High-entropy ejecta plumes in Cassiopeia A from neutrino-driven convection.

Recent multi-dimensional simulations suggest that high-entropy buoyant plumes help massive stars to explode1,2. Outwardly protruding iron (Fe)-rich fingers of gas in the galactic supernova remnant3,4 Cassiopeia A seem to match this picture. Detecting the signatures of specific elements synthesized in the high-entropy nuclear burning regime (that is, α-rich freeze out) would constitute strong substantiating evidence. Here we report observations of such elements-stable titanium (Ti) and chromium (Cr)-at a confidence level greater than 5 standard deviations in the shocked high-velocity Fe-rich ejecta of Cassiopeia A. We found that the observed Ti/Fe and Cr/Fe mass ratios require α-rich freeze out, providing evidence of the existence of the high-entropy ejecta plumes that boosted the shock wave at explosion. The metal composition of the plumes agrees well with predictions for strongly neutrino-processed proton-rich ejecta2,5,6. These results support the operation of the convective supernova engine via neutrino heating in the supernova that produced Cassiopeia A.

Individualised prediction of resilience and vulnerability to sleep loss using EEG features.

It is well established that individuals differ in their response to sleep loss. However, existing methods to predict an individual's sleep-loss phenotype are not scalable or involve effort-dependent neurobehavioural tests. To overcome these limitations, we sought to predict an individual's level of resilience or vulnerability to sleep loss using electroencephalographic (EEG) features obtained from routine night sleep. To this end, we retrospectively analysed five studies in which 96 healthy young adults (41 women) completed a laboratory baseline-sleep phase followed by a sleep-loss challenge. After classifying subjects into sleep-loss phenotypic groups, we extracted two EEG features from the first sleep cycle (median duration: 1.6 h), slow-wave activity (SWA) power and SWA rise rate, from four channels during the baseline nights. Using these data, we developed two sets of logistic regression classifiers (resilient versus not-resilient and vulnerable versus not-vulnerable) to predict the probability of sleep-loss resilience or vulnerability, respectively, and evaluated model performance using test datasets not used in model development. Consistently, the most predictive features came from the left cerebral hemisphere. For the resilient versus not-resilient classifiers, we obtained an average testing performance of 0.68 for the area under the receiver operating characteristic curve, 0.72 for accuracy, 0.50 for sensitivity, 0.84 for specificity, 0.61 for positive predictive value, and 3.59 for likelihood ratio. We obtained similar performance for the vulnerable versus not-vulnerable classifiers. These results indicate that logistic regression classifiers based on SWA power and SWA rise rate from routine night sleep can largely predict an individual's sleep-loss phenotype.

Drug-drug interactions and the risk of adverse drug reaction-related hospital admissions in the older population.

AIMS: The aims of this study were to estimate potentially clinically important drug-drug interaction (DDI) prevalence, and the average causal effect of DDI exposure on adverse drug reaction (ADR)-related hospital admission, and to examine differences in health-related quality of life (HRQoL) and length of stay (LOS) per DDI exposure in an older (≥65 years) population acutely hospitalized. METHODS: This was a cross-sectional study conducted among 798 older individuals acutely admitted to hospital in Ireland between 2016 and 2017. Medication (current/recently discontinued/over-the-counter) and clinical data (e.g., creatinine clearance) were available. DDIs were identified using the British National Formulary (BNF) and Stockley's Drug Interactions. Causal inference models for DDI exposure on ADR-related hospital admission were developed using directed acyclic graphs. Multivariable logistic regression was used to estimate the average causal effect. Differences in HRQoL (EQ-5D) and LOS per DDI exposure were examined non-parametrically. DDI prevalence, adjusted odds ratios (aOR), and 95% confidence intervals (CIs) are reported. RESULTS: A total of 782 (98.0%) individuals using two or more drugs were included. Mean age was 80.9 (SD ± 7.5) years (range: 66-105); 52.2% were female; and 45.1% (n = 353) had an ADR-related admission. At admission, 316 (40.4% [95% CI: 37.0-43.9]) patients had at least one DDI. The average causal effect of DDI exposure on ADR-related hospital admission was aOR = 1.21 [95% CI: 0.89-1.64]. This was significantly increased by exposure to: DDIs which increase bleeding risk (aOR = 2.00 [1.26-3.12]); aspirin-warfarin (aOR = 2.78 [1.37-5.65]); and esomeprazole-escitalopram (aOR = 3.22 [1.13-10.25]. DDI-exposed patients had lower HRQoL (mean EQ-5D = 0.49 [±0.39]) compared those non-DDI-exposed (mean EQ-5D = 0.57 [±0.41]), (P = .03); and greater median LOS in hospital (8 [IQR5-16]days) compared those non-DDI-exposed (7 [IQR 4-14] days),(P = .04). CONCLUSIONS: Potentially clinically important DDIs carry an increased average causal effect on ADR-related admission, significantly (two-fold) by exposure to DDIs that increase bleeding risk, which should be targeted for medicine optimization.

