diagnosed with SU problems showed mean adherence of 81.1% at 12 months after initiating HAART in comparison to 83.5% among patient without a SU problem diagnosis. Because adherence rates were similar across diagnostic status, we did not conduct a subanalysis of ARV-experienced patients only, where adherence would have been included as a covariate in the regression model. The distribution of cause of death cross-tabulated by psy chiatric diagnosis is presented in Table 2. The majority of deaths among patients with or without a psychiatric diagnosis were attributed to HIV/AIDS. The remaining causes of death had proportionately the same distribution across categories of psychiatric diagnosis status, with the possible exception of suicide which was twice as common among patients with a psychiatric diagnosis in comparison to pa tients with no diagnosis. Examining all-cause mortality for the entire study follow-up, we found an age-adjusted mortality rate of 28.6 deaths per 1000 person–years for patients with a psychiatric diagnosis versus 17.5 deaths for those with out a psychiatric diagnosis. To examine the joint effects of psychiatric diagnosis, psychiatric treatment visits, SU diagnosis, and SU treatment on mortality, relative hazards were estimated using Cox proportional hazards regression. As mentioned in Statistical methods, the effects of psychiatric diagnosis/treatment and SU diagnosis/treatment were not additive, with statistically significant interactions between these covariates.

RHs and 95% Confidence Intervals estimated from unadjusted and adjusted models are presented in Table 3. Categories of diagnosis and treatment are ordered from lowest to highest RH in the unadjusted model 1. In comparison to patients with neither a psychiatric diagnosis nor a SU diagnosis , the highest risk of dying was found among patients with dual diagnoses but who had no psychiatric treatment visits and no SU treatment. This effect was somewhat attenuated after adjustment for potential confounders but remained statistically significant. Similar results were observed for patients who had a psychiatric diagnosis but no psychiatric services and no SU diagnosis that were very similar to those parameter estimates in model 2.During 12 years of follow-up , we observed a higher mortality risk for HIV-infected patients diagnosed with both psychiatric and SU disorders in comparison to patients with neither diagnosis. However, we observed that psychiatric and SU treatment, in general, reduced mortality risk in single and dual diagnosed patients, and remained statistically significant even after adjustment for age, race, immune status, HIV viral load, antiretroviral therapy use, and other potential confounders. Accessing psychiatric treatment reduced mortality risk among dual diagnosed patients who were treated or not treated for SU disorder. Previous studies of individuals with HIV infection have found that those with psychiatric disorders are at elevated risk for poor medication adherence and clinical outcomes.There is substantial evidence that depression, stressful life events and trauma affect HIV disease progression and mortality.This effect has been found even controlling for medication adherence, in a study that showed that HAART adherent patients with depressive symptoms were 5.90 times more likely to die than adherent patients with no depressive symptoms.Depressive symptoms in dependently predicted mortality among women with HIV,18 and also in a separate study of men.17 Similarly, in multi variate analyses controlling for clinical characteristics and treatment, women with chronic depressive symptoms were 2 times more likely to die than women with limited or no depressive symptoms.Among women with CD4 cell counts of less than 200 10/ L, HIV-related mortality rates were 54% for those with chronic depressive symptoms and 48% for those with intermittent depressive symptoms compared with 21% for those with limited or no depressive symptoms. Chronic depressive symptoms were also associated with significantly greater decline in CD4 cell counts after controlling for other variables.These mechanisms could help to explain the greater risk of mortality ob served in our sample. Our findings strongly highlight the importance of access to psychiatric and SU disorder treatment for this population. It was estimated that during a 6-month period, 61.4% of 231,400 adults in the United States receiving treatment for HIV/AIDS used psychiatric or SU disorder treatment services.A significant number of HIV-infected patients report accessing psychiatric services.Such visits are associated with decreased risk of discontinuing HAART.Burnam et al.found that those with less severe HIV-related illness were less likely to access psychiatric or SU disorder treatment. One study found that engagement in SU disorder treatment was not associated with a decrease in hospital use by HIV-infected individuals with a history of alcohol problems.Improvement in depression was associated with increase in HAART adherence among injection drug users.A limitation of our study may have been the differences in timing of the psychiatric diagnosis and/or SU diagnosis. Some patients in our sample may have received their psychiatric diagnosis shortly after the onset of symptoms or in the initial phase of substance dependence or abuse, while other patients may have been diagnosed at a more advanced stage. Some patients may have met the criteria for a psychiatric or SU diagnosis without receiving one. In addition, some study subjects may have received psychiatric care or informal SU disorder services or self-pay services outside of the KPNC health plan, and our study does not have information about those services. We also could not control for level of comorbidity for other diseases and conditions at baseline, because many patients had insufficient health plan membership time prior to study entry. This study examined mortality among HIV-infected patients with private health insurance who received medical care in an integrated health plan, who had full access to psychiatric and SU disorder services, and who had received diagnoses of psychiatric disorder and substance dependence or abuse by a clinician.

This increase was driven by the brand Steel Reserve, with a %ABV of 8.1%, as the top-selling brand in the malt beer category from 2006 onwards. Also between 2005 and 2006 the market share of malt beer increased by about 29%, although it still only comprised less than 3% of the market share in 2006. The decline in the national mean %ABV of beer between 2006 and 2010 was explained by the continued decline in market shares of premium beer, which lost 20% of its market shares over this period. The marked increase in the national mean %ABV of beer from 2010 to 2016 was driven by the increase in mean %ABV and market shares of flavored malt beverages and of craft beer. The mean %ABV of FMBs increased from 5.9% to 6.5%, and of craft beer from 4.9% to 5.3% between 2011 and 2016. Over the same period FMBs increased its market share by approximately 56%, while craft beer increased by approximately 85%. It is also important to note that light beer, which had a stable %ABV over time of about 4.3%, showed a steady decline in market shares from a high of 52.9% in 2010 to 44.5% in 2016. The increase in the mean %ABV of wine between 2007 and 2010 was driven by increases in the sales-weighted mean %ABV of table wine. Table wines increased from 11.7 in 2007 to 12.4 %ABV in 2010 when the %ABV peaked and changed little thereafter. Table wines comprised the vast majority of wine sales nationally with a market share consistently around 90%. This market share changed little over the entire 2003-2016 period from 90.2% to 90.7%, and was highest in 2010 at 91.8%. The slight decline in the mean %ABV of wine between 2010 and 2011 was attributable to the decline in the mean %ABV of dessert and fortified wine from 15.0% to 14.1%, which also lost market shares by approximately 16% between 2010 and 2011, although comprised only 3% of the market in 2010. Spirits showed a steady increase in mean %ABV over the 2003 to 2016 period,microgreen rack for sale reflecting a gradual increase in the market shares of higher %ABV spirits and a gradual decrease in lower %ABV spirits.

Vodka, with a mean 40% ABV throughout the study period, showed the largest rise in market shares from 26.2% in 2003 to 33.6% in 2016. Similarly, market shares of tequila, also with a mean 40% ABV, increased market shares from 4.8% to 7.2%. Straight whiskey also increased its market shares from 8.4% to 9.5% between 2003 and 2016, and had a slight increase in mean %ABV from 41.1% to 41.9%. There were limited changes in the mean %ABV of spirits sub-types, with the exception of cordials & liqueurs and prepared cocktails. Cordials & liqueurs showed an increase of mean %ABV from 23.7% to 28.4%, and prepared cocktails from 9.7% to 11.9%. National beverage-specific and total per capita alcohol consumption estimates. The new national variant %ABV-based PCC estimates for beer, wine, and spirits, and for total consumption, with comparisons to AEDS estimates are presented in Figure 2. Overall, our new estimates showed that consumption of pure alcohol from beer was somewhat higher for every year and that consumption of alcohol from wine, spirits, and total PCC was lower in every year compared to AEDS estimates. Our PCC estimates from beer decreased from 4.8 to 4.4 liters per capita between 2003 and 2016 and showed a similar trend over time compared to AEDS estimates. However, the percent difference between the AEDS and our estimates increased between 2011 and 2016 from 3.2% to 5.1% showing that the trends diverge slightly. Our PCC estimates from wine increased from 1.2 to 1.6 liters per capita between 2003 and 2016. The trend is similar to AEDS estimates, although there is a notable convergence between our estimates and the AEDS estimates, where the percent difference decreased from 9.7% in 2003 to 5.0% in 2016. Our estimates of PCC from spirits increased between 2003 and 2016 from 2.31 to 2.98 liters per capita and followed a very similar trend to the AEDS estimates, remaining mostly parallel over the study period. A slight convergence was observed as the percent difference between our estimate and the AEDS estimate was 10.3% in 2003, 7.9% in 2015 and 6.8% in 2016. Our total PCC estimates followed a similar pattern over the 2003 to 2016 period to that of the AEDS estimates . However, there are important differences. Overall, our total PCC estimates were lower than the AEDS estimates.

