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With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5-7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P

BackgroundPavlovian fear paradigms involve learning to associate cues with threat or safety. Aberrances in Pavlovian fear learning correlate with psychopathology, especially anxiety disorders. This study evaluated symptom dimensions of anxiety and depression in relation to Pavlovian fear acquisition and generalization.Methods256 participants (70.31 % female) completed a Pavlovian fear acquisition and generalization paradigm at ages 18-19 and 21-22 years. Analyses focused on indices of learning (self-reported US expectancy, skin conductance). Multilevel models tested associations with orthogonal symptom dimensions (Anhedonia-Apprehension, Fears, General Distress) at each timepoint.ResultsAll dimensions were associated with weaker acquisition of US expectancies at each timepoint. Fears was associated with overgeneralization only at age 21-22. General Distress was associated with overgeneralization only at age 18-19. Anhedonia-Apprehension was associated with overgeneralization at ages 18-19 and 21-22.ConclusionsAnhedonia-Apprehension disrupts Pavlovian fear acquisition and increases overgeneralization of fear. These effects may emerge during adolescence and remain into young adulthood. General Distress and Fears also contribute to overgeneralization of fear, but these effects may vary as prefrontal mechanisms of fear inhibition continue to develop during late adolescence. Targeting specific symptom dimensions, particularly Anhedonia-Apprehension, may decrease fear generalization and augment interventions built on Pavlovian principles, such as exposure therapy.

BackgroundAdolescent behaviors and academic outcomes are thought to be shaped by school climate. We sought to identify longitudinal associations between school climate measures and downstream health and academic outcomes.MethodsData from a longitudinal survey of public high school students in Los Angeles were analyzed. Eleventh-grade health and academic outcomes (dependent variables, eg, substance use, delinquency, risky sex, bullying, standardized exams, college matriculation), were modeled as a function of 10th-grade school climate measures (independent variables: institutional environment, student-teacher relationships, disciplinary style), controlling for baseline outcome measures and student/parental covariates.ResultsThe 1114 student respondents (87.8% retention), were 46% male, 90% Latinx, 87% born in the United States, and 40% native English speakers. Greater school order and teacher respect for students were associated with lower odds of multiple high risk behaviors including 30-day alcohol use (odds ratio [OR] 0.81; 95% confidence interval [CI] [0.72, 0.92] and OR 0.73; [0.62, 0.85]) and 30-day cannabis use (OR 0.74; [0.59, 0.91] and OR 0.76; [0.63, 0.92]). Neglectful disciplinary style was associated with multiple poor health and academic outcomes while permissive disciplinary style was associated with favorable academic outcomes.Implications for school health policy, practice, and equitySchool health practitioners may prospectively leverage school environment, teacher-student relationships, and disciplinary style to promote health and learning.ConclusionsOur findings identify specific modifiable aspects of the school environment with critical implications for life course health.

BackgroundCOVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited.MethodsWe conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19.ResultsWe followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p

BackgroundOlder adults are the least active population in the U.S. Low-income communities have fewer physical activity (PA) resources, contributing to less PA and increased chronic disease risk. This study assessed the effect of the multilevel, peer-led, Peer Empowerment Program 4 Physical Activity (PEP4PA) on moderate-to-vigorous PA (MVPA) and health outcomes, over 2 years of follow up.MethodsIn a cluster-randomized controlled trial, 12 senior or community centers serving low-income older adults were assigned to a PA intervention (n = 6) or usual programming (n = 6) condition. PEP4PA included self-monitoring, health coaching, group walks, social support, and community advocacy to improve walking conditions. The primary outcome was daily minutes of MVPA (7-day accelerometer). Secondary outcomes included Perceived Quality of Life (PQoL), 6-Minute Walk Test (6-MWT), blood pressure (BP), and depressive symptoms at baseline, 6, 12, 18 and 24 months. Mixed effects regression models estimated the effects on outcomes between groups over time and included random effects for repeated measures and center clustering. Effect modification by sex and income status was assessed. We calculated the incremental cost per daily minute of MVPA gained in the intervention group relative to the control group to assess cost effectiveness.ResultsWe enrolled 476 older adults (50 + years). Participants were on average 71 years old, 76% female, 60% low income, and 38% identified as racial or ethnic minorities. Compared to the control group, intervention participants sustained roughly a 10 min/day increase in MVPA from baseline at all time points and increased mean PQoL scores from unsatisfied at baseline to satisfied at 12, 18 and 24 months. Males and higher-income groups had greater improvements in MVPA. No significant effects were observed for 6-MWT or depressive symptoms, and BP results were mixed. The incremental cost per minute MVPA gained per person was $0.25, $0.09, $0.06, and $0.05 at 6, 12, 18 and 24 months, respectively.ConclusionsPEP4PA achieved increases in MVPA and PQoL in low-income older adults, over 2 years of follow up. The peer-led, community-based intervention provides a sustainable and cost-effective model to improve health behaviors in underserved, aging populations.Trial registrationClinicalTrials.gov ( NCT02405325 ) March 20, 2015.

Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the US, partly due to the increasing incidence of metabolic syndrome, obesity, and type 2 diabetes. The roles of bile acids and their receptors, such as the nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, on the development of NASH are not fully clear. C57BL/6J male mice fed a Western diet (WD) develop characteristics of NASH, allowing determination of the effects of FXR and TGR5 agonists on this disease. Here we show that the FXR-TGR5 dual agonist INT-767 prevents progression of WD-induced hepatic steatosis, inflammation, and fibrosis, as determined by histological and biochemical assays and novel label-free microscopy imaging techniques, including third harmonic generation, second harmonic generation, and fluorescence lifetime imaging microscopy. Furthermore, we show INT-767 decreases liver fatty acid synthesis and fatty acid and cholesterol uptake, as well as liver inflammation. INT-767 markedly changed bile acid composition in the liver and intestine, leading to notable decreases in the hydrophobicity index of bile acids, known to limit cholesterol and lipid absorption. In addition, INT-767 upregulated expression of liver p-AMPK, SIRT1, PGC-1α, and SIRT3, which are master regulators of mitochondrial function. Finally, we found INT-767 treatment reduced WD-induced dysbiosis of gut microbiota. Interestingly, the effects of INT-767 in attenuating NASH were absent in FXR-null mice, but still present in TGR5-null mice. Our findings support treatment and prevention protocols with the dual FXR-TGR5 agonist INT-767 arrest progression of WD-induced NASH in mice mediated by FXR-dependent, TGR5-independent mechanisms.

Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76±5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95% CI, 0.99-1.26]), total DHT (HR, 1.10 [95% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.

Background The PET tracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) targets the system xC- cotransporter, which is overexpressed in various tumors. Purpose To assess the role of 18F-FSPG PET/CT in intracranial malignancies. Materials and Methods Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain 18F-FSPG PET/CT scan and a static whole-body (WB) 18F-FSPG PET/CT scan at 60-75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the 18F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. Results 18F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6-150.3). When 18F-FDG PET was performed, 18F-FSPG permitted visualization of non-18F-FDG-avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant Ki and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the 18F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. Conclusion PET/CT imaging with (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in 18F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.

ObjectiveCurrent lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment.MethodsWe quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients.ResultsOur analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in LN kidneys. IL-16-producing cells were found at key sites of kidney injury.ConclusionUrine proteomics may profoundly change the diagnosis and management of LN by noninvasively monitoring active intrarenal biologic pathways. These findings implicate IL-16 in LN pathogenesis, designating it as a potentially treatable target and biomarker.

Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia. Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort. Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs. Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.

HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.

BackgroundHIV testing is the gateway to HIV treatment and prevention. HIV self-testing (HIVST) has potential to increase testing; however, the potential population-level impact of HIVST on the HIV epidemic and the best strategies for promoting HIVST are unknown. Our aim is to inform public health approaches for promoting HIVST as part of a comprehensive strategy to reduce HIV incidence.MethodsStochastic network-based HIV transmission models were used to estimate how different HIVST strategies would affect HIV incidence in Seattle and Atlanta over 10 years. We included four types of HIV testers and implemented nine replacement and eleven supplementation strategies for HIVST.ResultsReplacement of clinic-based tests with HIVST increased HIV incidence in Seattle and Atlanta. The benefits of supplementary strategies depended on the tester type using HIVST. Targeting non-testers averted the highest number of cases per test. In Seattle 2.2 (95%SI=-77, 100.4) and 4.7 (95%SI=-35.7, 60.1) infections were averted per 1000 HIVST when non-testers used HIVST once or twice per year respectively. In Atlanta the comparable rates were 8.0 (95%SI=-60.3 to 77.7) and 6.7 (95%SI=-37.7, 41.0). Paradoxically, increasing testing among risk-based testers using HIVST increased incidence.ConclusionsThe population-level impact of HIVST depends on who is reached with HIVST, how kits are used, and by characteristics of the underlying epidemic and HIV care infrastructure. Targeted HIVST can be an effective component of a comprehensive HIV testing strategy. More work is needed to understand how to identify and target non-testers for self-testing implementation.

IntroductionSitting patterns predict several healthy aging outcomes. These patterns can potentially be measured using hip-worn accelerometers, but current methods are limited by an inability to detect postural transitions. To overcome these limitations, we developed the Convolutional Neural Network Hip Accelerometer Posture (CHAP) classification method.MethodsCHAP was developed on 709 older adults who wore an ActiGraph GT3X+ accelerometer on the hip, with ground-truth sit/stand labels derived from concurrently worn thigh-worn activPAL inclinometers for up to 7 d. The CHAP method was compared with traditional cut-point methods of sitting pattern classification as well as a previous machine-learned algorithm (two-level behavior classification).ResultsFor minute-level sitting versus nonsitting classification, CHAP performed better (93% agreement with activPAL) than did other methods (74%-83% agreement). CHAP also outperformed other methods in its sensitivity to detecting sit-to-stand transitions: cut-point (73%), TLBC (26%), and CHAP (83%). CHAP's positive predictive value of capturing sit-to-stand transitions was also superior to other methods: cut-point (30%), TLBC (71%), and CHAP (83%). Day-level sitting pattern metrics, such as mean sitting bout duration, derived from CHAP did not differ significantly from activPAL, whereas other methods did: activPAL (15.4 min of mean sitting bout duration), CHAP (15.7 min), cut-point (9.4 min), and TLBC (49.4 min).ConclusionCHAP was the most accurate method for classifying sit-to-stand transitions and sitting patterns from free-living hip-worn accelerometer data in older adults. This promotes enhanced analysis of older adult movement data, resulting in more accurate measures of sitting patterns and opening the door for large-scale cohort studies into the effects of sitting patterns on healthy aging outcomes.

BackgroundMultiple myeloma (MM) is an incurable cancer with complex treatment options. Trusting patient-clinician relationships are essential to promote effective shared decision-making that aligns best clinical practices with patient values and preferences. This study sought to shed light on the development of trust between MM patients and clinicians.MethodsNineteen individual semi-structured interviews were conducted with MM patients within 2 years of initial diagnosis or relapse for this qualitative study. Interviews were recorded and transcripts were coded thematically.ResultsWe identified three main themes: (1) externally validated trust describes patients' predisposition to trust or distrust clinicians based on factors outside of patient-clinician interactions; (2) internally validated trust describes how patients develop trust based on interactions with specific clinicians. Internally validated trust is driven primarily by clinician communication practices that demonstrate competence, responsiveness, listening, honesty, and empathy; and (3) trust in relation to shared decision-making describes how patients relate the feeling of trust, or lack thereof, to the process of shared decision-making.ConclusionMany factors contribute to the development of trust between MM patients and clinicians. While some are outside of clinicians' control, others derive from clinician behaviors and interpersonal communication skills. These findings suggest the possibility that trust can be enhanced through communication training or shared decision-making tools that emphasize relational communication. Given the important role trust plays in shared decision-making, clinicians working with MM patients should prioritize establishing positive, trusting relationships.

