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HIV is an independent risk factor for heart failure (HF). However, the association of HIV severity with incident HF and the potential interaction with sex are incompletely understood.Integrated health care system.We conducted a cohort study of people with HIV (PWH) and matched people without HIV (PWoH), all aged ≥ 21 years and with no previous HF. Poisson regression was used to compare incident HF by HIV status, with PWH stratified by severity of HIV infection [defined by recent (6 months) CD4 count, nadir CD4 count, or recent HIV RNA level]. Models were adjusted for sociodemographic characteristics, substance use, and HF risk factors. Analyses were conducted for men and women combined, then by sex.The study included 38,868 PWH and 386,569 PWoH (mean baseline age = 41.0 ± 10.8 years; 88% men). Compared with PWoH, incident HF risk was higher among PWH with lower recent CD4 [200-499 cells/µL, adjusted rate ratio (aRR) = 1.82, 95% confidence interval (CI) = 1.50 to 2.21 and200 cells/µL, aRR = 3.26 (2.47 to 4.30)] and a low nadir CD4 [200 cells/µL, aRR = 1.56 (1.37 to 1.79)] but not among PWH with normal CD4 [≥500 cells/µL, aRR = 1.14 (0.90 to 1.44)]. Higher incident HF risk was observed among PWH at all HIV RNA levels, with greater HF risk at higher HIV RNA levels. The excess HF risk associated with low CD4 (recent or nadir) and high HIV RNA was stronger among women than men (P interactions=0.05, 0.08, and 0.01, respectively).Given the association of HIV severity with HF, optimizing HIV treatment and management may be important for HF prevention among PWH.

Transcatheter pulmonary valve (TPV) replacement (TPVR) has become the standard therapy for postoperative pulmonary outflow tract dysfunction in patients with a prosthetic conduit/valve, but there is limited information about risk factors for death or reintervention after this procedure.This study sought to evaluate mid- and long-term outcomes after TPVR in a large multicenter cohort.International registry focused on time-related outcomes after TPVR.Investigators submitted data for 2,476 patients who underwent TPVR and were followed up for 8,475 patient-years. A total of 95 patients died after TPVR, most commonly from heart failure (n = 24). The cumulative incidence of death was 8.9% (95% CI: 6.9%-11.5%) 8 years after TPVR. On multivariable analysis, age at TPVR (HR: 1.04 per year; 95% CI: 1.03-1.06 per year; P 0.001), a prosthetic valve in other positions (HR: 2.1; 95% CI: 1.2-3.7; P = 0.014), and an existing transvenous pacemaker/implantable cardioverter-defibrillator (HR: 2.1; 95% CI: 1.3-3.4; P = 0.004) were associated with death. A total of 258 patients underwent TPV reintervention. At 8 years, the cumulative incidence of any TPV reintervention was 25.1% (95% CI: 21.8%-28.5%) and of surgical TPV reintervention was 14.4% (95% CI: 11.9%-17.2%). Risk factors for surgical reintervention included age (0.95 per year [95% CI: 0.93-0.97 per year]; P 0.001), prior endocarditis (2.5 [95% CI: 1.4-4.3]; P = 0.001), TPVR into a stented bioprosthetic valve (1.7 [95% CI: 1.2-2.5]; P = 0.007), and postimplant gradient (1.4 per 10 mm Hg [95% CI: 1.2-1.7 per 10 mm Hg]: P 0.001).These findings support the conclusion that survival and freedom from reintervention or surgery after TPVR are generally comparable to outcomes of surgical conduit/valve replacement across a wide age range.