Further, the trend for our estimate converged with the AEDS estimate trend. The difference between our estimates declined from 0.24 liters of alcohol per person in 2003 to a difference of just 0.08 liters in 2016. Importantly, the percent change between 2003 and 2016 for the AEDS estimates was 5.8% compared to a 7.9% change in our estimates over the same period. This 7.9% change represents 0.66 liters, which is a mean of approximately 37 drinks per person per year. In contrast, a 5.8% change represents 0.48 liters, which is a mean of approximately 27 drinks per person per year. State %ABV estimates for beer, wine, and spirits. The estimates of the mean %ABV of beer, wine,cannabis grow facility layout and spirits for each state and the District of Columbia for selected years are presented in Table 3. The mean %ABV of each beverage type are seen to vary by state in each year, reflecting the variation in preferences and mean %ABV for each beverage sub-type across states and time. All states and the District of Columbia showed an increase in the mean %ABV of beer between 2003 and 2016, and most states followed the national trend. The states with the least amount of change over the 2003-2016 period were North Dakota, Virginia, and Iowa with percent increases of 1.2%, 1.1%, and 0.9%, respectively, while New Mexico, Montana, and Maine experienced the greatest percent increases of 4.9%, 4.4%, and 4.3%, respectively. For wine, all states showed an increase in mean %ABV and followed the national trend. The states with the greatest increases between 2003-2016 were Idaho, Virginia, and Tennessee with increases of 6.8%, 6.8%, and 6.7%, respectively. The states with the lowest percent change were Illinois, North Carolina, and Mississippi with increases of 3.1%, 3.0%, and 2.9%, respectively. For spirits, 45 states and the District of Columbia showed increases in the mean %ABV of spirits, and of these the vast majority followed the national trend. Ohio, Rhode Island, and Nebraska had the largest percent increases at 10.5%, 7.9%,and 6.6%, respectively, while West Virginia, Mississippi, and Alabama had the largest decreases in %ABV for spirits of 0.4%, 0.5%, and 1.8%, respectively. State mean %ABVs and market shares for beverage sub-types. The change in the mean %ABV of beer, wine, and spirits was driven by changes in beverage sub-type mean %ABVs and preferences, and these %ABVs and preferences varied by state. To describe these state-level beverage sub-type %ABV and preference changes in relation to state-level changes in mean beverage-specific %ABV, we present data for the states with the largest change in mean %ABV for each beverage type.

The increase in %ABV of beer for New Mexico, which had the largest percent increase of 4.9%, is attributable to a decline in the market shares of beer with relatively low mean %ABV and an increase of relatively higher mean %ABV beer sub-types. Between 2006 and 2016 the market shares of light beer declined from 51.5% to 37.6%. The market shares of the super premium, micro/specialty, and FMBs sub-type category increased from 6.8% in 2006 to 11.9% in 2010, and between 2011 and 2016 the market shares of craft beer increased from 8.2% to 14.9%. Similar to the national trends in the mean %ABV of wine, state-level trends were driven by the increase in the mean %ABV and the market shares of table wine. Idaho, which had the largest percent change in mean %ABV of wine of 6.8%, had the largest market share of table wine for most years between 2003 and 2016, where market shares of table wine were 97.3% in 2003 and 97.4% in 2016. Comparable to national trends in the mean %ABV of spirits, state level trends were driven by declines in the market shares of low %ABV spirit sub-types and increases in high %ABV spirit sub-types. Between 2003 and 2016, Ohio had the largest increase in mean spirits %ABV of 10.5%. Unlike the national trend, it showed a marked increase between 2012 and 2014 after which it leveled off. The increase in %ABV between 2012 and 2014 was driven by a decline in the market shares of prepared cocktails from 9.3% in 2012 to 0.2% in 2014 and a concomitant increase in the market shares of cordials and liqueurs, straight whiskey, tequila, and brandy & cognac. State beverage-specific and total per capita alcohol consumption estimates. The new beverage-specific %ABV-variant PCC estimates for selected years for each state are presented in Table 3.The total PCC estimates for each state with comparisons to AEDS estimates for 2003 and 2016 are presented in Table 4. The estimates varied by state in each year, representing the range in total PCC by state. Table 4 also shows the percent change in total PCC for each state for both our new estimates and the AEDS estimates. The ranking by percent change varies by the new and AEDS estimates. North Dakota has the largest percent change in total PCC according to both estimates, however, the new estimates rank Vermont second followed by Idaho while the AEDS estimate rank Idaho second followed by Vermont. The vast majority of states showed an increase in total PCC, although 2 more states, Nebraska and Illinois, showed a decline according to AEDS estimates than did according to our new estimates. For all beverage types, our mean %ABV estimates increased nationally and for all but five states. These increases were driven by an increase in national and state preferences for beverages with a higher and increasing %ABV and a decrease in preferences for lower %ABV beverages. The estimates of PCC from wine and spirits utilizing variable %ABV conversion factors were lower than AEDS estimates, while consumption from beer was higher. While our total PCC estimates were also lower than AEDS estimates, the trends in PCC showed a more dramatic increase in pure alcohol volume than those using ABV-invariant methods. Researchers have used PCC estimates to try to understand the observed increases in alcohol-related morbidity and mortality in the U.S. over the first part of the 21st century. For example, White et al noted an increase of 1.7% in PCC and concluded that it did not appear to be related to the 47% increase in the rate of alcohol-related ED visits from 2006 to 2014 . Using our ABV variant method, PCC between 2006 and 2014 increased by 3.6%, over double the increase using the ABV invariant method. This difference and the absolute increase using the ABV variant method may not alone explain the increase in the rate of alcohol-related ED visits. However, because the change in PCC was likely underestimated, it suggests PCC should not be dismissed and may be one of many factors driving the increase in alcohol-related emergency room visits. This example also highlights the importance of the rate of change in PCC trends, and is consistent with findings from an Australian study that similarly showed the value of including time-varying ABV values to ensure precision in PCC estimates so change over time can be accurately measured . It is important to note that cohort and lag effects may also be drivers of the disparity between changes in alcohol-related morbidity and mortality and changes in PCC. Cohort effects may be related in that previous generations may have been drinking at high levels that resulted in death from alcohol-related diseases so that their alcohol consumption would not be included in current PCC estimates . Lag effects may contribute because the time from changes in PCC to the time to first effect for some alcohol-attributable diseases, such as alcohol-related cancers, is at least 10 years .

However, e-cigarette’s harm quotient should stay low, provided they are properly regulated in terms of their components, including nicotine. Social influences and attitudes drive harm through stigma, social exclusion and social marginalization; these are often side-effects of drug policies, which can bring more harm than drug use itself.Policies that reduce exposure to drugs are essentially those that limit availability by increasing the price and reducing physical availability.Limits to availability bring a range of co-benefits to educational achievement and productivity, for example, but they can also bring adverse effects – for example, the well documented violence, corruption and loss of public income associated with some existing ‘illegal’ drug policies. Individual choices and behaviour that drive harm from drug use are determined by the environment in which those choices and behaviours operate. Banning commercial communications, increasing price and reducing availability are all incentives that impact individual behaviour. Research and development can be promoted to reduce the potency of existing drugs and their drug delivery packages. Unfortunately, there remain enormous gaps between the supply and demand of evidence-based prevention, advice and treatment programmes. Called for by United Nations Sustainable Development Goal 3.5, their supply can bring many co-benefits to society, including reduced social costs and increased productivity. The harm driven by the gaps is due in large part to insufficient resources and insufficient implementation of effective evidence-based prevention and treatment programmes. Currently these programmes represents less than 1% of all costs incurred to society by drugs.

Similar to medicines agencies that assess and approve drugs,commercial greenhouse supplies prevention agencies could be created. Compounding the gap between supply and demand is the fact that often, considerable marginalization and stigmatization happens in the path to treatment, and this is then further exacerbated by the treatment itself. The use of pharmacotherapy as an adjunct may be further limited due to ideological stances, poorly implemented guidelines, lack of appropriate medication, and even a perceived lack of effect, if the drug is available. The private sector is a core driver of harm, through commercial communications which include all actions undertaken by producers of drugs to persuade consumers to buy and consume more. There are international models encouraging better control of commercial communications in the public health interest, the most notable being the Framework Convention on Tobacco Control. In addition to commercial communications, the private sector drives harm through shaping drug policies, leading to more drug-related deaths. Governance structures thus need to have the capability and expertise to supervise industry movements that shape drug-related legislation and regulations, including regulating and restricting political lobbying. One of the difficulties here is that politically driven change in difficult areas, such as drug policies, is highly dependent on collective decisions and influenced by what has been termed specular interaction, in which a politician’s actions may be less determined by their own conviction, and more by their evaluation of beliefs of their rivals and friends. The health footprint is the accountability system for who and what causes drug-related harm. Jurisdictional entities can be ranked according to their overall health footprint, in order to identify the countries that contribute most to drug attributable ill-health and premature death, and where the most health gain could be achieved at country level. Jurisdictional footprints could include ‘policy attributable health footprints’ which estimate the health footprint between current policy and ideal health policy. This would address the question: ‘what would be the improvement in the health footprint compared to present policies, were the country to implement strengthened or new policies?’ Conversely, the health footprint can provide accountability for when such evidence-based policy is not implemented correctly.

A range of sectors are involved in nicotine and alcohol related risk factors. These include producer and retail organizations such as large supermarket chains, and service provider companies such as advertising and marketing industries. There is considerable overlap between sectors, and estimates will need to determine appropriate boundaries for health footprint calculations. Companies could report their health footprints and choose to commit to reducing them by a specified amount over a five to ten-year time frame. Direct examples of producer action could include switching from higher to lower alcohol concentration products, and switching from smoked tobacco cigarettes to e-cigarettes.Cannabinoid receptors, the molecular targets of the active principle of cannabis 9 -tetrahydrocannabinol, are activated by a small family of naturally occurring lipids that include anandamide and 2-arachidonylglycerol . As in the case of other lipid mediators, these endogenous cannabis-like compounds may be released from cells upon demand by stimulus-dependent cleavage of membrane phospholipid precursors . After release, anandamide and 2-AG may be eliminated by a two-step mechanism consisting of carrier-mediated transport into cells followed by enzymatic hydrolysis . Because of this rapid deactivation process, the endocannabinoids may primarily act near their sites of synthesis by binding to and activating cannabinoid receptors on the surface of neighboring cells . The development of methods for endocannabinoid analysis and the availability of selective pharmacological probes for cannabinoid receptors have allowed the exploration of the physiopathological functions served by the endocannabinoid system. Although still at their beginnings, these studies indicate that the endocannabinoids may significantly contribute to the regulation of pain processing , motor activity , blood pressure , and tumor cell growth . Furthermore, these investigations point to the endocannabinoid system—with its network of endogenous ligands, receptors, and inactivating mechanisms—as a potentially important arena for drug discovery. In this context, emphasis has been especially placed on the possible roles that CB1 and CB2 receptors may play as drug targets .

