Underutilisation of no-tobacco-sale orders against retailers that repeatedly sell to minors, 2015-2019, USA.

IMPORTANCE: Research demonstrates that policies aimed at retailers who sell to minors must be strongly enforced to have an impact on youth usage rates. OBJECTIVES: In the USA, the Food and Drug Administration (FDA) conducts compliance checks, issues fines, and can order retailers to stop selling tobacco products (ie, no-tobacco-sale orders (NTSOs)) to enforce the Family Smoking Prevention and Tobacco Control Act. We sought to assess FDA's utilisation of NTSOs. METHODS: We conducted a quantitative content analysis of FDA's enforcement actions for inspections decided between 1 October 2015 and 29 March 2019. From the 536 134 inspection records we identified 148 NTSOs and 249 720 unique retailer locations, of which 2095 had three or more violations. We randomly sampled NTSOs (n=76) and retail locations (n=152) with frequent violations. We calculated the proportion of NTSOs that could have been issued earlier by FDA. We then calculated the proportion of retailers that could have been issued an NTSO, and the proportion actually issued an NTSO using FDA's approach and a more stringent approach. RESULTS: Among NTSOs, 94.7% (95% CI: 89.8% to 97.4%) of NTSOs could have been issued earlier under a more stringent approach. On average, when an NTSO could have been issued earlier, it could have been issued 453 days earlier (95% CI: 418 to 489; range: 89-1159). Among frequently violating retail locations, 73.6% (95% CI: 66.0% to 80.0%) were eligible for an NTSO. Of those, 1.9% (95% CI: 0.5% to 7.0%) had received an NTSO. CONCLUSIONS: The FDA's failure to fully leverage its powers to address retailers' underage sales of tobacco products has weakened efforts to curb the youth e-cigarette epidemic.

Association of co-pay elimination with medication adherence and total cost.

OBJECTIVES: To determine whether elimination of co-pays for prescription drugs affects medication adherence and total health care spending. STUDY DESIGN: Retrospective comparative study. METHODS: We conducted a difference-in-differences comparison in the year before and after expansion of a Zero Dollar Co-pay (ZDC) prescription drug benefit in commercially insured Louisiana residents. Blue Cross and Blue Shield of Louisiana members with continuous disease management program enrollment were analyzed, of whom 6463 were enrolled in the ZDC program and 1821 were controls who were ineligible because their employers did not opt in. RESULTS: After ZDC expansion, medication adherence fell in the control group and rose in the ZDC group, with a relative increase of 2.1 percentage points (P = .002). Medical spending fell by $71 per member per month (PMPM) (P = .027) in the ZDC group relative to controls. Overall, there was no significant increase in the cost of drugs between treatment and controls. However, when drugs were further categorized, there was a significant increase of $8 PMPM for generic drugs and no significant difference for brand name drugs. Comparisons of medication adherence rates by household income showed the largest relative increase post ZDC expansion among low-income members. CONCLUSIONS: Elimination of co-pays for drugs indicated to treat chronic illnesses was associated with increases in medication adherence and reductions in overall spending of $63. Benefit designs that eliminate co-pays for patients with chronic illnesses may improve adherence and reduce the total cost of care.

Hangings: Lessons Learned from the Coroner's Office.