Werner, TJ, Pellinger, TK, Rosette, VD, and Ortlip, AT. Effects of a 12-week resistance training program on arterial stiffness: a randomized controlled trial. J Strength Cond Res 35(12): 3281-3287, 2021-Arterial stiffness is an indicator of disease and is an independent predictor of cardiovascular events. Some reports indicate that resistance training increases indices of arterial stiffness, whereas others report no association. This study sought to determine the association between 2 common resistance training models and indices of arterial stiffness. We recruited 30 male, untrained subjects (18-30 years) and randomized them into 1 of 3 groups: control (CON, n = 10), high-intensity resistance exercise (HI, n = 10), and high-volume resistance exercise (HV, n = 10). Subjects randomized to the resistance training groups were required to perform whole-body strength training exercises 3-5 days a week for 12 weeks. The exercise regimen consisted of 2-3 sets of 3-8 repetitions (80-90% of 1 repetition maximum [1RM]) for the HI group and 3-4 sets of 10-15 repetitions (50-70% of 1RM) for the HV group. Anthropometry, carotid artery diameters, peripheral and central blood pressure, and maximal dynamic strength were measured before and after the 12-week study period. Subjects were instructed to maintain their normal diet and avoid aerobic exercise during the study. After the intervention, both the HI and HV groups increased their maximal strength on the back squat, bench press, and seated row (all p0.05). However, there were no changes in arterial stiffness indices between the groups. Using a randomized controlled trial with validated measurements of arterial stiffness, chronic resistance training does not appear to influence central arterial stiffness, regardless of training volume and load.

BACKGROUND Donor-recipient size-matching has been repeatedly reported to improve outcomes following lung transplantation (LTx). However, there is significant variability in practice and the optimal strategy for size-matching is yet to be defined. For recipients with ILD, size-matching decisions are complicated by concerns regarding the potential impact of pre-LTx pulmonary restriction. We evaluate whether a specific donor-to-recipient size-matching strategy, based on predicted total lung capacity, benefits this patient group. METHODS This retrospective, single-centre, cohort study describes the post-LTx outcomes of adults who underwent LTx for ILD between 1983 and 2020. Only patients with restrictive physiology, based on pre-LTx pulmonary function testing were included. Post-LTx outcomes were compared based on donor-recipient predicted TLC (D-R pTLC) ratio. A D-R pTLC ratio of ≥0.8 or

Background The value of neoadjuvant treatment in combination with resection as multimodality therapy (MMT) for stage IIB non-small cell lung cancer remains controversial. Methods This was a national cohort study of patients with clinical stage IIB non-small cell lung cancer (2006 to 2015) that used the National Cancer Database. Cohorts were defined on the basis of the MMT sequence and were categorized as follows: surgery plus adjuvant chemotherapy (AC), surgery plus adjuvant chemoradiation (ACRT), neoadjuvant therapy plus surgery (NA), surgery-alone, and definitive chemotherapy or chemoradiation (nonsurgical). The primary comparison was between the NA and AC cohorts. Propensity matching methods were used to match cohorts who had AC vs NA. Multivariable Cox regression was used to analyze the difference in risk of death between the NA and AC groups. Results There were 10,841 patients with stage IIB lung cancer: 2476 in the AC, 854 with ACRT, 1195 with NA, 2019 with surgery alone, and 4297 with nonsurgical treatment. Of the 6544 patients who underwent surgery, 37.8% had AC, 13.1% had ACRT, 18.3% had NA, and 30.9% had surgery alone. Relative to those patients treated with AC, nonsurgical treatment (hazard ratio [HR], 2.92; 95% confidence interval [CI], 2.69 to 3.17) or surgery-alone (HR, 1.26; 95% CI, 1.14 to 1.38) was associated with a significantly higher risk of death. After propensity matching, there was no difference in the risk of death between the NA and AC cohorts (HR, 1.07; 95% CI, 0.88 to 1.31). Conclusions MMT, including surgical resection, is associated with improved OS, regardless of treatment sequence, with no difference in survival on the basis of an NA or AC approach. The potential benefits of NA over AC to ensure that patients complete MMT warrant further prospective investigation.

Understanding the effects of age on longitudinal traumatic brain injury (TBI) outcomes requires attention to both chronic and evolving TBI effects and age-related changes in health and function. The present study examines the independent and interactive effects of aging and chronicity on functional outcomes after TBI. We leveraged a well-defined cohort of individuals who sustained a moderate/severe TBI and received acute inpatient rehabilitation at specialized centers with high follow up rate as part of their involvement in the TBI Model Systems longitudinal study. We selected individuals at one of two levels of TBI chronicity (either 2 or 10 years post-injury) and used an exact matching procedure to obtain balanced chronicity groups based on age and other characteristics (N = 1993). We found that both older age and greater injury chronicity were related to greater disability, reduced functional independence, and less community participation. There was a significant age by chronicity interaction, indicating that the adverse effects of greater time post-injury were most pronounced among survivors who were age 75 or older. The inflection point at roughly 75 years of age was corroborated by post hoc analyses, dividing the sample by age at 75 years and examining the interaction between age group and chronicity. These findings point to a need for provision of rehabilitation services in the chronic injury period, particularly for those who are over 75 years old. Future work should investigate the underlying mechanisms of this interaction towards the goal of developing interventions and models of care to promote healthy aging with TBI.