Here, we focus our attention on another facet of endocannabinoid pharmacology: the mechanisms by which anandamide and 2-AG are deactivated. We summarize current knowledge on how these mechanisms may function, describe pharmacological agents that interfere with their actions, and highlight the potential applications of these agents to medicine.Extracellular anandamide is rapidly recaptured by neuronal and non-neuronal cells through a mechanism that meets four key criteria of carriermediated transport: fast rate, temperature dependence, saturability, and substrate selectivity . Importantly, and in contrast with transport systems for classical neurotransmitters, [3 H]anandamide reuptake is neither dependent on external Na ions nor affected by metabolic inhibitors, suggesting that it may be mediated by a process of carrier-facilitated diffusion . How selective is anandamide reuptake? Cis-inhibition studies in a human astrocytoma cell line have shown that [ 3 H]anandamide accumulation is not affected by a variety of amino acid transmitters or biogenic amines . Furthermore, [3 H]anandamide reuptake is not prevented by fatty acids , neutral lipids , saturated fatty acyl ethanolamides ,cannabis dry rack prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids, and epoxyeicosatetraenoic acids. Even further, [ 3 H]anandamide accumulation is insensitive to substrates or inhibitors of fatty acid transport , organic anion transport , and P-glycoproteins . By contrast, in the same cells, [3 H]anandamide reuptake is competitively blocked by either of the two endogenous cannabinoids, anandamide or 2-AG . Similar selectivity profiles are observed in primary cultures of rat cortical neurons or astrocytes and rat brain slices . The fact that both anandamide and 2-AG prevent [ 3 H]anandamide transport in cis-inhibition studies suggests that the two compounds compete for the same transport system. This possibility is further supported by three observations: 1) anandamide and 2-AG can mutually displace each other’s transport ; 2) [3 H]anandamide and [3 H]2-AG are accumulated with similar kinetic properties ; and 3) the transports of both compounds are prevented by the endocannabinoid transport inhibitor, N–arachidonylamide. Together, these findings indicate that anandamide and 2-AG may be internalized via a common carrier-mediated process, which displays a substantial degree of substrate and inhibitor selectivity. The molecular structure of this hypothetical transporter remains, however, unknown.The structures of anandamide and 2-AG contain three potential pharmacophores: 1) the hydrophobic carbon chain; 2) the carboxamido/carboxyester group; and 3) the polar head group . Systematic modifications in the carbon chain suggest that the structural requisites for substrate recognition by the putative endocannabinoid transporter may be different from those of substrate translocation. Substrate recognition appears to require the presence of at least one cis double bond in the middle of the fatty acid chain, indicating a preference for substrates whose hydrophobic tail can adopt an extended U-shaped conformation. By contrast, a minimum of four cis nonconjugated double bonds may be required for translocation, suggesting that substrates need to adopt a closed “hairpin” conformation to be transported across the membrane . In agreement with this hypothesis, molecular modeling studies show that transport substrates have both extended and hairpin low-energy conformers . By contrast, extended, but not hairpin, conformations may be thermodynamically favored in pseudosubstrates such as oleylethanolamide , that displace [3 H]anandamide from transport without being themselves internalized .

The impact that modifications of the polar head group exert on endocannabinoid transport has also been investigated . The available data suggest that ligand recognition may be favored 1) by a head group of defined stereochemical configuration containing a hydroxyl moiety at its distal end; and 2) by replacing the ethanolamine group with a 4-hydroxyphenyl or 2-hydroxyphenyl moiety. The latter modification leads to compounds, such as AM404 , that are competitive transport inhibitors of reasonable potency and efficacy .Anatomical studies of endocannabinoid transport are greatly limited by the lack of transporter-specific markers. Nevertheless, biochemical experiments have documented the existence of [3 H]anandamide uptake in primary cultures of rat cortical neurons and astrocytes , rat cerebellar granule cells , human neuroblastoma cells , and human astrocytoma cells . The CNS distribution of endocannabinoid transport was investigated by exposing metabolically active rat brain slices to [14C]anandamide and analyzing the distribution of radioactivity in the tissue by autoradiography . A receptor antagonist was included in the incubations to prevent the binding of [14C]anandamide to CB1 receptors, which are very numerous in certain brain regions , and AM404 was used to differentiate transportmediated [14C]anandamide reuptake from nonspecific binding . Substantial levels of AM404-sensitive [14C]anandamide reuptake were observed in the somatosensory, motor, and limbic areas of the cortex and in the striatum. Additional brain regions showing detectable [14C]anandamide accumulation included the hippocampus, thalamus, septum, substantia nigra, amygdala, and hypothalamus . Thus, endocannabinoid transport may be present in discrete regions of the rat brain that also express CB1 receptors .The endocannabinoid system is not confined to the brain, and it is reasonable to anticipate that mechanisms of endocannabinoid inactivation may also exist in peripheral tissues. In keeping with this expectation, carrier-mediated [ 3 H]anandamide transport was demonstrated in J774 macrophages , RBL-2H3 cells , and human endothelial cells . Although the kinetic and pharmacological properties of endocannabinoid uptake in peripheral cells appear to be generally similar to those reported in the CNS, some important difference have been observed. For example, in contrast to neurons, [3 H]anandamide uptake in RBL-2H3 cells is inhibited by arachidonic acid . Such disparities might reflect the existence in non-neural tissues of mechanisms of endocannabinoid internalization that are distinct from those found in the CNS.A variety of compounds have been tested for their ability to interfere with [3 H]anandamide internalization . Amongever, that AM404 is readily transported inside cells , where it can reach concentrations that may be sufficient to inhibit anandamide hydrolysis . To what extent this effect contributes to the ability of AM404 to prolong anandamide’s life span is at present unclear. The selectivity of AM404 for endocannabinoid transport has been the object of investigation. An initial screening found that AM404 has no affinity for a panel of 36 different pharmacological targets, including G protein-coupled receptors and ligand-gated ion channels . However, additional studies revealed that AM404 activates capsaicin receptor channels at concentrations similar to those necessary to inhibit endocannabinoid transport . The fact that AM404 can produce undesired effects underscores the need to introduce appropriate controls in the design of in vivo experiments with this compound. In particular, the effects of a cannabinoid receptor antagonist should be routinely tested to verify that endogenously produced anandamide and 2-AG are involved in the response to AM404 .AM404 does not display a typical cannabimimetic profile when administered in vivo; this is consistent with its poor affinity for cannabinoid receptors. For example, AM404 has no antinociceptive effect in mice or rats and causes no hypotension in guinea pigs .

Ignorance leads to stigma, but with increased education and awareness, more are starting to be receptive of the fact that it is a general disease. Ghanaians, and most people in the world for that matter, view mental illnesses differently than physical illnesses because physical illnesses are tangible, easy to comprehend, and are generally easily treated with the right medication. People are more likely to attribute supernatural causes to things they do not understand. The average Ghanaian view is the same for both the mentally disabled and the mentally ill. Though epilepsy is a neurological condition and not a mental illness, people with epilepsy are also considered to be mentally ill in Ghana because they share the same stigma and because they have been historically treated by psychiatrists due to the lack of neurologists. The common Ghanaian perception of mental illness is changing. It was very troublesome for someone who was mentally ill, or related to someone who was mentally ill, to be married some time ago when families ran heritage checks for eligible bachelors or bachelorettes to be arranged in marriage. Now that families are becoming more independent and nuclear and the Western importance of romantic love is becoming a driving factor in marriage, a person who was mentally ill will no longer be completely disregarded as a potential mate. Also, in order to vote or become president it is written in the constitution that you “should be of sound mind, which becomes misinterpreted as denying the right to vote to anyone who has ever had a mental illness. There are many other unwritten rules that prevent the mentally ill from attaining full access to human rights. For example, a person might be evicted from an apartment if the property owner finds out that the person has, or has had, a mental illness. Although you would not be asked whether you have ever had malaria or AIDS at a job interview, it is commonplace in Ghana to ask if you have ever suffered from a mental illness,pot for growing marijuana which then becomes viable grounds for being denied the job. You can also be fired or denied a promotion if a co-worker discovers that you had or have a mental illness, though another random reason for dismissal is usually given.

Although there is no policy that denies access to school, the attitude and stigma held by peers and faculty often leads a mentally ill person to drop out of school. Up until three years ago, if there was an international event or conference planned, it was common practice for police to round up all of the wayfarers on the main streets and dump them at the psychiatric hospital or on the outskirts of town. Fortunately, Mind Freedom and Basic Needs spoke against this inhumane action and it has not occurred since. Due to a plethora of challenges the countries have to face, mental health in Africa is largely marginalized. Most African countries do not have mental health laws and the others have out dated, forty to fifty year old laws that were written when human rights were not an issue. On a scale from one to ten, Dr. Osei rated the quality of mental health care in Ghana as a four. All hospitals in Ghana are underfunded with 94% of the budget being spent on paying the necessary salaries of medical professionals and the remaining 6% going into running the hospitals. On average, the government allocates mental healthcare with 2.58% of the total health budget which is strictly limited to finance just the three psychiatric hospitals and not community care. The funding by the Ministry of Health has been unstable since 2003 because psychiatric care does not appear to address urgent, life-threatening issues. The funding is not based on needs but rather on limits set by the Ministry of Finance. Politicians in Ghana do not want to give attention to mental illness, a sickness with low morbidity, when high fatality conditions grab more national and international attention. Because of this and its stigma, mental health care receives little donations from charities. Amegatcher, Adico, and Taylor respectively rated the quality of Ghana’s mental health care on the same scale as a four, two, and five. These low scores were supported by the lack of resources and funding available to psychiatric hospitals and the lack of priority in the government’s agenda. The belief in superstition also deprives the mentally ill in Ghana of sympathy and compassion.