In this study, we developed angiotensin-converting enzyme 2 (ACE2)-specific, peptide-derived 68Ga-labeled radiotracers, motivated by the hypotheses that ACE2 is an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and that modulation of ACE2 in coronavirus disease 2019 (COVID-19) drives severe organ injury. Methods: A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears 2 cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with 68Ga to generate peptide radiotracers (68Ga-NOTA-PEP). The aminocaproate-derived radiotracer 68Ga-NOTA-PEP4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model. Results: Cyclic DX-600-derived peptides had markedly lower half-maximal inhibitory concentrations than their linear counterparts. The 3 cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated half-maximal inhibitory concentrations similar to or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga, and the biodistribution of 68Ga-NOTA-PEP4 was determined in an hACE2 transgenic murine cohort. Pharmacologic concentrations of coadministered NOTA-PEP (blocking) showed a significant reduction of 68Ga-NOTA-PEP4 signals in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to in vivo results. Conclusion: NOTA-conjugated cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer, 68Ga-NOTA-PEP4, showed specific binding in the heart, liver, lungs and intestine-organs known to be affected in SARS-CoV-2 infection. These results suggest that 68Ga-NOTA-PEP4 could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2-infected murine models and COVID-19 patients.

According to US Customs and Border Protection, over 473,000 family units and 76,000 unaccompanied children were apprehended in 2019, a multi-fold increase from previous years. Thus, the number of children who may be eligible for humanitarian relief has increased significantly. For those claiming humanitarian relief, forensic medical evaluations performed by health professionals can provide critical evidence to bolster claims. In this cross-sectional, nationwide survey-in which we sought to characterize specialties, forensic training, capacity, and scope of humanitarian relief evaluations for immigrant children under eighteen-years-old-only 28 providers, half of whom were Child Abuse Pediatricians, reported performing humanitarian relief evaluations. The most common reported type of humanitarian relief evaluation conducted was for asylum. We found that the current training for forensic medical evaluations for humanitarian relief in pediatrics is likely varied not well-defined, and not pediatric-specific. In order to protect the rights of children who are eligible for humanitarian relief, pediatric and family medicine forensic medical evaluation training standards and curricula need to be developed; validated humanitarian relief screening tools need to be tested and utilized; and residents and attending physicians, including specialists with expertise in forensic evaluations, need to be actively recruited to perform these evaluations in collaboration with legal aid organizations.

BackgroundSolriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA (37.5-150 mg/d).Research questionDoes solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use?Study design and methodsParticipants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated.ResultsAt baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, -2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were -2.4 (95% CI, -4.2 to -0.5), -1.3 (95% CI, -3.1 to 0.5), -4.2 (95% CI, -5.7 to -2.7), and -4.7 (95% CI, -6.1 to -3.2) and among nonadherent participants were -0.7 (95% CI, -3.5 to 2.1), -2.6 (95% CI, -5.4 to 0.1), -5.0 (95% CI, -7.2 to -2.9), and -4.6 (95% CI, -7.0 to -2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol.InterpretationSolriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol.Trial registryClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu.

This study employed novel GPS methods to assess the effect of a multilevel physical activity (PA) intervention on device-measured walking locations in 305 community dwelling older adults, ages 65+ (mean age = 83, 73% women). Retirement communities were randomized to a 1-year PA intervention that encouraged neighborhood walking, or to a healthy aging control condition. Total time and time spent walking in four life-space domains were assessed using GPS and accelerometer devices. The intervention increased the time spent walking as a proportion of total time spent in the Campus, Neighborhood and Beyond Neighborhood domains. Intervention effects on walking location were observed in both genders and across physical and cognitive functioning groups. Results demonstrate that an intervention providing individual, social and environmental support for walking can increase PA in larger life-space domains for a broad spectrum of older adults.

BACKGROUND: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. METHOD: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. FINDINGS: Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. INTERPRETATION: To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. FUNDING: F Hoffmann-La Roche/Genentech.

Background: Palliative care-related postdoctoral training opportunities are critical to increase the quantity and quality of palliative care research. Objective: To describe the history, activities, challenges, and future goals of the National Postdoctoral Palliative Care Research Training Collaborative. Design: National web-based survey of participating program leaders. Measurements: Information about participating programs, trainees, challenges faced, and future goals. Results: Nine participating programs at academic institutions across the United States focus on diverse aspects of palliative care research. The majority of 73 current and former fellows are female (75%) and white (84%). In total, 38% of fellows (n = 28) have MD backgrounds, of whom less than half (n = 12) completed hospice and palliative medicine fellowships. An additional 38% of fellows (n = 28) have nursing PhD backgrounds and 23% (n = 17) have other diverse types of PhD backgrounds. Key challenges relate to recruiting diverse trainees, fostering a shared identity, effectively advocating for trainees, and securing funding. Future goals include expanding efforts to engage clinician and nonclinician scientists, fostering the pipeline of palliative care researchers through expanded mentorship of predoctoral and clinical trainees, increasing the number of postdoctoral palliative care training programs, and expanding funding support for career development grants. Conclusion: The National Postdoctoral Palliative Care Research Training Collaborative fills an important role in creating a community for palliative care research trainees and developing strategies to address shared challenges.