Electroencephalographic markers from routine sleep discriminate individuals who are vulnerable or resilient to sleep loss.

Sleep loss impairs cognition; however, individuals differ in their response to sleep loss. Current methods to identify an individual's vulnerability to sleep loss involve time-consuming sleep-loss challenges and neurobehavioural tests. Here, we sought to identify electroencephalographic markers of sleep-loss vulnerability obtained from routine night sleep. We retrospectively analysed four studies in which 50 healthy young adults (21 women) completed a laboratory baseline-sleep phase followed by a sleep-loss challenge. After classifying subjects as resilient or vulnerable to sleep loss, we extracted three electroencephalographic features from four channels during the baseline nights, evaluated the discriminatory power of these features using the first two studies (discovery), and assessed reproducibility of the results using the remaining two studies (reproducibility). In the discovery analysis, we found that, compared to resilient subjects, vulnerable subjects exhibited: (1) higher slow-wave activity power in channel O1 (p < 0.0042, corrected for multiple comparisons) and in channels O2 and C3 (p < 0.05, uncorrected); (2) higher slow-wave activity rise rate in channels O1 and O2 (p < 0.05, uncorrected); and (3) lower sleep spindle frequency in channels C3 and C4 (p < 0.05, uncorrected). Our reproducibility analysis confirmed the discovery results on slow-wave activity power and slow-wave activity rise rate, and for these two electroencephalographic features we observed consistent group-difference trends across all four channels in both analyses. The higher slow-wave activity power and slow-wave activity rise rate in vulnerable individuals suggest that they have a persistently higher sleep pressure under normal rested conditions.

Evaluating awareness, knowledge and practice of healthcare professionals following implementation of a revised pregnancy prevention programme for isotretinoin in Ireland: A multi-stakeholder cross-sectional study.

PURPOSE: In 2018, following an EU-wide safety review, a revised pregnancy prevention programme (PPP) was introduced for isotretinoin (Roaccutane®). This study aimed to examine awareness, knowledge, and experience implementing the revised isotretinoin PPP in clinical practice across three healthcare professional (HCP) groups in Ireland. METHODS: A cross-sectional study using anonymous online surveys among general practitioners (GPs), community pharmacists, and specialist consultants was undertaken. Descriptive analyses are presented. RESULTS: Across all HCP groups there was high (≥87%) awareness that oral isotretinoin is contraindicated in women of childbearing potential (WCBP) unless the conditions of the PPP are fulfilled, but varying awareness among GPs (54.9%) and community pharmacists (45.9%) that exposure during pregnancy can cause both severe fetal malformations and spontaneous abortions. Implementation of the PPP in clinical practice varied across HCP groups. When initiating isotretinoin in WCBP, 66.7% of specialists and 40.8% of GPs indicated they had considered alternative treatment options, and 71.4% of specialists and 31.6% of GPs reported they first requested a pregnancy test. There was limited provision of the patient reminder card to WCBP, where 26.1% of community pharmacists provide this at each dispensing, while 47.6% of specialists and 11.8% of GPs ensured WCBP had a copy of the card when initiating treatment. Across all HCP groups, there was high (≥81.6%) awareness of the need for urgent consultation and immediate cessation of isotretinoin in the event of an unplanned or suspected pregnancy. CONCLUSIONS: Reinforcement of the provision and utilisation of the isotretinoin patient reminder card may be required, and further targeted education on specific elements of the PPP should be considered for GPs and community pharmacists.

Epitome: predicting epigenetic events in novel cell types with multi-cell deep ensemble learning.

The accumulation of large epigenomics data consortiums provides us with the opportunity to extrapolate existing knowledge to new cell types and conditions. We propose Epitome, a deep neural network that learns similarities of chromatin accessibility between well characterized reference cell types and a query cellular context, and copies over signal of transcription factor binding and modification of histones from reference cell types when chromatin profiles are similar to the query. Epitome achieves state-of-the-art accuracy when predicting transcription factor binding sites on novel cellular contexts and can further improve predictions as more epigenetic signals are collected from both reference cell types and the query cellular context of interest.