This combination of ignorance yields the mentally ill vulnerable to suffering human rights abuse, leading to Dr. Osei’s low rating. Fortunately or unfortunately, Dr. Osei believes that Ghana’s mental health care system is one of the best in West Africa besides maybe Nigeria. Instead of facilely increasing the number of psychiatric hospitals in Ghana, Dr. Osei wants to create 20-bed psychiatric wings in every regional hospital and 12-bed wings in every district hospital. Right now only five of ten regional hospitals have 20-bed psychiatric wings. General medical practitioners should also start receiving some training in psychiatric care so they can better treat their patients and discern when to refer them to a psychiatrist if necessary. The Chief Psychiatrist also wants to downsize the three psychiatric hospitals,container for growing weed ultimately changing Accra Psychiatric Hospital’s admittance from 1,200 to 300 patients, Pantang from 500 to 200, and Ankaful from 300 to 100 in-patients. The downsizing of the large hospitals and the creation of small wings throughout the whole country will deinstitutionalize the mental health care system in Ghana so it can ultimately focus on community care. Dr. Osei finds that many Ghanaians now believe that mentally ill patients can lead a happy, healthy life after treatment, but still there are only two rehabilitation services in all of Ghana that help reintegrate mental patients into society. These facilities are run by Catholics in Kumasi and discharged patients who permanently live near the Ashanti Region are sent there after treatment to learn some trade. Dr. Osei recommends that these services should be replicated and that there should be at least one rehabilitation resource in every region. The Pantang hospital would like to establish a Half-Way home for rehabilitation of chronic patients , start a fish pond rehabilitation project, develop an addiction outpatients clinic hot line, equip the laboratory, records, and pharmacy departments with a software, utilize a computerized data system, create a web page, expand a Drug Rehabilitation Centre, build more staff accommodation units, ensure accessibility to needed medications at the pharmacy, increase security, focus on prevention, recovery, and relapse-reducing programs and activities, and enhance staff morale by providing better incentives, training, equipment, and uniforms.

The Pantang Hospital is also working on a proposal to create an evaluation ward which would help to avoid long-stay patients and streamline the diagnosis and welfare process. In this ward the patients would be observed for a maximum of 72 hours by a specialized screening team in order to make sure the patients’ diagnoses are correct and that they require admittance into the hospital.The most recent mental health law, written in 1972 when international human rights was not much of a concern, also needs to be updated. Both the Chief Psychiatrist and Mind Freedom were involved in the drafting and advocacy of the new Mental Health Bill. The bill will address a lot of setbacks in the mental health system. If passed, the Mental Health Bill will commit the government to release more funds and resources for mental health care , train more mental health personnel including psychotherapists and counsellors, give incentive for people to work in mental health care, provide newer generation medicine, overhaul and decentralize the hospital-based system and make mental health care more community based, create an anti-stigma and education campaign, and protect the human rights of the mentally ill. Right now there are no checks for human rights abuses of the mentally ill, and this bill will make it illegal to put the mentally ill in chains and a new standard committee will work closely with prayer camps to oversee and enforce the upholding of all human rights. All in all, the Mental Health Bill will ensure effective treatment for the mentally ill and the law will serve as a standard for other African countries to follow. The bill was submitted in 2006 and did not reach parliament until the end of 2010, where it is sitting to this day. It took four years before the government bothered to address the situation simply because they did not value the issue. Mental illness is such a low priority for the government because of the stigma that exists even in the minds of politicians and because mental health disorders have a low fatality . Though mental illnesses do have a low morbidity, mentally ill people experience many years living with pain, stigma, lifestyle changes, complicated therapeutic regimes, the long-term threat of decline, and shortened life expectancy. With a lack of general funding for healthcare, more money is given to high fatality, international attention-grabbing physical diseases like malaria, AIDS, TB, cancer, etc. Now, after the advocacy from doctors and NGOs bombarded the media, the Ministry of Health is finally being forced to change their stance on mental health care. The Parliament is currently conducting consultations and is reviewing the bill to guarantee that fragmentation of the mental system is what is best for Ghana. Mind Freedom and Dr. Osei hope that the bill will be passed by June 2011, and if it is not, then Dr. Osei flippantly said he will personally march all of his patients at the Accra Psychiatric Hospital down to the Parliament building to fight for their rights. Dr. Osei hopes that the long struggling advocacy for mental health improvement will not lose steam and keep pushing until the bill is passed and even after to ensure the implementation of the law. Immediately after the bill is passed, he advises that a mental health board needs to be established with the purpose of overseeing the implementation of the bills requirements and the training of judiciaries, policemen, mental health personnel, nurses, and traditional faith healers in the law’s policies. He wants Ghana to have state-of-the-art mental health care which delivers care to the doorsteps of every Ghanaian, provides a wide range of medicine, is part of the national health insurance scheme, employs mental health personnel of various categories, and is adequately funded and operated by motivated leaders and supported by research and evidence based data. This could be achieved by having one of the best mental health laws in the world and by removing the emphasis from hospital based care to community care. Similar to Dr. Osei, Mind Freedom thinks that Ghana’s mental health system should change from institutional care to community care. The hospitals should be decongested, CPNs should be given transportation to move between communities, newer medication should be used, and mental health workers should be given more incentives and should be covered by insurance. Most importantly, psychiatrists need to more frequently go into the community, human resource needs to increase, and medication needs to be more available. Also, the perception of mental illness needs to be worked on. Stigma makes the situation drastically worse and makes people less likely to seek treatment even when it is important to seek early treatment so the problem does not aggravate. Despite the Accra Psychiatric Hospital’s disturbing conditions and appalling lack of resources, Dr. Osei’s undaunted and resolute passion for mental health is leading the country towards progress. In the beginning of 2011, Dr. Osei launched a repatriation of 600 recovered patients, whose families could be tracked down, to be discharged and returned home. Dr. Osei oversees each case to make sure that each discharged patient is well enough to go home and that they have a family or home to return to. So far the repatriation has been successful in decongesting the hospital, as 200 patients have been discharged by March 2011 and the total of 600 is expected to be achieved by June 2011.

The dependent variable was drinks per drinking day in the last week of the study.This was the first study to evaluate the effects of ibudilast, a neuroimmune modulator, on mood and drinking outcomes in a clinical sample with AUD. Contrary to our hypothesis, ibudilast did not have a significant effect on negative mood on drinking or non-drinking days. However, in support of our hypotheses, ibudilast significantly reduced the probability of heavy drinking compared to placebo. Ibudilast also significantly attenuated alcohol cue-elicited activation in the bilateral VS. Furthermore, exploratory analyses indicated that ventral striatal activation to alcohol cues was predictive of drinking in the week following the neuroimaging scan. These results suggest a bio-behavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking per se. Unexpectedly, this study did not find support for an effect of ibudilast on negative mood or a moderating effect of baseline depressive symptomology on medication response. This contrasts with previous findings from our lab in which ibudilast improved mood response to stress and alcohol cues. The current study differs from the previous study in several important methodological variables including using a between-subjects instead of a crossover design and the use of a daily-diary mood reporting approach compared to tightly controlled human laboratory experimental paradigms. Furthermore, the current study did not directly evaluate the effect of drinking on mood, which would be more comparable to the findings reported previously. Additionally, this study recruited individuals with mild-to-severe AUD. Negative mood states and negative reinforcement driven drinking may only occur at more severe presentations of AUD; therefore,cannabis grow tent the present study may have been under powered to identify medication effects on negative mood symptoms.

Regarding the drinking outcomes in this study, IBUD significantly reduced the probability of heavy drinking compared to placebo. Specifically, individuals treated with IBUD were 45.3% less likely to drink heavily compared to individuals treated with placebo. This resulted in a 24% predicted probability of heavy drinking over the course of the study in the ibudilast group, compared with a 37% predicted probability in the placebo group. Of note, there were no significant differences in AE’s between groups, indicating that this reduction was not due to increased side effects, including nausea, in the IBUD group. There was not a significant effect of IBUD on the probability of overall drinking compared to placebo. While non-significant, the effect of IBUD for any drinking days was in the expected direction, such that individuals on IBUD were 16.9% less likely to engage in any drinking relative to placebo, but high variability in the prediction prevented conclusive statistical findings. This non-significant effect may not be surprising, as the study sample was comprised of non-treatment-seekers and therefore not motivated to abstain from drinking altogether. Rather, participants treated with IBUD reduced their heavy drinking, which produces a harm reduction benefit, particularly for those with a mild-tomoderate AUD. This finding is also consistent with preclinical studies, where treatment with ibudilast reduced ethanol intake by 50% under maintenance conditions.Importantly, the drinking results combined with the AE reports indicate that ibudilast is a safe medication for individuals who are still drinking and may want to reduce their drinking. IBUD also reduced craving on non-drinking days, at trend level, as compared to placebo. This effect supports our previous finding of a reduction in tonic craving under ibudilast during a week-long human laboratory study during which participants were instructed not to drink. This study also examined a potential bio-behavioral mechanism underlying IBUD’s action using an fMRI alcohol cue-reactivity paradigm.