Background Motivational messaging is a frequently used digital intervention to promote positive health behavior changes, including smoking cessation. Typically, motivational messaging systems have not actively sought feedback on each message, preventing a closer examination of the user-system engagement. This study assessed the granular user-system engagement around a recommender system (a new system that actively sought user feedback on each message to improve message selection) for promoting smoking cessation and the impact of engagement on cessation outcome. Methods We prospectively followed a cohort of current smokers enrolled to use the recommender system for 6 months. The system sent participants motivational messages to support smoking cessation every 3 days and used machine learning to incorporate user feedback (i.e., user’s rating on the perceived influence of each message, collected on a 5-point Likert scale with 1 indicating strong disagreement and 5 indicating strong agreement on perceiving the influence on quitting smoking) to improve the selection of the following message. We assessed user-system engagement by various metrics, including user response rate (i.e., the percent of times a user rated the messages) and the perceived influence of messages. We compared retention rates across different levels of user-system engagement and assessed the association between engagement and the 7-day point prevalence abstinence (missing outcome = smoking) by using multiple logistic regression. Results We analyzed data from 731 participants (13% Black; 73% women). The user response rate was 0.24 (SD = 0.34) and user-perceived influence was 3.76 (SD = 0.84). The retention rate positively increased with the user response rate (trend test P Conclusions High user-system engagement was positively associated with both high retention rate and smoking cessation, suggesting that investigation of methods to increase engagement may be crucial to increase the impact of the recommender system for smoking cessation. Trial registration Registration Identifier: NCT03224520. Registration date: July 21, 2017.

Microglial activation and tau accumulation propagate together in patients with Alzheimer's disease, suggesting an interaction that determines disease progression. Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([C-11]PBR28), amyloid-beta (A beta) ([F-18]AZD4694) and tau ([F-18]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [C-11]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of A beta, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A beta and activated microglia sets the pace for tau spread across Braak stages.

Objective: Patients with recurrent respiratory papillomatosis (RRP) have significant vocal dysfunction which affects their performance at work. This study aimed to evaluate voice-related work productivity before and after ablative treatment for RRP. Methods: This is a prospective case series conducted at 2 academic laryngology outpatient clinics. Adult employed patients with RRP completed the Work Productivity & Activity Impairment instrument (WPAI), Voice Handicap Index (VHI-10), WorkHoarse, Hospital Anxiety and Depression Scale (HADS), and a demographics questionnaire immediately before and 1 month after ablative treatment of papilloma. The primary outcome measure was the change in work productivity impairment domain of the WPAI, and changes in ratings before and after ablation were compared using a Wilcoxon Signed-Rank test. Results: The 32 participants (mean age 45, 84% male) had a median (interquartile range) voice-related work productivity impairment score of 48.8% (30.0) at baseline which was improved to 5.0% (10.0) at 1 month after surgical ablation of papillomata (difference 30.0% (30.0) improvement). For the secondary outcome measures, there were significant improvements in VHI-10 ( P Conclusion: Patients with RRP experience significant voice-related work productivity impairment, and ablation of papillomata significantly improves work productivity.

ObjectiveTo evaluate the frequency of and risk factors for stroke as a presenting feature in adult patients with secundum atrial septal defect (ASD); rates of post-closure atrial fibrillation (AF) and stroke were also assessed.MethodsWe retrospectively reviewed adult patients who presented with an ASD between 2002 and 2018, excluding those with known atrial arrhythmias. Risk factors for stroke were identified using multivariable logistic regression. Post-closure stroke was evaluated using survival analysis stratified by the presence of post-procedure AF.ResultsOf 346 patients with ASD (median age 44 years), 34 (10%) presented with a history of stroke. Independent risk factors included elevated body mass index over 25 (OR: 18.2; 95% CI: 4.0 to 82.2; pConclusionsIn this study population, the incidence of stroke prior to ASD closure among patients without atrial arrhythmias was 10%. Risk factors included obesity, smoking and prominent Eustachian valve anatomy. Lifestyle changes should be recommended for at-risk patients, and it may be reasonable to consider ASD closure in the absence of haemodynamic indications in patients at increased risk of stroke.