ObjectiveThe impact of cognitive function and decline on political ideology is unknown. We studied the relationship between cognition and both political orientation and political policy choices in a population of older persons.DesignLongitudinal investigation.SettingA retirement community and its surroundings in Southern California.Participants151 members of a longitudinal investigation of aging and dementia in the oldest-old (the 90+ Study), mean age 95 years.MeasurementsParticipants self-reported their political ideology (7-point scale from extremely liberal to extremely conservative) and policy preferences for federal spending on public schooling, aid to the poor, and protecting the environment, as well as on preferences on immigration rates, death penalty, and university admission. The same political survey was mailed to participants twice: at time one and 6-months later. Cognitive function based on neurological examination and cognitive testing was classified as normal (55%), cognitive impairment/not dementia (CIND) (33%), or dementia (12%). We calculated rank correlations between ideology and policy choices, stratified by cognitive status, and agreement between Surveys 1 and 2.ResultsPolitical ideology/orientation was highly consistent over a six-month period (84% agreement) among the 122 who returned the second survey, with no significant relationship to cognitive status. Among cognitively impaired (CIND and dementia), however, there was significant loss of consistency between an individual's political orientation and their policy choices. Level of political engagement was high for participants, with more than 90% voting in the 2016 presidential election.ConclusionIn this population of older persons, political identification on the liberal-conservative spectrum was resilient despite cognitive decline, but its meaning and function were changed. For the cognitively impaired it remained a self-defining label, but no longer operated as a higher order framework for orienting specific policy preferences. There appeared to be loss of coherence between the political orientation and political policy choices of cognitively impaired individuals. Given the high level of political engagement of these individuals, these results have substantial public policy implications.

Human serum albumin (HSA) constitutes the primary transporter of fatty acids, bilirubin, and other plasma compounds. The binding, transport, and release of its cargos strongly depend on albumin conformation, which is affected by bound ligands induced by physiological and pathological conditions. HSA is both highly oxidized and heavily loaded with fatty acids and bilirubin in chronic liver disease. By employing small-angle X-ray scattering we show that HSA from the plasma of chronic liver disease patients undergoes a distinct opening compared to healthy donors. The extent of HSA opening correlates with clinically relevant variables, such as the model of end-stage liver disease score, bilirubin, and fatty acid levels. Although the mild oxidation of HSA in vitro does not alter overall structure, the alteration of patients' HSA correlates with its redox state. This study connects clinical data with structural visualization of albumin dynamicity in solution and underlines the functional importance of albumin's inherent flexibility.

BackgroundFew studies characterize older adult physical activity and sitting patterns using accurate accelerometer and concurrent posture measures. In this descriptive paper, we report accelerometer data collection protocols, consent rates, and physical behavior measures from a population-based cohort study (Adult Changes in Thought, ACT).MethodsThe ACT study holds enrollment steady at approximately 2000 members of Kaiser Permanente Washington aged 65+ without dementia undergoing detailed biennial assessments. In 2016 the ACT-Activity Monitor (ACT-AM) sub-study was initiated to obtain data from wearing activPAL and ActiGraph devices for 7 days following regular biennial visits. We describe the methods protocol of ACT-AM and present characteristics of people who did and did not consent to wear devices. We compute inverse probability of response weights and incorporate these weights in linear regression models to estimate means and 95% confidence intervals (CI) of device-based pattern metrics, adjusted for wear time and demographic factors, and weighted to account for potential selection bias due to device-wear consent.ResultsAmong 1885 eligible ACT participants, 56% agreed to wear both devices (mean age 77 years, 56% female, 89% non-Hispanic white, 91% with post-secondary education). On average, those who agreed to wear devices were younger and healthier. Estimated mean (95% CI) activPAL-derived sitting, standing, and stepping times were 10.2 h/day (603-618 min/day), 3.9 h/day (226-239 min/day), and 1.4 h/day (79-84 min/day), respectively. Estimated mean ActiGraph derived sedentary (Vector Magnitude [VM]  518 counts/15 s) physical activity durations were 9.5 h/day (565-577 min/day), 4.5 h/day (267-276 min/day), and 1.0 h/day (59-64 min/day). Participants who were older, had chronic conditions, and were unable to walk a half-mile had higher sedentary time and less physical activity.ConclusionsOur recruitment rate demonstrates the feasibility of cohort participants to wear two devices that measure sedentary time and physical activity. Data indicate high levels of sitting time in older adults but also high levels of physical activity using cut-points developed for older adults. These data will help researchers test hypotheses related to physical behavior and health in older adults in the future.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.

BackgroundWhether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown.ObjectiveWe sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma.MethodsBacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines.ResultsSputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders.ConclusionsNovel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.

Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2 .

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

IntroductionEverolimus and bendamustine both have single-agent activity against lymphoid hematologic malignancies. We examined this combination in a group of heavily pretreated patients with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM).Patients and methodsIn this phase I trial, 18 patients (8 with NHL, 6 with MM, and 4 with HL) were treated with bendamustine 90 mg/m2 on days 1 and 2 and everolimus from 5 to 10 mg daily on a 28-day cycle, for up to 4 cycles.ResultsAdverse events were generally mild and mostly hematologic in nature. The most frequent grade 3/4 adverse events were lymphopenia (61%), thrombocytopenia (22%), leukopenia (22%), neutropenia (17%), and fatigue (17%). Overall response rate varied by malignancy: diffuse large B-cell lymphoma, 20% (1 of 5 patients); HL (2 of 4 patients), 50%; MM, 80% (4 of 5 patients); and indolent lymphomas, 100% (3 of 3 patients). The maximum tolerated dose of everolimus was determined to be 7.5 mg daily.ConclusionThe combination of everolimus and bendamustine appeared to be well-tolerated and relatively efficacious.