IBUD attenuated alcohol cue-elicited reward activation in the VS compared to placebo. PDE4 and PDE10 are highly expressed in the striatum and negatively regulate dopaminergic signaling. Thus, inhibition of these PDEs through IBUD may reduce striatal excitability to alcohol cues. In rats IBUD reduced morphine-induced nucleus accumbens dopamine release. Moreover, IBUD has been shown to enhance the production of neurotrophic factors, including glia-derived neurotrophic factor, which is a critical survival factor for dopamine neurons. Preclinical findings indicate that infusion of GDNF normalizes dopamine levels in the ventral tegmental area and the VS and reduces alcohol seeking and alcohol consumption. In humans with AUD, GDNF levels are reduced in blood serum samples.Furthermore, in individuals with AUD, presentation of alcohol cues reduced interleukin-10, an anti-inflammatory cytokine, and the level of reduction was correlated with increased alcohol craving. Thus, though the underlying molecular mechanism is still unknown, this finding indicates that ibudilast may normalize the dopaminergic response to alcohol cues in individuals with AUD. This study has several strengths and limitations which should be considered when interpreting the results. Study strengths include the use of daily diary reporting, which captures real world drinking and minimizes recall bias, and the combination of neurobiological with behavioral and self-report methodologies. However, this study recruited a non-treatment seeking sample; therefore, these findings may not generalize to a treatment-seeking sample with AUD . An ongoing randomized controlled trial of IBUD in treatment-seeking individuals with AUD will address this open question. Relatedly, this study recruited individuals with mild-to severe AUD, which may not be representative of clinical samples. This limitation may have impacted our ability to detect medication effects that require a pathology associated with more severe AUD, which is particularly relevant for negative mood and withdrawal states. Furthermore, participants were required to have a 0.00 g/dl breath alcohol reading for each in person visit. This requirement was to ensure participant safety; however, it may have artificially reduced drinking on in-person study visit days. Of note, in the daily diary assessment,participants reported on their past day drinking for the full day and were able to begin drinking when they returned home after the study visit. Additionally, the sample size for this experimental study was modest, particularly for the fMRI outcomes.

This limited our ability to conduct additional,grow lights for cannabis whole-brain analyses which are necessary to fully elucidate the neural mechanism of ibudilast. Finally, this study did not include a fixed-dose alcohol challenge to evaluate the safety and efficacy of ibudilast in combination with alcohol and to replicate our previous work. However, given that our sample did report drinking while taking ibudilast, we believe that ibudilast can be safely taken with alcohol with limited side effects. In conclusion, this is the first combined clinical and neuroimaging study of ibudilast , a neuroimmune modulator, to treat AUD. Ibudilast did not improve negative mood on drinking or non-drinking days, indicating that its mechanism of action may be non-mood dependent in non-treatment-seeking individuals. Ibudilast reduced the probability of HDDs over 2 weeks for non-treatment-seeking individuals relative to placebo. Ibudilast also attenuated alcohol cue-elicited activation in the VS, potentially through a dopaminergic-related mechanism. This is a critical proof-of-mechanism whereby modulation of neuroimmune signaling via ibudilast reduced the incentive salience of alcohol cues in the brain. Exploratory analyses indicated that ventral striatal activation to alcohol cues was predictive of subsequent drinking in the ibudilast group, such that individuals who had attenuated ventral striatal activation and were treated with ibudilast had the fewest number of drinks per drinking day in the week following the scan. Overall, these findings extend preclinical and human laboratory demonstrations of the efficacy of ibudilast for the treatment of AUD and suggest a potential bio-behavioral mechanism through which ibudilast acts. This study also demonstrates that ibudilast has a favorable side effect profile, even when combined with alcohol. These findings also provide novel insights into the role of neuroimmune modulation in AUD, including its effects on neural and behavioral outcomes of high clinical significance.Recently, neuropsychiatric disorders have been conservatively estimated to be 14% of the global burden of disease, more than the burden of cardiovascular disease or cancer, and their conditions account for a quarter of disability adjusted life-years . The World Health Organization also estimates that 25% of the world’s population will suffer from mental, behavioural, and neurological disorders such as schizophrenia, mental retardation, alcohol and drug abuse, dementias, stress related disorders, and epilepsy during their lifetime. Mostly affecting the poor and people from developing countries, depression impinges on more than 450 million people and might become the second most important cause of disability by 2020. Despite these new insights, as the 20th century revealed Herculean advancements in somatic healthcare worldwide, the mental aspect of healthcare has remained stagnant and in some cases, gravely depreciated. Mentally ill people are some of the most vulnerable people in society. They are often subject to discrimination, social isolation and exclusion, human rights violations, and an ancient, demeaning stigma which leads to bereavement of social support, self-reproach, or the decaying or straining of important relationships. Consequences of poor mental health also include being predisposed to a variety of physical illnesses, having quality of life be reduced, having fewer opportunities for income, and having lower individual productivity, which affects total national output. Poor mental health can also account for violence, drug trafficking, child abuse, paedophilia, suicide, crime, and other social vices. Even though mental health is becoming a serious international health concern, many countries, specifically the more impoverished countries, struggle to address the inadequate amount of resources being funnelled into the nonphysical sector of health.

Low-income countries often have insufficient implementations of policies and limited mental health services confined to short staffed institutions. Furthermore, in both developed and undeveloped countries, the poor are more vulnerable to common mental disorders due to experiences of rapid social change, risks of violence, poor physical health, insecurity, and hopelessness. Women, slum dwellers, and people living in conflict, war prone, and disaster areas of civil unrest constitute a large portion of the population in developing countries, and are specifically susceptible to the burden of mental illness. For instance, 90% of the 12 million worldwide schizophrenia sufferers who do not receive adequate psychiatric services are located in developing countries. Only 50% of countries in Africa have a mental health policy, and if they do have a law, it is usually archaic and obsolete. Ninety percent of African countries have less than one psychiatrist per 100,000 people, and 70% of the countries allocate the mental health sector with less than 1% of the total health budget. Less than 60% of African countries have community mental health care while the rest are focused on psychiatric hospitals. The World Psychiatric Association suggested that the development of mental health programmes are impeded in Africa because of the scarcity of economic and staff resources, lack of awareness on the global burden of mental illness, and the stigma associated with seeking psychiatric care. Mental health has been shunned in Africa, and several reports disclose a higher prevalence of stigma in developing countries than in first world countries. Similar to many other developing countries, treatment of mental health in Ghana, West Africa is low and continues to rely on institutional care, a vestige from colonialism. In Ghana, it is roughly estimated that at least 2,816,000 people are suffering from moderate to severe mental disorders, and only 1.17% of these people receive treatment from public hospitals because only 3.4% of the total health budget is dedicated to psychiatric hospitals. Because there is one psychiatrist per 1.5 million people in the whole country, and the three major psychiatric hospitals are under-financed, congested, and under-staffed, many resort to more ever-present and more affordable, traditional or faith healing. Ghana has a deep-seated tradition of religious observance. Thus, 70– 80% of Ghanaians utilize unorthodox medicine from the 45,000 traditional healers, located in both urban and rural areas, for their vanguard healthcare despite recent advances in orthodox psychiatric services. Although research shows that mental-health patients who used spiritual healing usually reported an improvement in their condition, the quality of treatment is not easy to ensure. Sometimes in order to exorcise supposed demons, individuals are chained, flogged, or incarcerated into spiritual, prayer camps. In spite of these atrocious facts, policy-makers seem to have little concern for mental health, and focus more on physical health and population mortality. The Lunatic Asylum Ordinance of 1888, enacted by the Governor of the Gold Coast, Sir Griffith Edwards, marked the first official patronage to Ghana’s mental health services. This ordinance encouraged officials to arrest vagrant “insane people and place them in a special prison in the capital city of Accra.

Despite the success of GWAS of alcohol use the mechanisms by which these newly identified genetic associations exert their effects are largely unknown. More importantly, alcohol consumption and misuse appear to have distinct genetic architectures . Ever-larger studies, particularly those extending mere alcohol consumption phenotypes, are required to find the genetic variants that contribute towards the transition from normative alcohol use to misuse, and development of AUD.One successful application of GWAS has been their use for assigning polygenic risk scores , which provide estimates of an individual’s genetic risk of developing a given disorder. Reassuringly, PRS for alcohol use behaviors predict equivalent phenotypes in independent cohorts [e.g. alcohol consumption , AD , AUD symptoms. Johnson et al recently identified that, compared to PRS for alcohol consumption , PRS for alcohol misuse were superior predictors of a range of alcohol-related phenotypes, particularly those pertaining to the domains of misuse and dependence. These findings further illustrate that alcohol consumption alone may not be a good proxy for AUD. PRS can also be used to test specific hypotheses; for example, PRS can be used to measure how environmental, demographic, and genetic factors interact with one another. Are there developmental windows where the effects of alcohol use and misuse are more invasive? Can we identify biomarkers that would inform the transition from normative alcohol use to excessive use and dependence? For instance, the alcohol metabolizing genetic effects on alcohol use appeared to be more influential in later years of college than in earlier years ,mobile vertical rack revealing that the nature and magnitude of genetic effects vary across development.

It is worth noting important limitations of PRS analyses. First, polygenic prediction is influenced by the ancestry of the population studied. For example, PRS for AUD generated in an African American cohort explained more of the variance in AUD than PRS derived from a much larger cohort of European Americans . This illustrates that the prediction from one population to another does not perform well . Second, the method of ascertainment may bias the results. As an example, PRS for DSM-IV AD derived from a population based sample predicted increased risk for AD in other population samples but did not associate with AUD symptoms in a clinically ascertained sample . Third, the variance explained by PRS is still low, and hence PRS have limited clinical application. For example, in the largest study of alcohol consumption , the alcohol consumption PRS accounted for only ~2.5% of the variance in alcohol use in two independent datasets. Recent work suggested that predictions may improve by incorporating functional genomic information. For example, McCartney et al showed that, compared to conventional PRS, risk scores that took into account DNA methylation were better predictors of alcohol consumption. Nonetheless, the way in which such methods can be used for prevention or treatments of AUD has yet to be established. Lastly, it remains to be determined the nature of these associations. Mendelian randomization analyses can serve to further understand and explore the correlations between alcohol use behaviors and comorbid traits .Before the era of large-scale genomic research, twin and family-based studies identified a high degree of genetic overlap between the genetic risk for AUD and psychopathology by modeling correlations among family members ). With the recent development of linkage disequilibrium score regression , it is now possible to estimate the genetic correlations between specific alcohol use behaviors and a plethora of psychiatric, health and educational outcomes using GWAS summary statistics. Most notably, the genetic overlap between alcohol consumption and AD was positive but relatively modest , suggesting that, although the use of alcohol is necessary to develop AD, some of the genetic liability is specific to either levels of consumption or AD.