Objective Describe who is able to return to driving (RTD) after moderate-to-severe traumatic brain injury (TBI), when this occurs, who maintains that activity, and the association with outcome. Design Cross-sectional descriptive study. Setting Eight follow-up sites of the TBI Model Systems (TBIMS) program. Participants 618 participants enrolled in the TBIMS and 88 caregivers (N=706). Interventions Not applicable. Main Outcome Measures A survey was completed from 1-30 years postinjury focusing on RTD. Descriptors included demographic information, injury severity, and current employment status. Outcome was assessed at the time of the interview, including depression, quality of life, functional status, and community participation. Results Of 706 respondents, 78% (N = 552) RTD, but 14% (N = 77) of these did not maintain that activity. Of those who RTD, 43% (N = 192) did so within 6 months of the injury and 92% did so within 24 months postinjury. The percentage of people driving after TBI did not differ significantly based on age at time of injury or follow-up. There were significant differences between drivers and nondrivers with respect to severity of injury, seizures, race, education, employment, rural vs urban setting, marital status, and family income. We performed a multivariate logistic regression to examine the association between driving status and demographic variables, adjusting for other variables in the model. The strongest associations were with current employment, family income, race, seizures, and severity of injury. Driving was associated with greater community participation, better functional outcomes, fewer symptoms of depression, and greater life satisfaction. Conclusions Over a span of 30 years, three-quarters of people experiencing moderate-to-severe TBI return to driving a personal vehicle, although not everyone maintains this activity. Employment, race, family income, and seizures are strongly associated with RTD.

Limited data exist in large, representative populations about whether the risk of thromboembolic events varies after receiving four-factor human prothrombin complex concentrate (4F-PCC) versus treatment with human plasma for urgent reversal of oral vitamin K antagonist therapy. We conducted a multicenter observational study to compare the 45-day risk of thromboembolic events in adults with warfarin-associated major bleeding after treatment with 4F-PCC (Kcentra®) or plasma. Hospitalized patients in two large integrated healthcare delivery systems who received 4F-PCC or plasma for reversal of warfarin due to major bleeding from January 1, 2008 to March 31, 2020 were identified and were matched 1:1 on potential confounders and a high-dimensional propensity score. Arterial and venous thromboembolic events were identified up to 45 days after receiving 4F-PCC or plasma from electronic health records and adjudicated by physician review. Among 1119 patients receiving 4F-PCC and a matched historical cohort of 1119 patients receiving plasma without a recent history of thromboembolism, mean (SD) age was 76.7 (10.5) years, 45.6% were women, and 9.4% Black, 14.6% Asian/Pacific Islander, and 15.7% Hispanic. The 45-day risk of thromboembolic events was 3.4% in those receiving 4F-PCC and 4.1% in those receiving plasma (P = 0.26; adjusted hazard ratio 0.76; 95% confidence interval 0.49-1.16). The adjusted risk of all-cause death at 45 days post-treatment was lower in those receiving 4F-PCC compared with plasma. Among a large, ethnically diverse cohort of adults treated for reversal of warfarin-associated bleeding, receipt of 4F-PCC was not associated with an excess risk of thromboembolic events at 45 days compared with plasma therapy.

OBJECTIVES There are three surgical treatment options for patients with peritonsillar abscess (PTA): needle aspiration, incision and drainage (ID), and abscess tonsillectomy (ATE). The updated German national guideline (2015) included changes in the treatment of PTA. The indication for tonsillectomy (TE) in patients became more stringent and preference was given to ID in certain cases. STUDY DESIGN Retrospective analysis. METHODS We performed a retrospective systematic analysis of patient data using the in-house electronic patient records and considered a 4-year period from 2014 to 2017. About 584 patients were identified. Our aim was to analyze the influence of the updated guideline on clinical practice. RESULTS 236 of 584 patients (40.4%) underwent ATE with contralateral TE. In 225 patients (38.5%), unilateral ATE was performed. Mean surgery time was significantly shortened when only unilateral ATE was performed. Concerning postoperative bleeding, we noted a tendency toward a lower incidence after ATE in comparison to ATE with contralateral TE. Less than 1% of patients who underwent ATE had to be revised surgically due to postoperative hemorrhage. After the revision of the guideline, unilateral ATE and ID were conducted more frequently. CONCLUSION These results support that ATE in an inpatient setting is a considerably safe and effective primary therapeutic option. ID represents a favorable treatment option for patients with PTA and comorbidities, nevertheless, patient compliance is required and insufficient drainage or recurrence of PTA may occur. The revision of the guideline had a significant impact on the choice of interventions (P