Management of chronic primary pelvic pain syndromes.

Management of chronic pelvic pain (CPP) remains a huge challenge for care providers and a major burden for healthcare systems. Treating chronic pain that has no obvious cause warrants an understanding of the difficulties in managing these conditions. Chronic pain has recently been accepted as a disease in its own right by the World Health Organization, with chronic pain without obvious cause being classified as chronic primary pain. Despite innumerable treatments that have been proposed and tried to date for CPP, unimodal therapeutic options are mostly unsuccessful, especially in unselected individuals. In contrast, individualised multimodal management of CPP seems the most promising approach and may lead to an acceptable situation for a large proportion of patients. In the present review, the interdisciplinary and interprofessional European Association of Urology Chronic Pelvic Pain Guideline Group gives a contemporary overview of the most important concepts to successfully diagnose and treat this challenging disease.

Potential effects of nicotine content in cigarettes on use of other substances.

A national nicotine reduction policy has the potential to reduce cigarette smoking and associated adverse health impacts among vulnerable populations. However, possible unanticipated adverse effects of reducing nicotine content in cigarettes, such as increasing the use of alcohol or other abused substances, must be examined. The purpose of this study was to evaluate the effects of exposure to varying doses of nicotine in cigarettes on use of other substances. This was a secondary analysis (n = 753) of three simultaneous, multisite, double-blind, randomized-controlled trials examining 12 weeks of exposure to study cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco) among daily smokers from three vulnerable populations: individuals with affective disorders (n = 251), individuals with opioid use disorder (n = 256), and socioeconomically-disadvantaged women of reproductive age (n = 246). Effect of study cigarette assignment on urine toxicology screens (performed weekly) and responses to drug and alcohol use questionnaires (completed at study weeks 6 and 12) were examined using negative binomial regression, logistic regression, or repeated measures analysis of variance, controlling for sex, age, and menthol status. The most common substances identified using urine toxicology included tetrahydrocannabinol (THC; 44.8%), cocaine (9.2%), benzodiazepine (8.6%), and amphetamines (8.0%), with 57.2% of participants testing positive at least once for substance use (27.3% if excluding THC). No significant main effects of nicotine dose were found on any of the examined outcomes. These results suggest that reducing nicotine content does not systematically increase use of other substances, even among individuals at increased risk of substance use. ClinicalTrials.gov Identifiers: NCT02232737, NCT2250664, NCT2250534.

'It's helped me to learn to deal with it': a mixed methods service evaluation of a multicomponent fibromyalgia service.

OBJECTIVES: To evaluate the Royal London Hospital for Integrated Medicine (RLHIM) multicomponent fibromyalgia service. METHODS: Mixed methods approach consisting of the completion of validated quantitative outcome measures (Patient Health Questionnaire-9; Generalised Anxiety Disorder-7; Pain Catastrophising Scale; Patient Self-Efficacy Questionnaire) pre- and post-treatment to explore the impact of treatment; and qualitative focus groups with patients at their follow-up appointments to explore patients' experiences and perspectives on the service. RESULTS: 138 fibromyalgia patients attended the RLHIM group fibromyalgia service during the period of the evaluation. Baseline scores demonstrate that patients were significantly impaired pre-treatment according to all outcome measures. At the end of the course of treatment, scores for all outcome measures showed clinically and statistically significant improvements. These improvements were maintained at both 6- and 9-month follow-up appointments. Qualitative analysis indicated that those participating valued the multicomponent treatment approach, and perceived the service as having a positive impact on their fibromyalgia and overall quality of life, enabling patients to effectively manage their condition. CONCLUSIONS: Patients attending the RLHIM multicomponent fibromyalgia service appear to have demonstrable improvements in presenting symptoms, and quality of life. The findings support a multicomponent approach to the treatment of fibromyalgia.

Valproate utilisation trends among women of childbearing potential in Ireland between 2014 and 2019: A drug utilisation study using interrupted time series.