BACKGROUND: Hangings are an infrequent wounding mechanism among patients arriving alive to hospital but are frequently encountered by the Coroner's Office. It is unclear if classically described hanging injuries, such as the Hangman's fracture, are common among contemporary hangings patients who typically do not suspend from height. This study was undertaken to define patient and injury characteristics after hangings causing death. METHODS: All patients presenting to the Los Angeles County Medical Examiner/Coroner's Office (January 2016 - May 2020) who died by hanging were included. Demographics, psychiatric history, hanging details, autopsy type, and sustained injuries were collected. Data variables were summarized with descriptive statistics and the diagnostic yield of a ligature mark in the diagnosis/exclusion of cervical injuries was calculated. RESULTS: Over the study, 1,401 patients died by hanging. Patients underwent external exam alone (n = 1,282, 92%), traditional neck autopsy (n = 114, 8%), or traditional neck autopsy plus postmortem computed tomography scan (n = 5, <1%). Home was the most frequent hanging setting (n = 1,028, 73%) followed by public spaces (n = 80, 6%) and jail (n = 28, 2%). The manner of death was almost exclusively suicide (n = 1,395, >99%) and psychiatric disease was common (n = 968, 69%). Of the patients undergoing traditional autopsy, most had a ligature mark (n = 109, 92%) and only 9 (8%) had a cervical injury (hyoid fractures, n = 6, 5%; thyroid cartilage fractures, n = 4, 3%). None had a vertebral fracture/dislocation. Sensitivity, specificity, positive predictive value, and negative predictive value of a ligature mark were 100%, 5%, 8%, and 100%. CONCLUSIONS: Hangings are a frequent cause of death in Los Angeles County. Patients typically have a psychiatric history and die almost exclusively from suicide. Hangings commonly occur at home, in public places, and in jail. Injuries were exceedingly rare and no patient sustained a Hangman's fracture, which may be related to the lack of significant suspension with modern hangings.

Implicit and Explicit Attitudes Toward Antihypertensive Medications Explain Variation in Pharmacy Refill and Self-Reported Adherence Beyond Traditional Risk Factors: Potential Novel Mechanism Underlying Adherence.

Background In pursuit of novel mechanisms underlying persistent low medication adherence rates, we assessed contributions of implicit and explicit attitudes, beyond traditional risk factors, in explaining variation in objective and subjective antihypertensive medication adherence. Methods and Results Implicit and explicit attitudes were assessed using the difference scores from the computer-based Single Category Implicit Association Test and the Necessity and Concerns subscales of the Beliefs about Medicines Questionnaire, respectively. Antihypertensive medication adherence was measured using pharmacy refill proportion of days covered (PDC: mean PDC, low PDC <0.8) and the self-report 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4: mean K-Wood-MAS-4, low adherence via K-Wood-MAS-4 ≥1). Hierarchical logistic and linear regression models controlled for traditional risk factors including social determinants of health, explicit, and implicit attitudes in a stepwise fashion. Community-dwelling insured participants (n=85: 44.7% female; 20.0% Black; mean age, 62.3 years; 43.5% low PDC, and 31.8% low adherence via K-Wood-MAS-4) had mean (SD) explicit and implicit attitude scores of 7.188 (5.683) and 0.035 (0.334), respectively. Low PDC was inversely associated with more positive explicit (adjusted odds ratio [aOR], 0.87; 95% CI, 0.78-0.98; P=0.022) and implicit (aOR, 0.12; 95% CI, 0.02-0.80; P=0.029) attitudes, which accounted for an additional 8.6% (P=0.016) and 6.5% (P=0.029) of variation in low PDC, respectively. Lower mean K-Wood-MAS-4 scores (better adherence) were associated only with more positive explicit attitudes (adjusted ß, -0.04; 95% CI, -0.07 to -0.01; P=0.026); explicit attitudes explained an additional 5.6% (P=0.023) of K-Wood-MAS-4 variance. Conclusions Implicit and explicit attitudes explained significantly more variation in medication adherence beyond traditional risk factors, including social determinants of health, and should be explored as potential mechanisms underlying adherence behavior.

Value-based insurance design in Louisiana: Blue Cross Blue Shield's Zero Dollar Co-pay program.