Describe driving patterns following moderate-to-severe traumatic brain injury (TBI). Participants: Adults (N = 438) with TBI that required inpatient acute rehabilitation who had resumed driving.Cross-sectional, observational design.Eight TBI Model System sites.A driving survey was completed at phone follow-up.Most respondents reported driving daily, although 41% reported driving less than before their injury. Driving patterns were primarily associated with employment, family income, sex, residence, and time since injury, but not injury severity. Confidence in driving was high for most participants and was associated with a perception that the TBI had not diminished driving ability. Lower confidence and perceived loss of ability were associated with altered driving patterns.Most people with moderate-to-severe TBI resume driving but perhaps not at pre-injury or normal levels compared to healthy drivers. Some driving situations are restricted. The relationship between low confidence/perceived loss of ability and driving patterns/restrictions suggests people with TBI are exhibiting some degree of caution consistent with those perceptions. Careful assessment of driving skills and monitoring during early stages of RTD is warranted, particularly for younger, male, and/or single drivers who express higher levels of confidence.

Background A minimally invasive step-up approach to necrotizing biliary pancreatitis often requires multiple interventions, delaying cholecystectomy. The risk of gallstone-related complications during this time interval is unknown, as is the feasibility and safety of cholecystectomy after minimally invasive step-up treatment. In this paper, we analyzed both. Methods Necrotizing pancreatitis patients treated with a minimally invasive step-up approach who underwent interval cholecystectomy at 2 tertiary care centers between 2014 and 2019 were included. Gallstone-related complications prior to cholecystectomy were examined, as were surgical approaches to cholecystectomy and complications. Necrotizing pancreatitis patients treated without mechanical intervention were also examined. Results Seven of 31 patients developed gallstone-related complications between minimally invasive step-up treatment initiation and cholecystectomy. One patient developed biliary colic. Six patients developed acute cholecystitis. Two of these patients also developed choledocholithiasis, and 1 developed cholangitis, all requiring endoscopic retrograde cholangiopancreatography. Cholecystectomy was performed laparoscopically in 27 of 31 patients. One patient required open conversion, and 3 patients underwent planned cholecystectomy during another open operation. Four patients developed postoperative complications. Two of 14 necrotizing pancreatitis patients treated without mechanical intervention developed recurrent pancreatitis while awaiting cholecystectomy. Conclusion Over 20% of necrotizing pancreatitis patients treated by a minimally invasive step-up approach developed gallstone-related complications while awaiting cholecystectomy. Laparoscopic cholecystectomy is feasible and safe in the great majority of necrotizing pancreatitis patients treated by a minimally invasive step-up approach.

A 75-year-old male patient with suspicious cervical lymph nodes in level IV on the left side is presented. The cervical mass was detected in PSMA-PET-MRI as part of a restaging examination conducted due to an increase of PSA levels in the context of the patient's known prostate cancer. We conducted a selective cervical level IV lymphadenectomy with the aid of a gamma probe subsequent to radiolabelling withWir berichten über einen 75 Jahre alten Patienten mit suspekten linksseitig zervikalen Lymphknoten in Region IV. Detektiert wurden diese in der PSMA-PET-MRT (Prostataspezifisches Membranantigen-Positronenemissions-Magnetresonanztomographie) zum Restaging bei bekanntem Prostatakarzinom mit laborchemischem PSA(Prostataspezifisches Antigen)-Anstieg in der onkologischen Nachsorgeuntersuchung. Zur histologischen Sicherung wurde eine hochselektive Lymphadenektomie in der linksseitigen Region IV unter γ‑Sonden-Kontrolle nach