PURPOSE: This study aimed to examine trends in valproate use among women of childbearing potential (WCBP) aged 16-44 years in Ireland following two European-directed regulatory interventions in December 2014 and April 2018. METHODS: This was a repeated cross-sectional study using monthly national pharmacy claims data, to examine trend changes in the prevalence of valproate use among WCBP pre and post two separate regulatory events in December 2014 and April 2018. Annual population estimates from the Central Statistics Office were used to calculate the prevalence rate per 1000 eligible women. Segmented regression analysis of interrupted time series with negative binomial regression was used to examine rates for WCBP aged 16-44 years, and by 10-year age groups. Prevalence ratios (PR) are presented with 95% confidence intervals (CIs). RESULTS: Among WCBP aged 16-44 years, there was no statistically significant change in the month-to-month prevalence ratio in the post- compared to pre-December 2014 intervention period. A significant decline was, however, observed in the post-, compared to pre-April 2018 intervention period (PR = 0.998, [95% CIs: 0.996, 1.000]; p = 0.029). Among those aged 16-24 years, a significant decreasing trend in the month-to-month prevalence ratio was found in the post- compared to pre-December 2014 intervention period (PR = 0.991, [95% CIs: 0.984, 0.998];p <0.01). A marginal effect was observed in the post- compared to pre-April 2018 intervention period for those aged 25-34 years (PR = 0.996, [95% CIs: 0.992, 1.000]; p = 0.048). CONCLUSION: Although no evidence of change was observed following the December 2014 intervention period, a significant decline in the prevalence ratio of valproate use was observed after the 2018 intervention, which may reflect the introduction of the most recent contraindication measures.

Responses of Lotus corniculatus to environmental change. 4: Root carbohydrate levels at defoliation and regrowth climatic conditions are major drivers of phenolic content and forage quality.

MAIN CONCLUSION: Differential accumulation of root carbohydrates at defoliation have a higher impact than regrowth environmental conditions on the phenolic content and feed quality of the perennial forage legume Lotus corniculatus. The unpredictable nature of proanthocyanidin (condensed tannin) accumulation in regrowth vegetation of the perennial forage legume Lotus corniculatus represents a dilemma to the wider use of this species in agriculture, and a potential problem in the nutritional ecology of some terrestrial herbivores, as variable condensed tannin levels can result in either beneficial or detrimental effects on animal nutrition. However, the source of this variation has not been extensively explored. High levels of carbon allocation to roots during low-temperature preconditioning of clonal plants were found to significantly increase condensed tannin and flavonol levels in regrowth foliage, while low levels of carbon allocation to roots during periods of high-temperature preconditioning significantly decreased condensed tannin and flavonol levels. Phenolic accumulation and tissue digestibility were also differentially affected by regrowth of these defoliated plants at high CO2 concentrations and by drought. Lower rates of digestion generally paralleled increases in tannin levels in regrowth leaves under the different environmental conditions, with rates of digestion falling in high tannin plants, despite correspondingly higher levels of leaf carbohydrates. Differential accumulation of root carbohydrates between seasons and years may therefore explain some of the variability found in the nutritional quality of the forage of this species.

Cumulative vulnerabilities as a potential moderator of response to reduced nicotine content cigarettes.

Risk for smoking increases in a summative manner corresponding to the number of co-occurring vulnerabilities present (cumulative vulnerability). We examined whether cumulative vulnerabilities moderate response to reduced nicotine content cigarettes in a secondary analysis of results from 775 participants in three 12-week randomized clinical trials examining research cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco). Participants were categorized as having 0-1, 2-3, or ≥ 4 cumulative vulnerabilities. Vulnerabilities included: rural residence, current substance use disorder, current affective disorder, low educational attainment, poverty, unemployment, physical disability. The primary outcome was total cigarettes per day (CPD) during Week 12; secondary outcomes included CPD across weeks, toxin exposure, dependence severity, craving/withdrawal (17 dependent measures). Results were analyzed using repeated measures analysis of covariance and growth-curve modeling. Total CPD during Week 12 increased as cumulative-vulnerability increased (P = 0.004), and decreased as nicotine content decreased (P < 0.001), with no significant interaction of cumulative vulnerability and dose (P = 0.67). Effects on other outcomes generally followed that same pattern. The only exception across the other outcomes was on Questionnaire-on-Smoking-Urges Factor-2 ratings for usual-brand cigarettes where cumulative vulnerability, dose, and time interacted (P = 0.007), with craving at the 0.4 and 2.4 mg/g doses decreasing over time, but inconsistently across vulnerability categories. Overall, we saw little evidence that cumulative vulnerabilities moderate response to reduced nicotine content cigarettes suggesting that a policy reducing nicotine content in cigarettes to minimally addictive levels could benefit even highly vulnerable smokers including those residing in rural or other regions with overrepresentation of co-occurring vulnerabilities. Clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

Tobacco and Nicotine Use Among US Adult "Never Smokers" in Wave 4 (2016-2018) of the Population Assessment of Tobacco and Health Study.