Working memory function changes across development and varies across individuals. The patterns of behavior and brain function that track individual differences in working memory during human development, however, are not well understood. Here, we establish associations between working memory, other cognitive abilities, and functional MRI (fMRI) activation in data from over 11,500 9- to 10-year-old children (both sexes) enrolled in the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing longitudinal study in the United States. Behavioral analyses reveal robust relationships between working memory, short-term memory, language skills, and fluid intelligence. Analyses relating out-of-scanner working memory performance to memory-related fMRI activation in an emotional n-back task demonstrate that frontoparietal activity during a working memory challenge indexes working memory performance. This relationship is domain specific, such that fMRI activation related to emotion processing during the emotional n-back task, inhibitory control during a stop-signal task (SST), and reward processing during a monetary incentive delay (MID) task does not track memory abilities. Together, these results inform our understanding of individual differences in working memory in childhood and lay the groundwork for characterizing the ways in which they change across adolescence.SIGNIFICANCE STATEMENT Working memory is a foundational cognitive ability that changes over time and varies across individuals. Here, we analyze data from over 11,500 9- to 10-year-olds to establish relationships between working memory, other cognitive abilities, and frontoparietal brain activity during a working memory challenge, but not during other cognitive challenges. Our results lay the groundwork for assessing longitudinal changes in working memory and predicting later academic and other real-world outcomes.

Currently, there exists no accurate, noninvasive clinical imaging method to detect living bacteria in vivo. Our goal is to provide a positron emission tomography (PET) method to image infection by targeting bacteria-specific metabolism. Standard of care methodologies detect morphologic changes, image immunologic response to infection, or employ invasive tissue sampling with associated patient morbidity. These strategies, however, are not specific for living bacteria and are often inadequate to detect bacterial infection during fever workup. As such, there is an unmet clinical need to identify and validate new imaging tools suitable for noninvasive, in vivo (PET) imaging of living bacteria. We have shown that d-[methyl-11C]methionine (d-[11C]Met) can distinguish active bacterial infection from sterile inflammation in a murine infection model and is sensitive to both Gram-positive and Gram-negative bacteria. Here, we report an automated and >99% enantiomeric excess (ee) synthesis of d-[11C]Met from a linear d-homocysteine precursor, a significant improvement over the previously reported synthesis utilizing a d-homocysteine thiolactone hydrochloride precursor with approximately 75-85% ee. Furthermore, we took additional steps toward applying d-[11C]Met to infected patients. d-[11C]Met was subject to a panel of clinically relevant bacterial strains and demonstrated promising sensitivity to these pathogens. Finally, we performed radiation dosimetry in a normal murine cohort to set the stage for translation to humans in the near future.

BACKGROUND:To determine whether gender-based differences may be present in letters of recommendation written for ophthalmology residency applicants. METHODS:All applications submitted through SF Match to the UCLA Stein Eye Institute Residency Training Program from the 2017-2018 application cycle were analyzed using validated text analysis software (Linguistic Inquiry and Word Count (Austin, TX)). The main outcome measures were differences in language use in letters of recommendation by gender of applicant. RESULTS:Of 440 applicants, 254 (58%) were male and 186 (42%) were female. The two gender groups had similar United States Medical Licensing Exam (USMLE) Step 1 scores, undergraduate grade point averages (uGPA's), proportions of underrepresented minority (URM) applicants and Gold Humanism Honor Society members, numbers of academic and service activities listed, and gender distributions of their letter writers (all P values > 0.05). However, letters written for male applicants were determined to use more "authentic" words than those written for female applicants (mean difference, 0.800; 95% CI, 0.001-1.590; P = 0.047). Letters written for male applicants also contained more "leisure" words (mean difference, 0.056; 95% CI, 0.008-0.104; P = 0.023) and fewer "feel" words (mean difference, 0.033; 95% CI, 0.001-0.065; P = 0.041) and "biological processes" words (mean difference, 0.157; 95% CI, 0.017-0.297; P = 0.028). CONCLUSIONS:There were gender differences detected in recommendation letters in ophthalmology consistent with prior studies from other fields. Awareness of these differences may improve residency selection processes.

Background and Purpose- Imaging is frequently used to select acute stroke patients for intra-arterial therapy. Quantitative cerebral blood flow can be measured noninvasively with arterial spin labeling magnetic resonance imaging. Cerebral blood flow levels in the contralateral (unaffected) hemisphere may affect capacity for collateral flow and patient outcome. The goal of this study was to determine whether higher contralateral cerebral blood flow (cCBF) in acute stroke identifies patients with better 90-day functional outcome. Methods- Patients were part of the prospective, multicenter iCAS study (Imaging Collaterals in Acute Stroke) between 2013 and 2017. Consecutive patients were enrolled after being diagnosed with anterior circulation acute ischemic stroke. Inclusion criteria were ischemic anterior circulation stroke, baseline National Institutes of Health Stroke Scale score ≥1, prestroke modified Rankin Scale score ≤2, onset-to-imaging time