Landing biomechanics provide important information pertaining to second anterior cruciate ligament (ACL) injury risk in patients following ACL reconstruction (ACLR). While traditional motion analysis technologies are often impractical for use in non-laboratory settings, methods to assess landing biomechanics which are inexpensive, portable, and user-friendly have recently been developed and validated. The purpose of this study was to compare landing kinematics and kinetics between ACLR patients and uninjured controls in a non-laboratory setting. Sixteen ACLR patients (7 male/9 female, 6-12 months post-ACLR) and 16 gender-matched controls completed seven bilateral drop vertical jumps and seven unilateral drop landings on each limb. Plantar force was measured bilaterally using force sensing insoles and frontal and sagittal-plane knee kinematics were measured using two tablets, six reflective markers, and automated point tracking software. Plantar force impulse normalized symmetry index (NSI) and knee frontal plane projection angle (FPPA) range of motion were computed during bilateral landing, and knee flexion range of motion NSI was computed during unilateral landing and compared between groups using independent samples t tests. ACLR patients had larger NSIs (reflecting less symmetry) for plantar force impulse during bilateral landing (p < 0.001) and knee flexion range of motion during unilateral landing (p = 0.004). No between-group differences were observed for knee FPPA range of motion (p = 0.111). This study is an important step towards assessing landing biomechanics in non-research settings with the goal of providing quantitative injury risk metrics in a clinical setting that can be used for return to sport decision making.

BACKGROUND: Policy support research identifies demographic profiles of those who support policies, but community organizers aim to mobilize groups with an existing structure. Thus, identifying established groups that support alcohol policies may aid organizing efforts. OBJECTIVE: This paper calculates prevalence and odds of policy support among three potential constituency groups (i.e., religious affiliation, persons harmed by others’ drinking, and persons in recovery from alcohol) for three policies: alcohol tax increases, banning alcohol in corner stores, and universal coverage for alcohol treatment. METHODS: Using the 2014–15 National Alcohol Survey (n = 3,444; 1,457 male, 1,987 female) and logistic regression, this study explores associations between constituency groups and policy support. RESULTS: Support was higher for the individual-level strategy of alcohol treatment (80.8%) than raising taxes (27.5%) and banning sales in corner stores (52.2%). Support for taxes was higher among persons who valued religion highly (vs not; aOR = 1.46, p < .01), persons harmed by others’ drinking (vs not; aOR = 1.71, p < .001), and persons in recovery (vs. not; aOR = 1.76, p = .02); Catholics had lower odds of support for taxes (vs no denomination; aOR = 0.63, p = .01). Persons who valued religion highly (aOR = 1.53, p < .001), Protestants (aOR = 1.63, p < .01), Catholics (aOR = 1.46, p = .03), and persons with other religious denominations (aOR = 2.17, p = .02) had higher odds of supporting bans in corner stores. Only those in recovery showed greater support for treatment (aOR = 3.20, p < .001). CONCLUSION: Overall, support was lower for population-wide approaches, but results revealed constituency groups that supported these policies. These groups may be allies to organizers who seek to reduce population-level alcohol consumption and harms.

Aims Negative consequences of alcohol (or secondhand effects) extend beyond drinkers to affect other people, including both known others (friends, family members, spouses/partners) and strangers. Secondhand effects of alcohol manifest across various social environments, including the places where people drink and the neighborhoods where they live. These neighborhoods are characterized by different levels of alcohol availability and degrees of residential social cohesion. Hence, social environments may confer risk or protect from harms from others’ drinking. The current study explores: (a) how drinking venues and neighborhood contexts relate to harms from other people’s drinking (both known others and strangers), and (b) whether these associations vary by gender. Methods Using pooled data from the National Alcohol Survey and National Alcohol’s Harms to Others Survey (N = 5425), we regressed harms from various drinking others on social environment characteristics (drinking venues, alcohol availability and social cohesion) for the full sample and separately by gender. We used the false discovery rate method to adjust for multiple testing. Results Overall, greater neighborhood social cohesion was associated with lower odds of harm from drinking others and, specifically, harm from drinking strangers. The effect of social cohesion was most pronounced for men. Conclusions Social cohesion was the most salient neighborhood factor associated with reduced alcohol-related harms from strangers. Directions for future research and policies to mitigate these harms are discussed.