INTRODUCTION: A common criterion for being labeled a "never smoker" is having smoked <100 lifetime cigarettes. This category is often used as an unexposed reference group to estimate the relative harm from cigarettes. We examined the amount of current and past cigarette and non-cigarette tobacco/nicotine use among adults who met this "never smoker" criterion. METHODS: We analyzed cross-sectional data from 17 179 adult "never smokers" (ie, reported <100 lifetime cigarettes) in Wave 4 (2016-2018) of the Population Assessment of Tobacco and Health (PATH) Study, a United States nationally representative sample. We used PATH-derived variables to describe "never smokers'" demographics as well as cigarette and non-cigarette tobacco/nicotine use. RESULTS: Approximately half of "never smokers" were young adults (49.3%). Most were white (68.6%) with some college or more (64.4%). Most "never smokers" had tried any cigarette or non-cigarette tobacco/nicotine in their lifetime (66.7%), 8.5% smoked cigarettes in the past 30 days, and 5.3% were current experimental (ie, some days or every day) cigarette smokers. By definition, "never smokers" reported smoking <100 lifetime cigarettes. One fifth (22.8%) had a lifetime history of established regular non-cigarette tobacco/nicotine use and 8.6% were current established regular non-cigarette tobacco/nicotine users. In total, 9.4% of "never smokers" were current experimental or established regular users of combustible tobacco. CONCLUSIONS: The 100-cigarette lifetime threshold includes substantial amounts of current and past tobacco use and thus does not represent lack of exposure to cigarette or non-cigarette tobacco. "Never smoker" reference groups may produce underestimates of the relative harms from cigarettes. IMPLICATIONS: The <100 lifetime cigarettes criterion may not capture what many would consider true "never smokers." Relying on the current definition of "never smokers" as a reference group will include a substantial number of those currently and recently using combustible tobacco and thus produce data that may underestimate the relative harm from cigarettes. Prospective longitudinal research is needed to compare how the 100-cigarette lifetime threshold versus other definitions of regular cigarette smoking differ in predictive validity of clinically meaningful outcomes and health harms to determine the optimal criteria to define established cigarette smoking.

Possible New Symptoms of Tobacco Withdrawal III: Reduced Positive Affect-A Review and Meta-analysis.

INTRODUCTION: Most descriptions of tobacco withdrawal have not changed in >30 years despite new research. This meta-analysis tested whether abstinence leads to decreased positive affect (PA) because abstinence-induced symptom changes are a core feature of the tobacco withdrawal syndrome. In addition, we examined whether reduced PA was due to withdrawal (ie, temporary decrease in a "U-shaped" curve) or offset (ie, return to baseline) effect. METHODS: Our main inclusion criterion was a prospective within-participant test of change in PA during abstinence conditions among people who smoke cigarettes daily who were not using a cessation medication. Our search of PubMed, PsycINFO, and personal libraries yielded a total of 32 tests with 2054 participants. RESULTS: There was a medium effect size indicating an overall decrease in PA following abstinence from cigarettes (Cohen's d = -0.40, 95% CI = -0.30 to -0.49). There was large heterogeneity (I2 = 70.7%). Most (79%) of the 24 trials that conducted significance tests reported that reduction in PA was significant. Seven tests were adequately designed to detect a withdrawal versus offset effect. Over half (57%) displayed a U-shaped curve for abstinence-induced change in PA indicative of a withdrawal symptom rather than offset effect. CONCLUSIONS: Abstinence from cigarettes is associated with a decrease in PA. Whether low PA should be added to withdrawal measures and diagnostic criteria requires replication of the time-course of change in PA and tests of whether abstinence-induced changes in PA and negative affect occur independently. IMPLICATIONS: Though there was substantial heterogeneity among trials, our findings suggest that (1) abstinence from cigarettes decreases positive affect and (2) this decrease may represent a withdrawal effect (vs. an offset effect). However, it is unclear whether abstinence-induced losses in positive affect are independent from increased negative affect.

Surgery and opioids: evidence-based expert consensus guidelines on the perioperative use of opioids in the United Kingdom.