Conditionally essential (CE) genes are required by pathogenic bacteria to establish and maintain infections. CE genes encode virulence factors, such as secretion systems and effector proteins, as well as biosynthetic enzymes that produce metabolites not found in the host environment. Due to their outsized importance in pathogenesis, CE gene products are attractive targets for the next generation of antimicrobials. However, the precise manipulation of CE gene expression in the context of infection is technically challenging, limiting our ability to understand the roles of CE genes in pathogenesis and accordingly design effective inhibitors. We previously developed a suite of CRISPR interference-based gene knockdown tools that are transferred by conjugation and stably integrate into bacterial genomes that we call Mobile-CRISPRi. Here, we show the efficacy of Mobile-CRISPRi in controlling CE gene expression in an animal infection model. We optimize Mobile-CRISPRi in Pseudomonas aeruginosa for use in a murine model of pneumonia by tuning the expression of CRISPRi components to avoid nonspecific toxicity. As a proof of principle, we demonstrate that knock down of a CE gene encoding the type III secretion system (T3SS) activator ExsA blocks effector protein secretion in culture and attenuates virulence in mice. We anticipate that Mobile-CRISPRi will be a valuable tool to probe the function of CE genes across many bacterial species and pathogenesis models.IMPORTANCE Antibiotic resistance is a growing threat to global health. To optimize the use of our existing antibiotics and identify new targets for future inhibitors, understanding the fundamental drivers of bacterial growth in the context of the host immune response is paramount. Historically, these genetic drivers have been difficult to manipulate precisely, as they are requisite for pathogen survival. Here, we provide the first application of Mobile-CRISPRi to study conditionally essential virulence genes in mouse models of lung infection through partial gene perturbation. We envision the use of Mobile-CRISPRi in future pathogenesis models and antibiotic target discovery efforts.

ObjectiveThe authors investigated if the physical activity increases observed in the Multilevel Intervention for Physical Activity in Retirement Communities (MIPARC) improved cognitive functions in older adults. The authors also examined if within-person changes in moderate to vigorous physical activity (MVPA), as opposed to low-light and high-light physical activity, were related to cognitive improvements in the entire sample.MethodsThis was a cluster randomized control trial set in retirement communities in San Diego County, CA. A total of 307 older adults without a formal diagnosis of dementia (mean age: 83 years; age range: 67-100; standard deviation: 6.4 years; 72% women) were assigned to the physical activity (N = 151) or healthy education control (N = 156) groups. Interventions were led by study staff for the first 6 months and sustained by peer leaders for the next 6 months. Components included individual counseling and self-monitoring with pedometers, group education sessions, and printed materials. Measurements occurred at baseline, 6 months, and 12 months. Triaxial accelerometers measured physical activity for 1 week. The Trail Making Test (TMT) Parts A and B and a Symbol Search Test measured cognitive functions.ResultsThere were no significant differences in cognitive functions between the MIPARC intervention and control groups at 6 or 12 months. Within-person increases in MVPA, and not low-light or high-light physical activity, were associated with improvements in TMT Parts B, B-A, and Symbol Search scores in the entire sample.ConclusionFindings suggest that MVPA may have a stronger impact on cognitive functions than lower intensity physical activity within retirement community samples of highly educated older adults without dementia.

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P

BACKGROUND:The impact of cancer and its treatment on employment and financial burden in adolescents/young adults (AYAs) is not fully known. METHODS:Eligibility for this cross-sectional study of AYA cancer survivors included the diagnosis of a malignancy between ages 18 and 39 years and survey completion within 1 to 5 years from diagnosis and ≥1 year after therapy completion. Participants were selected randomly from the tumor registries of 7 participating sites and completed an online patient-reported outcomes survey to assess employment and financial concerns. Treatment data were abstracted from medical records. Data were analyzed across diagnoses and by tumor site using logistic regression and Wald-based 95% confidence intervals adjusting for age (categorized), sex, insurance status, education (categorized), and treatment exposures. RESULTS:Participants included 872 survivors (breast cancer, n = 241; thyroid cancer, n = 126; leukemia/lymphoma, n = 163; other malignancies, n = 342). Exposure to chemotherapy in breast cancer survivors was associated with an increase in self-reported mental impairment in work tasks (odds ratio [OR], 2.66) and taking unpaid time off (OR, 2.62); survivors of "other" malignancies reported an increase in mental impairment of work tasks (OR, 3.67) and borrowing >$10,000 (OR, 3.43). Radiation exposure was associated with an increase of mental impairment in work tasks (OR, 2.05) in breast cancer survivors, taking extended paid time off work in thyroid cancer survivors (OR, 5.05), and physical impairment in work tasks in survivors of "other" malignancies (OR, 3.11). Finally, in survivors of "other" malignancies, having undergone surgery was associated with an increase in physical (OR, 3.11) and mental impairment (OR, 2.31) of work tasks. CONCLUSIONS:Cancer treatment has a significant impact on AYA survivors' physical and mental work capacity and time off from work.

BACKGROUND: This population-based study considered the influence of rituximab on the survival of children (0-19 years), adolescents, and young adults (AYAs, 20-39 years) with diffuse large B-cell lymphoma (DLBCL), including patients with human immunodeficiency virus (HIV) infection. METHODS: Data on 642 children and AYAs diagnosed with DLBCL during 2001-2014 were obtained from the Greater Bay Area Cancer Registry in California. Facility-level reports provided treatment details. The Kaplan-Meier method estimated survival and Cox regression models examined the association between survival and rituximab use, adjusting for sociodemographic and clinical factors. RESULTS: Rituximab use increased from 2001-2007 to 2008-2014 among children (from 32% to 48%), AYAs (from 68% to 84%), and HIV patients (from 57% to 67%). Five-year survival was higher among children (91%) than AYAs (82%). On multivariable analysis, the hazard of death was 44% lower among rituximab recipients, and higher among uninsured patients, those with HIV, and those with advanced stage at diagnosis. HIV patients who received rituximab were 60% less likely to die than nonrecipients. CONCLUSIONS: Our study suggests a benefit of rituximab on the treatment of AYAs and HIV patients with DLBCL. The worse survival observed among HIV-positive and uninsured patients is of concern and calls for further investigation. Careful consideration should be given on whether to recommend rituximab more often on the front-line treatment of children and HIV-positive patients with DLBCL.