Cancer-associated cachexia, characterized by muscle wasting, is a lethal metabolic syndrome without defined etiology or established treatment. We previously found that p300 mediates cancer-induced muscle wasting by activating C/EBPβ, which then upregulates key catabolic genes. However, the signaling mechanism that activates p300 in response to cancer is unknown. Here, we show that upon cancer-induced activation of Toll-like receptor 4 in skeletal muscle, p38β MAPK phosphorylates Ser-12 on p300 to stimulate C/EBPβ acetylation, which is necessary and sufficient to cause muscle wasting. Thus, p38β MAPK is a central mediator and therapeutic target of cancer-induced muscle wasting. In addition, nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38β MAPK, inhibited p300 activation 20-fold more potently than the p38α/β MAPK inhibitor, SB202190, and abrogated cancer cell–induced muscle protein loss in C2C12 myotubes without suppressing p38α MAPK–dependent myogenesis. Systemic administration of nilotinib at a low dose (0.5 mg/kg/day, i.p.) in tumor-bearing mice not only alleviated muscle wasting, but also prolonged survival. Therefore, nilotinib appears to be a promising treatment for human cancer cachexia due to its selective inhibition of p38β MAPK. Significance: These findings demonstrate that prevention of p38β MAPK–mediated activation of p300 by the FDA-approved kinase inhibitor, nilotinib, ameliorates cancer cachexia, representing a potential therapeutic strategy against this syndrome.

Summary Background People with epilepsy are burdened with the apparent unpredictability of seizures. In the past decade, converging evidence from studies using chronic EEG (cEEG) revealed that epileptic brain activity shows robust cycles, operating over hours (circadian) and days (multidien). We hypothesised that these cycles can be leveraged to estimate future seizure probability, and we tested the feasibility of forecasting seizures days in advance. Methods We did a feasibility study in distinct development and validation cohorts, involving retrospective analysis of cEEG data recorded with an implanted device in adults (age ≥18 years) with drug-resistant focal epilepsy followed at 35 centres across the USA between Jan 19, 2004, and May 18, 2018. Patients were required to have had 20 or more electrographic seizures (development cohort) or self-reported seizures (validation cohort). In all patients, the device recorded interictal epileptiform activity (IEA; ≥6 months of continuous hourly data), the fluctuations in which helped estimate varying seizure risk. Point process statistical models trained on initial portions of each patient's cEEG data (both cohorts) generated forecasts of seizure probability that were tested on subsequent unseen seizure data and evaluated against surrogate time-series. The primary outcome was the percentage of patients with forecasts showing improvement over chance (IoC). Findings We screened 72 and 256 patients, and included 18 and 157 patients in the development and validation cohorts, respectively. Models incorporating information about multidien IEA cycles alone generated daily seizure forecasts for the next calendar day with IoC in 15 (83%) patients in the development cohort and 103 (66%) patients in the validation cohort. The forecasting horizon could be extended up to 3 days while maintaining IoC in two (11%) of 18 patients and 61 (39%) of 157 patients. Forecasts with a shorter horizon of 1 h, possible only for electrographic seizures in the development cohort, showed IoC in all 18 (100%) patients. Interpretation This study shows that seizure probability can be forecasted days in advance by leveraging multidien IEA cycles recorded with an implanted device. This study will serve as a basis for prospective clinical trials to establish how people with epilepsy might benefit from seizure forecasting over long horizons. Funding None. Video Abstract Download : Download video (38MB) Forecasting seizure risk over days In this video abstract, the authors review the discovery of cycles of epileptic brain activity. They explain the computational advances that made seizure forecasting possible and the practical implications of providing personalised seizure risk forecasts days in advance. https://youtu.be/z-SJV8TBbPE

Introduction: Medication nonadherence contributes to poor blood pressure control and increases cardiovascular disease risk in patients with hypertension. Identifying modifiable risk factors for low or nonadherence to antihypertensive medication is needed. Studies that have examined the relationship between herbal or dietary supplement (HDS) use and antihypertensive medication nonadherence provide inconsistent findings. Data from the National Health and Nutrition Examination Survey were used to examine the association between HDS use, current use of prescribed antihypertensive medication, and blood pressure status. Methods: The study sample included hypertensive adults (n = 5,478) who have been told by a health professional to take prescribed medication for their health condition. Respondents were classified as either HDS users or HDS nonusers. Depending on the kind of supplement used, HDS users were further divided into three mutually exclusive groups: hypertension HDS users, nonhypertension HDS users, and those who used both kinds of supplements. Supplements groupings were based on reports in the literature. Blood pressure status definition was based on Eighth Joint National Committee (JNC 8) recommendations. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were obtained from logistic models. Results: Overall HDS use prevalence was 62%. Current medication use did not significantly differ between patients reporting no HDS use and those reporting HDS use (aOR: 1.45; 95% CI: 0.78–2.69). No observable differences were found in current medication use between patients reporting no HDS use and those taking nonhypertension HDS or both kinds of supplements. Use of hypertension HDS was associated with improved blood pressure (aOR: 1.90; 95% CI: 1.07–3.36) compared with no HDS use. Conclusion: In a nationally representative U.S. sample, HDS use did not compromise current use of prescribed medication and was associated with improved blood pressure control. More research is needed to better understand why HDS use is associated with better blood pressure control.