OBJECTIVES: To determine whether a program that eliminated pharmacy co-pays, the Blue Cross Blue Shield of Louisiana (BCBSLA) Zero Dollar Co-pay (ZDC) program, decreased health care spending. Previous studies have found that value-based insurance designs like the ZDC program have little or no impact on total health care spending. ZDC included an expansive set of medications related to 4 chronic diseases rather than a limited set of medications for 1 or 2 chronic diseases. Additionally, ZDC focused on the most at-risk patients. STUDY DESIGN: ZDC began in 2014 and enrolled patients over time based on (1) when a patient answered a call from a nurse care manager and (2) when a patient or their employer changed the benefit structure to meet the program criteria. During 2015 and 2016, 265 patients with at least 1 chronic condition (asthma, diabetes, hypertension, mental illness) enrolled in ZDC. METHODS: Observational study using within-patient variation and variation in patient enrollment month to identify the impact of the ZDC program on health spending measures. We used 100% BCBSLA claims data from January 2015 to June 2018. Monthly level event studies were used to test for differential spending patterns prior to ZDC enrollment. RESULTS: We found that total spending decreased by $205.9 (P = .049) per member per month, or approximately 18%. We saw a decrease in medical spending ($195.0; P = .023) but did not detect a change in pharmacy spending ($7.59; P = .752). We found no evidence of changes in spending patterns prior to ZDC enrollment. CONCLUSIONS: The ZDC program provides evidence that value-based insurance designs that incorporate a comprehensive set of medications and focus on populations with chronic disease can reduce spending.

Strengthening a Tobacco-Free College Campus Policy Through Signage: GIS Mapping for Advocacy to Improve Implementation.

Implementing tobacco-free policies on university campuses has become increasingly common. However, promoting policy compliance remains a challenge. It is important to develop strategies that can overcome barriers to successful policy implementation and promote compliance. This Practice Note presents a case study of a practical strategy for addressing poor implementation of a newly adopted tobacco-free policy. Following principles of advocacy research, a team of student researchers and a faculty advisor developed a protocol to identify tobacco-related signage and environmental cues for tobacco use (e.g., cigarette-butt receptacles, designated smoking areas) on campus. Ten months after a tobacco-free campus policy went into effect, we identified 153 signs and 65 environmental cues. Of these, only two signs accurately described the current policy. Mapping signage and cues to use tobacco on campus can be an important advocacy tool to improve the implementation of tobacco-free campus policies. Increased adherence to new policies can be achieved through advocacy and outreach to university administrators.

Abdominal Wall Schwannoma.

This rare form of subcutaneous nodule can be identified through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Oral health and dental morbidity in long-term allogeneic blood and marrow transplant survivors in Australia.

BACKGROUND: Oral and dental disease is a major cause of long-term morbidity following allogeneic blood and marrow transplantation (Allo-BMT). This study aimed to describe the extent and range of oral and dental complications in BMT recipients and to identify gaps in service provision provided to this high-risk group. METHODS: Participants were Allo-BMT recipients, aged >18 years, and received transplants between 2000 and 2012 in NSW. They completed seven surveys, the purpose-designed Sydney Post-BMT Study survey and six other validated instruments. RESULTS: Of 441 respondents, many reported dry mouth (45.1%), dental caries (36.7%), mouth ulcers (35.3%), oral GVHD (35.1%), gingivitis (16.2%), tooth abscess (6.1%) and oral cancer (1.5%). Regular dental visits were reported by 66.2% of survivors. Middle-high income, older age and geographic location showed a positive association with regular dental visits. Of those who did not visit the dentist regularly, 37% stated they did not feel it necessary, 36% reported cost and 20% stated it was not advised by the treating team. CONCLUSION: Despite oral complications commonly occurring after Allo-BMT, many survivors receive inadequate dental care. These results emphasize the need for improved oral health education, the importance of regular dental checks and improvement in the delivery of dental health services for BMT survivors.

Deep Immune Profiling of an Arginine-Enriched Nutritional Intervention in Patients Undergoing Surgery.

Application of high-content immune profiling technologies has enormous potential to advance medicine. Whether these technologies reveal pertinent biology when implemented in interventional clinical trials is an important question. The beneficial effects of preoperative arginine-enriched dietary supplements (AES) are highly context specific, as they reduce infection rates in elective surgery, but possibly increase morbidity in critically ill patients. This study combined single-cell mass cytometry with the multiplex analysis of relevant plasma cytokines to comprehensively profile the immune-modifying effects of this much-debated intervention in patients undergoing surgery. An elastic net algorithm applied to the high-dimensional mass cytometry dataset identified a cross-validated model consisting of 20 interrelated immune features that separated patients assigned to AES from controls. The model revealed wide-ranging effects of AES on innate and adaptive immune compartments. Notably, AES increased STAT1 and STAT3 signaling responses in lymphoid cell subsets after surgery, consistent with enhanced adaptive mechanisms that may protect against postsurgical infection. Unexpectedly, AES also increased ERK and P38 MAPK signaling responses in monocytic myeloid-derived suppressor cells, which was paired with their pronounced expansion. These results provide novel mechanistic arguments as to why AES may exert context-specific beneficial or adverse effects in patients with critical illness. This study lays out an analytical framework to distill high-dimensional datasets gathered in an interventional clinical trial into a fairly simple model that converges with known biology and provides insight into novel and clinically relevant cellular mechanisms.

Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy.

Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4+ and CD8+ T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet+CD4+ T cells, CD8+ T cells, B cells, and CD56loCD16+ NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.

The experience of survival following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) entails long-term morbidities that impair survivors' quality of life through broad physical and psychosocial sequelae. Current data and survival measurements may be inadequate for contemporary Australian allo-HSCT recipients. This study sought to comprehensively describe survivorship in an up-to-date, local setting through validated measurements and a novel questionnaire designed to complement and address limitations of current instruments. All adults who received an allo-HSCT between 2000 and 2012 in New South Wales were eligible and included, if alive, those literate and consenting to the study, which encompassed seven survey instruments. Four hundred and forty-three survivors participated, which is 76% of contactable (n=583) and 66% of eligible survivors (n= 669). Chronic GVHD (cGVHD) and co-morbidity rates were similar to published data. Noteworthy results include prevalent sexual dysfunction (66% females, 52% males), loss of income (low income increased from 21 to 36%, P<0.001) and employment (full-time employment fell from 64 to 33%, P<0.001), suboptimal vaccination (31% complete), and health screening (≈50%). Risk factors for poor vaccination and health screening were cGVHD, younger age, less education, rural/regional residence and transplantation <2 years. This study suggests that improvement in survivorship may necessitate structural changes in the current delivery of health services.

REPRODUCIBLE AND SHAREABLE QUANTIFICATIONS OF PATHOGENICITY.

There are now hundreds of thousands of pathogenicity assertions that relate genetic variation to disease, but most of this clinically utilized variation has no accepted quantitative disease risk estimate. Recent disease-specific studies have used control sequence data to reclassify large amounts of prior pathogenic variation, but there is a critical need to scale up both the pace and feasibility of such pathogenicity reassessments across human disease. In this manuscript we develop a shareable computational framework to quantify pathogenicity assertions. We release a reproducible "digital notebook" that integrates executable code, text annotations, and mathematical expressions in a freely accessible statistical environment. We extend previous disease-specific pathogenicity assessments to over 6,000 diseases and 160,000 assertions in the ClinVar database. Investigators can use this platform to prioritize variants for reassessment and tailor genetic model parameters (such as prevalence and heterogeneity) to expose the uncertainty underlying pathogenicity-based risk assessments. Finally, we release a website that links users to pathogenic variation for a queried disease, supporting literature, and implied disease risk calculations subject to user-defined and disease-specific genetic risk models in order to facilitate variant reassessments.

Influence of access to an integrated trauma system on in-hospital mortality and length of stay.

BACKGROUND: Few data are available on population-based access to specialised trauma care and its influence on patient outcomes in an integrated trauma system. We aimed to evaluate the influence of access to an integrate trauma system on in-hospital mortality and length of stay (LOS). METHODS: All adults admitted to acute care hospitals for major trauma [International Classification of Diseases Injury Severity Score (ICISS<0.85)] in a Canadian province with an integrated trauma system between 2006 and 2011 were included using an administrative hospital discharge database. The influence of access to an integrated trauma system on in-hospital mortality and LOS was assessed globally and for critically injured patients (ICISS<0.75), according to the type of injury [traumatic brain injury (TBI), abdominal/thoracic, spine, orthopaedic] using logistic and linear multivariable regression models. RESULTS: We identified 22,749 injury admissions. In-hospital mortality was 7% and median LOS was 9 days for all injuries. Overall, 92% of patients were treated within the trauma system. Globally, patients who did not have access had similar mortality and LOS compared to patients who had access. However, we observed a 62% reduction in mortality for critical abdominal/thoracic injuries (odds ratio=0.38; 95% CI, 0.16-0.92) and an 8% increase in LOS for TBI patients (geometric mean ratio=1.08; 95% CI, 1.02-1.14) treated within the trauma system. CONCLUSIONS: Results provides evidence that in a health system with an integrated mature trauma system, access to specialised trauma care is high and the small proportion of patients treated outside the system, have similar mortality and LOS compared to patients treated within the system. This study suggests that the Québec trauma system performs well in its mandate to offer appropriate treatment to victims of injury that require specialised care.