Another consistent finding from genetic correlation analyses has been that alcohol consumption and AUD show distinct patterns of genetic overlap with disease traits. Counterintuitively, alcohol consumption tends to correlate with desirable attributes including educational attainment and is negatively genetically correlated with coronary heart disease, type 2 diabetes and BMI . These genetic correlations are unlike those observed when analyzing alcohol dependent individuals: AD was negatively genetically correlated with educational attainment and positively genetically correlated with other psychiatric diseases, including major depressive disorder , bipolar disorder, schizophrenia and attention deficit/hyperactivity disorder . Importantly, alcohol consumption and misuse measured in the same population showed distinct patterns of genetic association with psychopathology and health outcomes . This set of findings emphasize the importance of deep phenotyping and demonstrates that alcohol consumption and problematic drinking have distinct genetic influences. Ascertainment bias may explain some of the paradoxical genetic correlations associated with alcohol consumption . Population based cohorts, such as UKB and 23andMe, are based on voluntary participation and tend to attract individuals with higher education levels and socioeconomic status than the general population and, crucially, lower levels of problem drinking. In contrast, ascertainment in the PGC and MVP cohorts was based on DSMIV AD diagnosis and ICD codes for AUD, respectively. Collider bias has been proposed to underlie some of the genetic correlations between alcohol consumption and BMI ; however, BMI has been consistently negatively correlated with alcohol use in several subsequent studies . Furthermore, it is also possible that the genetic overlap between AD and aspects of alcohol consumption are dependent on the specific patterns of drinking. For example, Polimanti et al identified a positive genetic correlation between AD and alcohol drinking quantity , but not frequency. Prior to the availability of large population studies and collaborative consortia efforts, few genes were reliably associated with AUD. The use of intermediate traits or endophenotypes has become increasingly common and hundreds of new loci have now been associated with alcohol use behaviors.

Using intermediate phenotypes also facilitates translational research; we can mimic aspects of human alcohol use using animal models, including alcohol consumption, novelty response, impulsivity,vertical grow rack withdrawal and sensitivity . Animal models provide an opportunity to evaluate the role of newly identified genes at the molecular, cellular and circuit level. We may also be able to perform human genetic studies of specific components of AUD such as DSM-IV AD criterion count and alcohol withdrawal . To date these traits have only been studied in smaller samples but this approach will be invaluable as sample sizes increase. Another challenge for AUD genetics is that AUD is a dynamic phenotype, even more so than other psychiatric conditions, and therefore may necessitate yet larger sample sizes. Everlarger studies, particularly those extending mere alcohol consumption phenotypes, are required to find the genetic variants that contribute towards the transition from normative alcohol use to misuse, and development of AUD. Furthermore, genetic risk unfolds across development, particularly during adolescence, when drug experimentation is more prominent and when the brain is most vulnerable to the deleterious effects of alcohol . The Adolescent Brain Cognitive Development , with neuroimaging, genotyping and extensive longitudinal phenotypic information including alcohol use behaviors , offers new avenues for research, namely to understand how genetic risk interacts with the environment across critical developmental windows. Population biobanks aligning genotype data from thousands of individuals to electronic health records are also promising emerging platforms to accelerate AUD genetic research . Despite these caveats, the GWAS described in Table 1 have already vastly expanded our understanding of the genetic architecture of alcohol use behaviors. It is evident that alcohol use behaviors, like all complex traits, are highly polygenic .

The proportion of variance explained by genetic variants on GWAS chips ranges from 4 to 13% . It is possible that a significant portion of the heritability can be explained by SNPs not tagged by GWAS chips, including rare variants . For instance, a recent study showed that rare variants explained 1-2% of phenotypic variance and 11-18% of total SNP heritability of substance use phenotypes . Nonetheless, rare variants are often not analyzed when calculating SNP heritability, which can lead to an underestimate of polygenic effects, as well as missing biologically relevant contributions for post-GWAS analyses . Equally important is the need to include other sources of -omics data when interpreting genetic findings, and the need to increase population diversity . Therefore, a multifaceted approach targeting both rare and common variation, including functional data, and assembling much larger datasets for meta-analyses in ethnically diverse populations, is critical for identifying the key genes and pathways important in AUD.Alcohol use disorder is a highly prevalent, chronic relapsing disorder with a high disease burden in the United States. Despite current and lifetime prevalence rates of 13.9% and 29.1%, respectively, it remains largely untreated as only 7.7% of those with 12-month and 19.8% of those with lifetime diagnoses sought treatment in 2012– 2013. In spite of low treatment rates, pharmacotherapy offers a promising treatment method for AUD. The Federal Drug Administration has approved of four medications for AUD: disulfiram , oral naltrexone , extended-release injectable naltrexone , and acamprosate. However, these currently approved pharmacotherapies are only modestly effective, so there is still a great need to develop more effective interventions. Medications development is a very costly, cumbersome, and inefficient process that can take nearly 20 years from discovery to market. In particular, the development of treatments for alcoholism has been difficult with over 20 medications having been tested in humans yet only three were able to receive FDA approval, the last of which was granted over a decade ago. Therefore, there is a pressing need to develop valid and efficient methods to decrease the cost and length of medications development to better shepherd novel compounds from the lab to dissemination. The development of novel medications for AUD is a high priority research area, but the drug development process is long and challenging, with many compounds stuck in the transition from preclinical to clinical testing, also known as the “valley of death”. Beyond the “valley of death,” there is an overall need to develop effective methodologies for efficiently running clinical trials, particularly in screening novel compounds in early phase 2 trials. Early phase 2 trials, also known as “proof-of concept” studies, help determine if a novel medication is safe, tolerable, and efficacious using clinically relevant phenotypes such as cue-induced craving or subjective response to alcohol. These trials largely incorporate human laboratory paradigms to assess medication efficacy, providing valuable information on whether or not the medication warrants a larger clinical trial. However, human laboratory paradigms have not always demonstrated translational validity and often lack the ecological validity of clinical trials where medication efficacy is established through clinically meaningful endpoints. Therefore, there are major opportunities to refine this process of screening novel medications by combining the internal validity of human laboratory models and the external validity of clinical trials. To that end, the current study aims to develop and validate a novel early efficacy paradigm to screen medications for AUD. This early efficacy paradigm is the practice quit attempt model adapted from the smoking cessation medication development literature. In the original practice quit attempt model, individuals who report intrinsic motivation to quit smoking undergo a 7-day practice quit attempt while taking study medication. Individuals with high intrinsic motivation to quit smoking fared better on active medication, compared to placebo, on increased abstinence, while individuals with low intrinsic motivation showed no effect of active medication. Additionally, the practice quit model demonstrated specificity in which bupropion, an FDA-approved medication for smoking cessation, increased number of days abstinent, whereas modafinil, a medication ineffective for smoking cessation, was no different than placebo. The success of the practice quit attempt model for screening medications for nicotine dependence provides a basis for the development of a similar approach modified for AUD. In addition to the standard procedures of the practice quit attempt, we have included an established human laboratory paradigm to ensure that the novel model will be sensitive to medication effects. The cue-reactivity paradigm measures alcohol craving by having individuals hold and smell their preferred alcoholic beverage and a control beverage. Naltrexone , which is FDA-approved for AUD, is effective at significantly reducing alcohol-cue elicited craving compared to matched placebo.Thus, our current study will include CR in order to detect medication effects on cue-induced craving which will also verify the sensitivity of the novel practice quit attempt model to those medication effects.

Our findings support the need for clinical screening for binge drinking behavior given that many adults who engage in binge drinking behavior do not meet criteria for an AUD, as well as psychoeducation and psychosocial interventions targeting the reduction of binge drinking among older PWH. Additionally, given evidence that improvements in neurocognitive functioning may be possible after sustained sobriety following AUD recovery among HIV- populations , future work is needed to understand whether this may also be true among PWH who reduce or cease binge drinking behavior.There are significant barriers to recruiting and retaining individuals with overlapping vulnerabilities in the pregnancy or postpartum period Wetherington & Roman, 1998. This may result in challenges for generalizability and therein create a relatively sparse knowledge base about the long-term outcomes for these women and their children including the environmental, mental health, physiological, and neurological factors. Filling these knowledge deficits and gaps requires ongoing assessment because research tools including those for recruitment and retention change; in addition, substance exposures in pregnancy change , thereby shifting methods to reach target populations of interest and methods to measure outcomes of interest. It is imperative for the field to identify and address engagement in research,cannabis grow equipment to ensure representation of pregnant and postpartum women that use substances. Engagement in longitudinal studies will allow a more complete understanding of maternal and child health outcomes as a result of new and emerging trends in prenatal substance exposure. Enhanced understanding of participants’ perspectives on engagement and study participation will allow researchers to more fully address this pressing research and public health need.

Prenatal exposure studies began in earnest in the 1970s, after the identification and diagnosis of fetal alcohol syndrome . Careful participant selection and comparison selection were and are necessary to classify effects of prenatal exposures. Protectionist and paternalistic regulations excluded women from health research and limited the field’s understanding about how sex and gender shape substance use and SUD . Research studies on substance exposures during pregnancy expanded rapidly in the past 30 years, in recognition of the cocaine epidemics of the 90s, and the current increases in prenatal opioid and methamphetamine exposures . Indeed, research that focused specifically on prenatal exposures and other women’s health issues has been encouraged by journal editors, policymakers, and funding agencies including the NIH Helping End Addiction Long term initiative. Despite bioethical, legal, and social concerns regarding the risks and benefits of research participation for pregnant and postpartum women who use alcohol and drugs , the inclusion of vulnerable populations who are marginalized or stigmatized in research on sensitive topics has not demonstrated undue harm or exposure to unacceptable risk, and in fact, has been associated with potential benefits, such as altruism, catharsis, and gained knowledge . Of course, it is important for researchers to adopt careful experimental design and safeguards that will uphold the principal of non-maleficence and protect vulnerable participants from harm . Exclusion of substance using populations may violate important bioethical principles of human subjects research, particularly the principles of autonomy, beneficence, and justice . Exclusion from research not only strips individuals from making decisions about their own autonomy and denies them potential benefits of participating, but also exposes them to greater societal marginalization and may ultimately place them at increased risk of harm due to deficits in critical health knowledge and exposure to inappropriate or ineffective treatments . Unfortunately, prenatal exposures to alcohol, tobacco, and other drugs are rising , with 1 in 4 pregnancies exposed to tobacco , alcohol consumption , or illicit drug use . Specifically, opioid exposed pregnancies have increased from 1.5 to 6.5 per 1000 pregnancies . Yet, cannabis exposures are the most prevalent drug exposure, with nearly 7–8% reported exposure in the first trimester .