There are significant concerns regarding prescription and misuse of prescription opioids in the perioperative period. The Faculty of Pain Medicine at the Royal College of Anaesthetists have produced this evidence-based expert consensus guideline on surgery and opioids along with the Royal College of Surgery, Royal College of Psychiatry, Royal College of Nursing, and the British Pain Society. This expert consensus practice advisory reproduces the Faculty of Pain Medicine guidance. Perioperative stewardship of opioids starts with judicious opioid prescribing in primary and secondary care. Before surgery, it is important to assess risk factors for continued opioid use after surgery and identify those with chronic pain before surgery, some of whom may be taking opioids. A multidisciplinary perioperative care plan that includes a prehabilitation strategy and intraoperative and postoperative care needs to be formulated. This may need the input of a pain specialist. Emphasis is placed on optimum management of pain pre-, intra-, and postoperatively. The use of immediate-release opioids is preferred in the immediate postoperative period. Attention to ensuring a smooth care transition and communication from secondary to primary care for those taking opioids is highlighted. For opioid-naive patients (patients not taking opioids before surgery), no more than 7 days of opioid prescription is recommended. Persistent use of opioid needs a medical evaluation and exclusion of chronic post-surgical pain. The lack of grading of the evidence of each individual recommendation remains a major weakness of this guidance; however, evidence supporting each recommendation has been rigorously reviewed by experts in perioperative pain management.

Evaluation of Alitretinoin for the Treatment of Mycosis Fungoides and Sézary Syndrome.

BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). There is currently no cure for CTCL, and treatment is aimed at limiting disease progression. This study evaluated the efficacy and tolerability of alitretinoin in CTCL management. METHODS: A retrospective, multicenter study was conducted on CTCL patients treated with alitretinoin as a primary agent or in combination with standard therapies. RESULTS: Forty-eight patients with MF (n = 40) and SS (n = 8) with a median age of 59.7 years (±14.3) were eligible for study inclusion. Treatment response data were evaluated in 40 patients and safety in 42 patients. 40.0% of the patients had early-stage, 43.8% had advanced-stage CTCL, and in 16.7% of patients there was insufficient information for staging. 40.0% (16/40) of the patients achieved a complete or partial response, whereas 47.5% (19/40) achieved stable disease, 12.5% (5/40) had progressive disease, and there were no cases of disease relapses in responders. Both early and advanced stages of CTCL were responsive to alitretinoin as a primary or combined modality. Alitretinoin was well tolerated, and 64.3% (27/42) of patients did not report any side effects. The most commonly observed side effect was hypertriglyceridemia. CONCLUSIONS: This retrospective analysis supports the efficacy and safety of alitretinoin in clearing skin disease and preventing disease progression in CTCL as a monotherapy or in combination with standard therapies.

Reflections on New Evidence on Crisis Standards of Care in the COVID-19 Pandemic.

Crisis standards of care have been widely developed by healthcare systems and states in the United States during the COVID-19 pandemic, and in some rare cases have actually been used to allocate medical resources. All publicly available U.S. crisis standards of care with a mechanism for allocating scarce resources make use of the Sequential Organ Failure Assessment (SOFA) score in hopes of assigning scarce resources to those patients who are more likely to survive. We reflect on the growing body of evidence suggesting that the SOFA score has limited accuracy in predicting mortality among patients hospitalized with COVID-19 and that the SOFA score systematically disfavors Black patients. Use of the SOFA score for allocating scarce resources may therefore result in Black patients with equal likelihood of survival being deprived of life-saving medical resources. There is also a risk of injustice for patients with non-COVID-19 diagnoses, for whom the SOFA score may be a more accurate prognostic score, but who might nevertheless be unfairly (de)prioritized when assessed alongside COVID-19 patients using the same scoring system. For these reasons we recommend that the SOFA score not be used for triage purposes during the COVID pandemic, and that a national effort be made to develop and empirically test crisis standards of care in advance of the next public health emergency.

Abuse liability of cigarettes with very low nicotine content in pregnant cigarette smokers.