In meiotic prophase, chromosomes are organized into compacted loop arrays to promote homolog pairing and recombination. Here, we probe the architecture of the mouse spermatocyte genome in early and late meiotic prophase using chromosome conformation capture (Hi-C). Our data support the established loop array model of meiotic chromosomes, and infer loops averaging 0.8-1.0 megabase pairs (Mb) in early prophase and extending to 1.5-2.0 Mb in late prophase as chromosomes compact and homologs undergo synapsis. Topologically associating domains (TADs) are lost in meiotic prophase, suggesting that assembly of the meiotic chromosome axis alters the activity of chromosome-associated cohesin complexes. While TADs are lost, physically separated A and B compartments are maintained in meiotic prophase. Moreover, meiotic DNA breaks and interhomolog crossovers preferentially form in the gene-dense A compartment, revealing a role for chromatin organization in meiotic recombination. Finally, direct detection of interhomolog contacts genome-wide reveals the structural basis for homolog alignment and juxtaposition by the synaptonemal complex.

BackgroundThe Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events.MethodsWe did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed.FindingsOf the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase.InterpretationAt 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis.FundingNational Institutes of Health, National Institute of Neurological Disorders and Stroke.

Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [15O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P

BackgroundAutologous hematopoietic stem cell transplant (aHSCT) is an efficacious treatment for newly diagnosed multiple myeloma patients. However, as rapid advances have resulted in other highly efficacious and less intensive therapies, the role of aHSCT has been questioned.MethodsWe utilized population-based data to identify 13 494 newly diagnosed patients younger than age 80 years between 1998 and 2012. Patient characteristics of aHSCT and non-aHSCT groups were balanced using inverse probability weighting of a propensity score predicting aHSCT use. Multivariable models adjusted for baseline comorbidities, demographics, and socioeconomic status estimated the adjusted hazard ratio (aHR) and 95% confidence intervals (CIs) of death.ResultsTwenty point eight percent (2807) of patients underwent aHSCT, and this rate increased over time from 15.4% in 1998-2002 to 23.9% in 2008-2012. aHSCT was utilized among 37.6% and 11.5% of patients younger than age 60 years and 60 to 79 years, respectively. The median time to aHSCT was 9.4 months, and 89% of all aHSCTs occurred within two years of diagnosis. The median overall survival from time of aHSCT was 72.9 months (95% confidence interval [CI] = 68 to 78). Autologous HSCT at any time was associated with improved survival (aHR = 0.83, 95% CI = 0.75 to 0.92). Among aHSCT recipients, transplant more than 12 months after diagnosis (vs ≤12 months) was associated with worse survival (aHR = 1.33, 95% CI = 1.16 to 1.51). The positive effect of aHSCT on overall survival was similar across study time periods and age groups.ConclusionIn the era of highly efficacious induction therapies, aHSCT remained infrequently used but continued to be associated with improved survival for multiple myeloma patients and should be considered for newly diagnosed patients.

This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months.

BackgroundAs the US population ages, there is an increasing need for evidence based, peer-led physical activity programs, particularly in ethnically diverse, low income senior centers where access is limited.Methods/designThe Peer Empowerment Program 4 Physical Activity' (PEP4PA) is a hybrid Type II implementation-effectiveness trial that is a peer-led physical activity (PA) intervention based on the ecological model of behavior change. The initial phase is a cluster randomized control trial randomized to either a peer-led PA intervention or usual center programming. After 18 months, the intervention sites are further randomized to continued support or no support for another 6 months. This study will be conducted at twelve senior centers in San Diego County in low income, diverse communities. In the intervention sites, 24 peer health coaches and 408 adults, aged 50 years and older, are invited to participate. Peer health coaches receive training and support and utilize a tablet computer for delivery and tracking. There are several levels of intervention. Individual components include pedometers, step goals, counseling, and feedback charts. Interpersonal components include group walks, group sharing and health tips, and monthly celebrations. Community components include review of PA resources, walkability audit, sustainability plan, and streetscape improvements. The primary outcome of interest is intensity and location of PA minutes per day, measured every 6 months by wrist and hip accelerometers and GPS devices. Secondary outcomes include blood pressure, physical, cognitive, and emotional functioning. Implementation measures include appropriateness & acceptability (perceived and actual fit), adoption & penetration (reach), fidelity (quantity & quality of intervention delivered), acceptability (satisfaction), costs, and sustainability.DiscussionUsing a peer led implementation strategy to deliver a multi-level community based PA program can enhance program adoption, implementation, and sustainment.Trial registrationClinicalTrials.gov, USA ( NCT02405325 ). Date of registration, March 20, 2015. This website also contains all items from the World Health Organization Trial Registration Data Set.

BackgroundPerturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma.ResultsBacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p

BACKGROUND:Older adults are the least active population group. Interventions in residential settings may support a multi-level approach to behavior change. METHODS:In a cluster randomized control trial, 11 San Diego retirement communities were assigned to a physical activity (PA) intervention or a healthy aging attention control condition. Participants were 307 adults over 65 years old. The multilevel PA intervention was delivered with the assistance of peer leaders, who were trained older adult from the retirement communities. Intervention components included individual counseling & self-monitoring with pedometers, group education sessions, group walks, community advocacy and pedestrian community change projects. Intervention condition by time interactions were tested using generalized mixed effects regressions. The primary outcomes was accelerometer measured physical activity. Secondary outcomes were blood pressure and objectively measured physical functioning. RESULTS:Over 70% of the sample were 80 years or older. PA significantly increased in the intervention condition (56 min of moderate-vigorous PA per week; 119 min of light PA) compared with the control condition and remained significantly higher across the 12 month study. Men and participants under 84 years old benefited most from the intervention. There was a significant decrease in systolic (p