Rising rates of substance exposure correspond to increasing health risks and adverse outcomes at great societal cost and burden to systems of health care and social services, as well as criminal justice. Notably, researchers involved in the NIDA-funded Perinatal-20 Treatment Research Demonstration Program that focused on SUD treatment for pregnant and postpartum women identified seven clinical factors that contributed to significant difficulty and complexity in the recruitment and retention of women in substance use treatment research, including as follows: severity of SUD, legal system involvement, housing instability, interpersonal relationship challenges, parenting responsibilities, employment challenges, and need for more intensive services. These difficulties with recruitment and retention contribute to additional complications for research, including biased samples of convenience recruited through referrals from social and health agencies, limited sample diversity, deviations from the research design, and ethical issues associated with risk and benefits of participation and involvement with the criminal justice or child welfare system. In particular, when research designs do not involve the possibility of direct benefit due to participation , it is important to understand the unique reasons and motivations that drive decision-making about research participation . Due to all of the aforementioned factors that potentially inhibit the inclusion and engagement of high-risk participants , it is imperative to understand the motivations for engagement in research among high-risk participants, focusing specifically on understanding motivation for research participation, factors that influence decision-making about participation, and barriers to participation.The current study reports results from a qualitative research study conducted as part of an 18-month, multi-site pilot study aimed to develop and demonstrate feasibility of an experimental design for a 10-year, prospective,cannabis cultivation technology longitudinal investigation of normative childhood brain development, beginning in pregnancy. A major aim of the 10-year study will be to determine factors that alter brain development including prenatal exposure to opioids and other psychoactive substances, as well as other prenatal and childhood environmental exposures.

This goal necessitates recruiting pregnant women previously or currently using substances, as well as a large group of pregnant women who are at low risk of prenatal substance use. Two of the primary aims of the pilot are developing and testing recruitment and retention strategies and addressing ethical and legal challenges of conducting research with a stigmatized and vulnerable population.The current qualitative study is one arm of the 5-site consortium to improve understanding, from a qualitative perspective, the continuum of engagement of low- and high risk participants in research. This manuscript focuses on the results of the distinct needs and responses of high-risk participants. Specifically, the objectives in this analysis were to address important factors that impact best practices in promoting longitudinal research to high-risk participants, enrolling high-risk participants in research, and retaining high-risk participants in research studies.Individual interviews and one focus group were conducted with a total of 41 women . Women were at high-risk of prenatal or postnatal substance use and were identified through medical clinics, other research study involvement, or SUD treatment programs. Recruitment took place across five sites in the USA located in California, Georgia, New Mexico, Ohio, and Oklahoma . High-risk pregnant and postpartum women were defined in the current study as a parenting or pregnant woman who had used alcohol and tobacco and/or had a current or past history of SUD. Some participants were currently receiving SUD treatment. Contact was made through trained research personnel located at each specific site with 41 total participants taking part in the current study. Only one focus group that included five women was combined with the individual interviews. The one focus group was conducted in New Mexico prior to group restrictions imposed due to COVID-19.Qualitative methods for the research team, study design, and analysis followed the guidelines recommended by Tong, Sainsbury, and Craig . Qualitative study recruitment began with sites contacting participants in person or by phone and describing the current study and qualitative interview process. All women who expressed interest in participating were scheduled for either a focus group or individual interview depending on whether the interview took place prior to or following COVID-19 restrictions regarding in-person gatherings.All participants gave oral informed consent. During the consent process, a brief overview of the qualitative study and all safety measures taken to ensure confidentiality were discussed. Trained qualitative research assistants collected all qualitative data from March 2020 through June 2020. Before engaging in focus groups/individual phone interviews, all participants completed an in-person or online survey that included a demographic questionnaire and watched a short video describing the protocols planned for the larger, longitudinal study including neuroimaging , neurodevelopmental, and biospecimen collection.

For the focus group, snacks were provided. Participants received a $50–75 incentive for their participation, and this varied based on site. All focus groups and individual interviews were audio-recorded and lasted approximately 45–60 min. Transcription work was conducted by qualitative team members or a transcription company, with team members crosschecking all transcripts to verify accuracy. During the transcription process, all identifying information was removed to ensure privacy. All procedures were approved by the sIRB for the 5-site consortium.Focus group and individual interview guides for the current project were developed by the first author, in conjunction with the evaluation team and other sites within the research consortium reviewing and revising the guide as needed. Focus group and individual interviews were coded individually and combined for data analysis. All coding and data analysis was conducted at one site. Recordings were transferred securely according to IRB-approved methods. It is important to note that focus group and individual data themes were examined a priori and themes were congruent and therefore data were merged.Qualitative data was analyzed using the NVivo© 11 software. Five qualitative researchers worked together to develop a codebook focused on broad themes influenced by the semi-structured interview guide. Thematic analysis was used to define specific themes within the broader categories . The codebook was developed using an agreed upon coding scheme with themes not being predetermined but rather emerging from the data. Upon completion of the codebook, two teams consisting of two qualitative researchers coded all transcriptions using developed coding templates. Cleaning of data took place as needed . Once coded, inter-coder reliability was established using simple percent agreement, which is a commonly used method for assessing reliability in qualitative studies . Average inter-coder reliability was over 85%. In the “Results” section, themes are described in more detail. The validity of the current research findings are enhanced by several design factors such as the calculation of salient factors using percentage of comments and the team-based approach used for coding. Specifically, calculating the percentage of comments from participants related to specific themes allowed the research team to ensure that themes discussed in the current paper were saturated or were discussed frequently in focus group/individual interviews. Therefore, relying on percent of comments strengthens demonstration of saturation in the current study. Further, the majority of qualitative data were collected from individual interviews rather than a focus group , which allows for a more in-depth conversation. Specifically, during individual interviews, comments were able to be probed deeply with rich content emerging throughout the qualitative data, rather than simple agreement or disagreement that often emerges from focus group data collection. Additionally, the fact that both primary researchers as well as consortium partners were involved in developing the focus group/individual interview guide is a strength, increasing the likelihood that the items on the interview guide validly and comprehensively captured the intent of the research aims.Other suggested locations included bus stops , billboards , and grocery/ convenience stores . Participants also reported that child-friendly locations and educational settings were good locations to share study information. One participant explained, “Maybe flyers at childcare centers and stuff like that, where they have the younger school-aged kids from infant to whatever. I know a lot of moms frequent those places.” When participants were asked about locations they would trust the most to receive information, it was disclosed that medical offices such as doctor offices/clinics, state agencies , and educational settings were considered most trustworthy. Participants also discussed the type of material they would recommend using to promote research studies with participants explaining they would use commercials , brochures , and radio to share information about research studies. It was also reported that using news/newspapers , online marketing strategies , and sharing information through word of mouth would be most effective. In terms of the individuals that would be best to share research study information, participants stated that study information would best come from medical personnel , friends , family members , other participants , and professionals .

The Family Smoking Prevention and Tobacco Control Act of 2009 banned the use of all natural and artificial compounds characterized as flavors in combustible cigarettes and any of their component parts to eliminate flavored tobacco products that held special appeal in the youth market. In 2020, the US FDA finalized their enforcement policy on flavored cartridge based e-cigarette products, including fruit and mint flavors, but excluded menthol and tobacco flavors.However, since this enforcement policy only applies to prefilled cartridges, flavored eliquids in bottles and refillable empty cartridges are still commercially available. Flavored products can be legally marketed in the USA if they receive a tobacco product marketing order from the FDA, and this may become common in the coming years. There is sufficient evidence to suggest that flavorings influence the perception, use, and safety of e-cigarettes.Flavor compounds,particularly sweet ones, have the potential to mask and/or ameliorate irritant and bitter sensations, such as the taste of nicotine.The route of delivery has an impact on the toxicology of a compound. Indeed, many flavor compounds have only been tested for safety following oral delivery , and to date have not been tested for inhalation safety. The potential risk of flavor compounds when inhaled rather than ingested has been demonstrated by occupational and consumer inhalation of high doses of the buttery flavor diacetyl , which leads to irreversible lung disease, namely bronchiolitis obliterans or “popcorn lung” in microwave popcorn factory workers.At one time, diacetyl was found in 70% of 159 sweet flavorings used in e-cigarettes,while a more recent study found diacetyl in only a few flavorings. Flavored e-liquids and individual flavors induce toxicity and/ or exert biological effects: Sassano et al. found vanillin is the most common flavor.The number of flavors used varies considerably across e-liquid products. Notably, in 20 e-liquids, Hua et al. found 99 different flavors.Sassano et al. studied 148 eliquids and found 100 flavor constituents.