The U.S. Food and Drug Administration has proposed reducing the nicotine content of cigarettes to a minimally-addictive level. To our knowledge, this study is the first to examine how pregnant smokers respond to very low nicotine content (VLNC) cigarettes. In Phase 1, participants blindly sampled two VLNC cigarettes (0.4 and 2.4 mg/g of tobacco) and their usual brand (UB) cigarette in separate sessions, then completed a behavioral economic simulation task and measures of subjective effects, craving/withdrawal, and smoking topography. Phase 2 directly compared the relative reinforcing effects of the cigarettes using concurrent choice testing. All possible dose-pair combinations were tested in separate sessions where puffs were earned ad libitum by clicking the code associated with their preferred cigarette 10 times. Phase 3 tested the 0.4 mg/g-UB dose-pair where UB puffs could be earned with a progressively incremented number of clicks (maximum 8400). Ten pregnant smokers in Burlington, VT and Baltimore, MD participated in 2017-2018. Regarding abuse liability, participants chose the 0.4-mg/g dose less than UB (22% vs. 78%) during concurrent choice testing and the 0.4-mg/g dose sustained less demand than the 2.4-mg/g and UB doses on the simulation task. Positive subjective effects were also lower for both VLNC cigarettes vs. UB. Each cigarette reduced nicotine craving/withdrawal and no significant changes indicative of compensatory smoking were noted. Reducing the nicotine content of cigarettes may decrease their abuse liability in pregnant smokers without causing untoward craving/withdrawal or compensatory smoking. Studies of extended exposure to VLNCs in pregnant women are warranted.

Relating individual differences in nicotine dependence severity to underpinning motivational and pharmacological processes among smokers from vulnerable populations.

We examined whether elucidating underpinning smoking motivation and related pharmacological processes enhances understanding of nicotine dependence among smokers from vulnerable populations. Data were obtained between Oct, 2016 and Sept, 2019 from 745 adult smokers with co-morbid psychiatric conditions or socioeconomic disadvantage at University of Vermont, Brown University, Johns Hopkins University. Smoking motivation was assessed using the Cigarette Purchase Task (CPT), a behavioral-economic task that models the relative reinforcing value of smoking under varying monetary constraint. Dependence severity was measured using the Heaviness of Smoking Index (HSI), Fagerström Test for Nicotine Dependence total scores (FTND), and FTND total scores minus items 1 and 4 (FTND2,3,5,6). We also assessed associations between dependence severity and smoking motivation with nicotine levels and metabolism rate. Principal Component Analysis was used to examine the latent structure of the conventional five CPT indices; bivariate and multivariable modeling was used to test associations. Factor analysis resulted in a two-factor solution, Amplitude (demand unconstrained by price) and Persistence (price sensitivity). CPT latent factors were associated with each dependence-severity measure (ps ≤ 0.0001), with associations stronger for Amplitude than Persistence across each, especially HSI which was exclusively associated with Amplitude. Amplitude and each dependence measure were associated with nicotine intake (ps ≤ 0.0002); Persistence was not (p = .19). Demand Amplitude more than Persistence appears key to understanding individual differences in dependence severity. Regarding potential application, the results suggest a need for interventions that more effectively target demand Amplitude to make greater headway in reducing smoking in vulnerable populations. Trial Registration:clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

An Update on Hardening: A Qualitative Review.

INTRODUCTION: This review examines the evidence for the hardening hypothesis; that is, the prevalence of (1) becoming a former smoker is decreasing over time due to (2) decreased quit attempts, or (3) decreased success on a given quit attempt. METHODS: PubMed, EMBASE, PsychINFO, trial registries, and other databases were searched for population-based surveys that reported whether one of the aforementioned three outcomes decreased over time. RESULTS: None of the 26 studies found that conversion from current to former smoking, number of quit attempts, or success on a given quit attempt decreased over time and several found these increased over time. These results appeared to be similar across survey dates, duration of time examined, number of data points, data source, outcome definitions, and nationality. CONCLUSIONS: These results convincingly indicate hardening is not occurring in the general population of smokers. On the other hand, the prevalence of smoking is declining less among older and women smokers, and smokers with low education, low income, psychological problems, alcohol or drug abuse, medical problems, and greater nicotine dependence, than among those without these characteristics, presumably due to less quitting. Why this has not lead to decreased success in stopping smoking in the general population is unclear. IMPLICATIONS: Some have argued that a greater emphasis on harm reduction and more intensive or dependence-based treatments are needed because remaining smokers are those who are less likely to stop with current methods. This review finds no or little evidence for this assumption. Psychosocial factors, such as low education and psychiatric problems, predict less ability to quit and appear to becoming more prevalent among smokers. Why this is not leading to decreased quitting in the general population is an anomaly that may be worth trying to understand.