Access to a Canadian provincial integrated trauma system: a population-based cohort study.

BACKGROUND: Access to specialised trauma care is an important measure of trauma system efficiency. However, few data are available on access to integrated trauma systems. We aimed to describe access to trauma centres (TCs) in an integrated Canadian trauma system and identify its determinants. METHODS: We conducted a population-based cohort study including all injured adults admitted to acute care hospitals in the province of Québec between 2006 and 2011. Proportions of injured patients transported directly or transferred to TCs were assessed. Determinants of access were identified through a modified Poisson regression model and a relative importance analysis was used to determine the contribution of each independent variable to predicting access. RESULTS: Of the 135,653 injury admissions selected, 75% were treated within the trauma system. Among 25,522 patients with major injuries [International Classification of diseases Injury Severity Score (ICISS<0.85)], 90% had access to TCs. Access was higher for patients aged under 65, men and among patients living in more remote areas (p-value <0.001). The region of residence followed by injury mechanism, number of trauma diagnoses, injury severity and age were the most important determinants of access to trauma care. CONCLUSIONS: In an integrated, mature trauma system, we observed high access to TCs. However, problems in access were observed for the elderly, women and in urban areas where there are many non-designated hospitals. Access to trauma care should be monitored as part of quality of care improvement activities and pre-hospital guidelines for trauma patients should be applied uniformly throughout the province.

How international is Medical Education?

AIMS: To consider Medical Education's claim to international status in terms of the extent of international authorship within published articles, the degree to which authors draw on the international literature to support their work, and its self-citation rates and publication decisions. METHOD: We examined 6 journals' citation rates for the period 1997-2001 to see if there was evidence of national publication bias; we calculated their self-citation rates to see if this had any influence on impact factor, and we examined Medical Education's management files for trends which might indicate publication bias due to country of origin of authors. RESULTS: All 6 journals exhibited a bias in favour of citing journals from their own countries. The US journals were more likely to cite journals from their own country. Medical Education was most likely to cite journals from non-UK countries. Self-citation rates did not appear to affect impact factors. The ratio of UK to non-UK papers published in Medical Education has not changed significantly over the period studied although non-UK submissions increased sharply in 2002 and the number of North American submissions has doubled since 1998. CONCLUSION: Medical Education is justified in calling itself an international journal to the extent that the majority of papers it publishes are from countries other than the UK, and it is more likely than other journals in the field to publish papers which cite work in journals published outside the UK. Nevertheless, there is some evidence of publication bias in the journal and more work is needed to discover why this is the case. Various strategies to address the issue of national bias in Medical Education are discussed.

Computational methods to estimate drug development parameters.

Computational methods are currently available to estimate oral bioavailability, solubility, metabolism, toxicity, pKa, blood-brain barrier permeability and other ADME and physicochemical parameters. Decisions as to which methods to implement and to employ must be made in accordance with the stated goals of a drug discovery organization, the timeline for these goals, and the budgetary limitations as set forth to accomplish these goals. Certain methods are more attractive to the production environment of a pharmaceutical project team where early ADME and Tox information is sought to aid in drug design decisions and prioritization. Practical limitations of these methods, ease of use, utility of results, as well as their scope and limitations are discussed. Recommendations as to which parameters are best estimated by commercial products, as opposed to those that can be developed in-house, are delineated. Special attention is given to those methods that can be integrated into the current high-throughput paradigms of drug discovery programs. Together, these considerations define a 'zero-infrastructure' approach to provide ADME and Tox information during the early stages of the drug design process.