They also found the more flavors contained in an e-liquid, the more likely it was to be cytotoxic,cannabis indoor greenhouse while concentrations of vanillin and cinnamaldehyde in e-liquids significantly correlated with toxicity.Cinnamaldehyde, was found to be >7.6 mM in multiple e-liquids, and in some cases, levels exceeded 1 M.These concentrations were sufficient to induce cytotoxicity and ciliary dysfunction. However, flavor concentrations in most e-liquids have not yet been determined. Menthol is biologically active and can activate the transient receptor potential channel in pulmonary neurons to suppress cough and irritation,making it easier to tolerate cigarette smoking. Menthol flavors are significantly more popular among African Americans and tobacco companies have marketed them accordingly.Flavorings including vanillin and cinnamaldehyde are aldehydes that have the potential to form adducts with proteins and DNA. Vanillin can also activate TRP channels to exert biological effects .They can also react with base constituents in e-liquids, leading to the formation of acetals, which can stimulate irritant receptors.Sweet and bitter taste receptors are G-protein-coupled receptors expressed in airway epithelia where they regulate innate immunity. The sweet and bitter taste receptors are expressed in the nasal passages/upper airways, while only bitter/T2R taste receptors are expressed in the lower airways.This raises the possibility that inhalation of flavor compounds may stimulate airway taste receptors and affect immune function. Their activation may disrupt innate airway defense by suppressing the release of antimicrobial peptides that are capable of killing a variety of respiratory pathogens. In the lower airways, T2R activation leads to an increase in ciliary beating and may have other physiological functions via its effects on cytoplasmic Ca2þ, a universal second messenger. There is some evidence that toxicity is cell type-dependent, suggesting that mechanistic investigations must be cell-specific.In summary, the adverse impact of flavor compounds in e-cigarettes include the potential for increased appeal of these products, particularly to the youth market, influence on patterns of use and smoking topography, changes in cell signaling, and increased cellular toxicity .PG and VG are commercially available in different mixture ratios, and the ratio of PG to VG in the e-liquid can affect taste sensation, the amount of aerosol generated, the amount of nicotine delivered, and the overall user experience.Predominantly PG-based e-liquids deliver more nicotine systemically, but taste less pleasant than VG-rich e-liquids.PG is used to deliver pharmaceuticals intravenously and while it is generally considered safe, higher PG doses can lead to metabolic acidosis, acute renal injury, and sepsis-like syndrome.

In Sprague-Dawley rats, nasally inhaled PG of up to 2.2 mg/L for 90 days led to nasal hemorrhaging. Similar short-term exposures of mice to PG/VG resulted in changes to tissue elasticity, static compliance, and airway resistance, although these effects waned after 1 month of exposure, suggesting that there may be a long-term adaptive response.In contrast, a recent study funded by Philip Morris International found that nasal exposure to PG/VG mixtures of up to 1.5 mg/L PG and 1.9 mg/L VG for 90 days had minimal effects on respiratory organs, gene transcription, proteomics, and lipid profiles in Sprague-Dawley rats.Lipid-laden macrophages were recently observed in mice that were chronically-exposed to PG/VG.While this exposure was not fatal, these mice had decreased macrophage function and were more vulnerable to influenza A infection.Mucin abnormalities correlate with a decline in forced expiratory volume in 1 s in chronic obstructive pulmonary disease patients,indicating that mucins are important biomarkers of harm. Importantly, increased MUC5AC mucin levels were also detected in human e-cigarette users’ bronchial epithelia obtained by bronchoscopy and in sputum,and these increases in MUC5AC levels could be replicated in the laboratory by exposing both primary bronchial epithelial cultures and mice airways to PG/VG.While the underlying mechanism whereby PG/VG can exert their effects are unknown, Ghosh et al. found that PG/VG rapidly alters membrane rheology.Altered membrane properties could affect a number of aspects of fundamental cell biology including endocytosis, exocytosis, and cell division. In vitro,cannabis growing equipment higher levels of both PG and VG can prevent cell growth and/or induce cell death. However, more work will be required to fully appreciate the effects of PG/ VG. The potential effects of PG/VG at the cellular level are summarized in Figure 2. The concentrations of PG and VG saw in the lung and systemically after vaping are poorly understood, and additional studies to determine PG/VG pharmacokinetics and pharmacodynamics after inhalation are required.This may subject them to chemical reactions that result in the formation of new compounds including reactive oxygen species . For example, the hydroxyl radical was produced from PG/VG at higher power settings.

Carbonyl compounds were formed in e-liquid aerosols as a result of dehydration and oxidation, and was dependent on the PG/VG ratio, the wattage used to heat the e-liquid, as well as other factors including brand, and type of e-liquid used.Exposing biological tissues to carbonyl compounds can deplete glutathione, induce DNA damage, alter ion channel function, and elicit cell death.Thus, both reactive aldehyde production and subsequent reactive aldehyde metabolism in biological tissues need to be considered. This may be particularly important since nearly 8% of the world’s population has an impaired capability to metabolize reactive aldehydes, and they may show altered responses to e-cigarette/reactive aldehyde exposure.Importantly, aldehydes can form adducts with both proteinsand DNA.Adduct binding can impair protein function, as recently noted for the short palate and nasal epithelial clone 1 , which is an innate defense protein expressed in the lung. Here, crotonaldehyde bound to SPLUNC1, which prevented it from regulating lung hydration.Similarly, acrolein can form adducts with surfactant protein A, which leads to impaired innate defense by decreasing antimicrobial activity and reducing phagocytosis by macrophages.Aldehyde adducts can also bind to DNA, leading to frame shift and base-pair substitution mutations, which may contribute to cytotoxic and genotoxic effects.These results indicate that as a result of reactive aldehyde inhalation from heat-coil aerosolization of PG/VG, the lung may be especially vulnerable to adduct formation and the associated macromolecule damage. In addition to decomposition products resulting from heating e-liquids, emissions may also contain contaminants from components of the e-cigarette device itself. These can include toxic metals such as chromium, nickel, and lead.Therefore, understanding the potential health effects of thermal decomposition products remains key to delineating the overall e-cigarette health effects.There is a common perception e-cigarettes may be safer than combustible cigarettes, since they deliver much lower levels of oxidants, volatile organic chemicals, and other noxious chemicals associated with tobacco cigarette smoke and cardiovascular risk.However, both combustible tobacco products and e-cigarettes deliver oxidants, toxic metals, and potentially toxic carbonyls, which have been associated with cardiovascular disease.Moreover, e-cigarette-derived particles are spread among a wider size range than those generated by standard cigarettes. Known toxicants in e-cigarettes may also contribute to cardiovascular damage in a different manner than toxicant-induced cardiovascular damage from combustible cigarettes. There is an urgent need to determine both the acute and the long-term effects of e-cigarettes on the hearts and blood vessels of healthy adults and children, as well as those with either risk factors for cardiovascular disease or outright cardiovascular disease and to determine the comparative safety of e-cigarettes relative to combustible cigarettes.

A summary of the potential cardiovascular biomarkers of exposure/harm following vaping are shown in Table 1 and are discussed in more detail below.E-cigarette use has been consistently connected to reductions in vascular function and damage to ECs. For example, several studies have established that e-cigarette inhalation leads to increased arterial stiffness in humans and rodents, as evidenced by increases in augmentation index and pulse wave velocity.One crossover design study compared e-cigarette vaping 6 nicotine and found that pulse wave velocity, aortic pulse pressure, augmentation index corrected for heart rate, and sub-endocardial viability ratio were all significantly increased, but only when subjects vaped with nicotine.However, another study found that inhalation of nicotine free e-cigarette vapor caused an increase in aortic pulse wave velocity and resistivity index.These results have made it unclear as to whether nicotine is required to elicit these adverse effects: Additional factors such as e-cigarette wattage, which affects toxicant production, and/or the presence of flavors may also affect arterial stiffness. In addition to arterial stiffness, e-cigarette use impaired endothelial nitric oxide synthase signaling,which could be considered a biomarker of endothelial dysfunction in several vascular diseases including hypertension and atherosclerosis. Participants exposed to e-cigarettes showed significantly reduced flow-mediated dilation of the brachial artery, demonstrating endothelial dysfunction compared to non-users.However, in a separate study, smokers who switched to e-cigarettes for one month showed an improvement in FMD, suggesting that there may be a difference between acute and chronic effects of vaping on FMD.The mechanisms by which electronic cigarettes lead to these adverse vascular effects remain incompletely defined. However, a number of studies suggested that e-cigarettes might cause ROSmediated damage, including damage to ECs.Carnevale et al. performed a crossover study of 40 healthy subjects, half of whom were smokers. The subjects were asked to smoke combustible cigarettes for 1 week and were then crossed over to e-cigarettes.Both combustible cigarettes and e-cigarettes increased markers of oxidative stress and worsened FMD after a single use. Lee et al. exposed human-induced pluri potent stem cell-derived ECs to various flavored e-cigarette liquids and assessed endothelial integrity. A cinnamon-flavored e-cigarette product was most potent in reducing cell viability and increasing ROS levels.In multiple studies, subjects who used e-cigarettes either acutely or chronically were found to have altered blood and plasma biomarkers linked to oxidative stress and cardiovascular disease, including increased myeloperoxidase,increased isoprostanes such as 8-iso-PGF2a, reduced NO bio-availability, increased levels of the oxidantgenerating enzyme nicotinamide adenine dinucleotide phosphate oxidase ,and reduced levels of the non-enzymatic antioxidant vitamin E.Anderson et al.showed that e-cigarette aerosol exposure induced ROS in vitro, which caused DNA damage and cell death. Of note, the antioxidants alpha-tocopherol and n-acetyl cysteine were effective in alleviating the damage. After e-cigarette exposure, activated ECs may have been the source of vascular ROS: Chatterjee et al. exposed serum to e-liquids and observed a NOX2-dependent increase in ROS, coupled with inhibition of NADPH oxidase 2 reduced ROS production by 75%.Kuntic et al. extended these observations and demonstrated that e-cigarette-induced ROS burden and endothelial dysfunction could be rescued by NOX2 inhibition or NOX2 gene knockout in mice.These findings were nicotine-independent, and acrolein treatment alone was capable of causing NOX2- dependent ROS production in primary murine ECs. Together, these studies link e-cigarette use with NOX2 activation, endothelial oxidative stress, and subsequent endothelial damage/dysfunction, which may contribute to adverse vascular outcomes.