The autism spectrum disorder (ASD) research community is increasingly considering the importance of measuring outcomes that are meaningful to individuals with ASD and their families. The 2017 IMFAR preconference aimed to gain the perspectives of how to define and measure "meaningful outcomes" from 280 participants, including people with ASD and their families, service providers, and researchers. Six themes were identified: (a) the definition of "outcome" varies by context and perspective; (b) the need to broaden the scope of what researchers measure; (c) the need for new assessment tools; (d) the need to expand data analytic methods; (e) where to focus (with emphasis on considering different developmental stages and aspects of diversity); and (f) a need for community partnerships to bridge research and daily practice. The challenge that the research community now faces is how to move the evidence base for clinical practice forward while keeping alive the divergence of views and considerations that are relevant for thinking about complex outcomes for the highly heterogeneous group of individuals with ASD. This commentary provides recommendations, with an emphasis on lifespan viewpoints that encompass individual strengths and preferences. Autism Research 2018, 11: 1446-1454. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The 2017 IMFAR preconference aimed to gain the perspectives of how to define and measure "meaningful outcomes" from a variety of stakeholders. This commentary outlines the six themes identified from keynote and panel presentations and audience-participated discussions. Recommendations are made to emphasize perspectives that look across the lifespan and encompass individual strengths and preferences.

The ABCD study is recruiting and following the brain development and health of over 10,000 9-10 year olds through adolescence. The imaging component of the study was developed by the ABCD Data Analysis and Informatics Center (DAIC) and the ABCD Imaging Acquisition Workgroup. Imaging methods and assessments were selected, optimized and harmonized across all 21 sites to measure brain structure and function relevant to adolescent development and addiction. This article provides an overview of the imaging procedures of the ABCD study, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature.

ObjectiveHispanics/Latinos have the highest risks for metabolic syndrome (MetS) in the U.S. and are also at increased risk for Alzheimer disease. In this study, we examined associations among neurocognitive function, MetS, and inflammation among diverse middle-aged and older Hispanics/Latinos.Research design and methodsCross-sectional data (2008-2011) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analyzed to examine associations between neurocognition and MetS among diverse Hispanics/Latinos (N = 9,136; aged 45-74 years).ResultsMetS status was associated with lower global neurocognition, mental status, verbal learning and memory, verbal fluency, and executive function. Age significantly modified the associations between MetS and learning and memory measures. Significant associations between MetS and neurocognition were observed among middle-aged Hispanics/Latinos, and all associations remained robust to additional covariates adjustment.ConclusionsWe found that MetS was associated with lower neurocognitive function, particularly in midlife. Our findings support and extend current hypotheses that midlife may be a particularly vulnerable developmental period for unhealthy neurocognitive aging.

Aging is a complex process strongly determined by genetics. Previous reports have shown that the genome of neuronal cells displays somatic genomic mosaicism including DNA copy number variations (CNVs). CNVs represent a significant source of genetic variation in the human genome and have been implicated in several disorders and complex traits, representing a potential mechanism that contributes to neuronal diversity and the etiology of several neurological diseases and provides new insights into the normal, complex functions of the brain. Nonetheless, the features of somatic CNV mosaicism in nondiseased elderly brains have not been investigated. In the present study, we demonstrate a highly significant increase in the number of CNVs in nondiseased elderly brains compared to the blood. In two neural tissues isolated from paired postmortem samples (same individuals), we found a significant increase in the frequency of deletions in both brain areas, namely, the frontal cortex and cerebellum. Also, deletions were found to be significantly larger when present only in the cerebellum. The sizes of the variants described here were in the 150-760 kb range, and importantly, nearly all of them were present in the Database of Genomic Variants (common variants). Nearly all evidence of genome structural variation in human brains comes from studies detecting changes in single cells which were interpreted as derived from independent, isolated mutational events. The observations based on array-CGH analysis indicate the existence of an extensive clonal mosaicism of CNVs within and between the human brains revealing a different type of variation that had not been previously characterized.

BACKGROUND:The adverse impact of second primary malignancies (SPMs) on survival is substantial for adolescents and young adults (AYAs; ie, those 15-39 years old). No studies have evaluated whether the latency time between the first malignancy (the primary malignancy [PM]) and the SPM affects cancer-specific survival (CSS). METHODS:A multivariate Cox proportional hazards regression with Surveillance, Epidemiology, and End Results data for 13 regions from 1992 to 2008 was used to ascertain whether the latency time (1-5 vs ≥ 6 years) to the development of an SPM affected the CSS and overall survival with respect to either the PM or SPM for AYAs with common SPMs. RESULTS:The majority of 1515 AYAs with an SPM had their PM diagnosed between the ages of 26 and 39 years (74.2%) and an SPM diagnosed within 1 to 5 years (72.9%) of the PM's diagnosis. Overall, AYAs that developed an SPM 1 to 5 years after the diagnosis (vs ≥ 6 years) had an increased risk of death from cancer (hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.92-3.29) as well as any cause (HR, 2.60; 95% CI, 2.04-3.32). Specifically, for AYAs with an SPM that was leukemia or a colorectal, breast, or central nervous system malignancy, a shorter latency time (1-5 years) from their PM diagnosis was associated with an overall significantly increased risk of death (2.6-fold) from either their PM or that particular SPM. However, latency did not appear to affect the CSS with respect to either the PM or SPM for AYA patients with a lymphoma or sarcoma SPM. CONCLUSIONS:Most AYAs who develop an SPM do so within 1 to 5 years of their primary cancer diagnosis, and they have an increased risk of death from cancer in comparison with AYAs with an SPM developing after longer survivorship intervals. Cancer 2018;124:1260-8. © 2017 American Cancer Society.