Purpose: Due to discrimination and stigma, sexual minority adults may be more likely than their heterosexual counterparts to experience harms from other people's drinking. We compared prevalence of second-hand alcohol harms for sexual minority and heterosexual adults in the United States. Methods: Data from the 2014–15 U.S. National Alcohol Survey (n = 5516; 10.2% sexual minority adults) were analyzed using logistic regression with survey weights to account for sampling and nonresponse. Multivariable models included simple main effects of sexual identity on the past-year harm outcomes, as well as interactions of drinker status with sexual identity. Results: In bivariate results stratified by sex, bisexual women were significantly more likely than heterosexual women to report all five types of harms. Lesbian respondents had greater odds relative to heterosexual women of reporting harm by a friend/coworker and assault or physical harm by a drinker. Bisexual identity among men was associated with greater odds of reporting assault/physical harm relative to heterosexual men in bivariate models. In adjusted models, differences by sexual identity were substantially reduced, with significance remaining only for friend/coworker-perpetrated harms and assault/physical harm among lesbian respondents compared with heterosexual women. For assault/physical harm, an interaction of sexual identity with the respondent's own drinking showed that the increased odds of harm associated with heavy drinking was even greater among sexual minority respondents (both bisexual and lesbian/gay respondents) than among heterosexual respondents. Conclusion: These findings underscore the importance of preventive interventions that consider disparities in risk for alcohol-related harms, particularly interpersonal violence, among sexual minority adults in the United States.

Alzheimer’s disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques—liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181—to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden’s index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548–0.691) and phospho-tau181 (0.707; 0.646–0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770–0.864 and amyloid-β composite: 0.820; 0.775–0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10–50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence., Keshavan et al. show that plasma Aβ1-42/1-40 and a plasma Aβ composite measured by liquid chromatography–mass spectrometry perform better than various blood biomarkers measured by single molecular array, and better than age, sex and APOE ε4, in screening for preclinical Alzheimer’s disease in the British 1946 birth cohort.

Background Patients with necrotizing pancreatitis (NP) have the highest rate of venous thromboembolism (VTE) of any hospitalized patient (57%). We hypothesized that VTE prophylaxis might be inadequate in the setting of this profound inflammatory disease and that early detection of deep vein thrombosis would limit pulmonary embolism. Study Design All patients with NP treated at a single center between August 2018 and December 2019 were enrolled in prospective, weekly VTE screening, including 4-extremity duplex ultrasound. Routine chemoprophylaxis included low-molecular-weight or unfractionated heparin. Peak serum anti-factor Xa concentration was measured during weekly screening (goal prophylaxis 0.2 to 0.4 IU/mL). Results Eighty-five patients with NP underwent a total of 201 screening events (mean 2.4 per patient). VTE developed in 55 patients (65%), including splanchnic vein thrombosis in 41 patients (48%) and extremity deep vein thrombosis (eDVT) in 32 patients (38%). Extremity DVT was diagnosed a mean ± SD of 44 ± 30 days after NP onset. Symptomatic pulmonary embolism was prevented in all patients diagnosed with eDVT and no contraindication to anticoagulation (0 of 29). Prophylactic anti-factor Xa concentration was only achieved in 21% (12 of 57 screening events); no eDVTs developed in patients achieving prophylactic anti-factor Xa concentration. Conclusions In patients with NP, identification of eDVT by screening ultrasound permits early treatment and prevents symptomatic pulmonary embolism. Fixed dosing of chemical prophylaxis is inadequate in most patients with NP and likely contributes to the mechanism of increased VTE in NP.

Introduction This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD.