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Introduction: Internal standards correct for measurement variation due to sample loss. Isotope labeled analytes are ideal internal standards for the measurement of fatty acids in human plasma but are not always readily available. For this reason, quantification of multiple analytes at once is most often done using only a single or few internal standards. The magnitude of the impact this has on method accuracy and precision is not well studied for gas chromatography-mass spectrometry systems. Objective: This study aims to estimate bias and changes in uncertainty associated with using alternative fatty acid isotopologue internal standards for the estimation of similar or dissimilar long chain fatty acids. Method: Using a previously reported method for the quantification of 27 fatty acids in human plasma using 18 internal standards we obtained estimates of bias and uncertainty at up to three levels of fatty acid concentration. Results: With some notable exceptions, method accuracy remained relatively stable when using an alternative internal standard (Median Relative Absolute Percent Bias: 1.76%, Median Spike-Recovery Absolute Percent Bias: 8.82%), with larger changes in method precision (Median Increase in Variance: 141%). Additionally, the degree of difference between analyte and internal standard structure was related to the magnitude of bias and uncertainty of the measurement. Conclusion: The data presented here show that the choice of internal standard used to estimate fatty acid concentration can affect the accuracy and reliability of measurement results and, therefore, needs to be assessed carefully when developing analytical methods for the measurement of fatty acid profiles.Disclaimer: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, the Public Health Service, and the US Department of Health and Human Services.

Background: Adequate sleep plays a crucial role in maintaining physical, mental, and emotional health. On average, adults require 7–9 h of sleep per night. However, less than two-thirds of women meet this recommendation. During the coronavirus disease 2019 (COVID-19) pandemic, poor sleep quality and moderate-to-severe stress were highly prevalent among healthcare workers (HCWs), especially women. While some interventions have been proposed to address stress/burnout in HCWs, few have focused specifically on women in healthcare. Therefore, this is a protocol for a study that aims to determine the efficacy of a mind–body intervention (MBI) to improve sleep duration among women HCWs aged 40–60 years using the personalized (N-of-1) trial design. Methods: A personalized (N-of-1) trials model will be employed to evaluate the efficacy of an MBI to improve sleep duration (primary endpoint) and explore its effects on sleep quality, physiological factors, and their relationships with participants’ perceived stress, anxiety, and depression. The series of personalized trials (n = 60) will be conducted over 16 weeks. The MBI will include mindfulness, yoga, and guided walking, delivered in two 2-week block sequences for 12 weeks, with two 2-week periods for baseline and follow-up. Participants will watch 30-min videos three times weekly and wear an activity tracker to monitor sleep and activity. They will receive daily text messages with questions about sleep quality and bi-weekly questionnaires about their stress, anxiety and depression scores, fatigue, concentration, confidence, mood, and pain levels. Conclusion: Results from this study will inform the development of N-of-1 methodology for addressing the health and wellness needs of middle-aged women.

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.

Background Mental health disorders (MHDs) are associated with physical health disparities, but underlying excess risk and health burden have not yet been comprehensively assessed.Objective To assess the burden of comorbid physical health conditions (PHCs) across serious MHDs in Europe.Methods We estimated the relative prevalence risk of PHCs associated with alcohol use disorders (AUD), bipolar disorder (BD), depressive disorders (DD) and schizophrenia (SZ) across working-age populations of 32 European countries in 2019 based on a targeted literature review. Excess physical health burden was modelled using population-attributable fractions and country-level prevalence data.Findings We screened 10 960 studies, of which 41 were deemed eligible, with a total sample size of over 18 million persons. Relative prevalence of PHCs was reported in 54%, 20%, 15%, 5% and 7% of studies, respectively, for SZ, DD, BD, AUD or mixed. Significant relative risk estimates ranged from 1.44 to 3.66 for BD, from 1.43 to 2.21 for DD, from 0.81 to 1.97 for SZ and 3.31 for AUD. Excess physical health burden ranged between 27% and 67% of the total, corresponding to 84 million (AUD), 67 million (BD), 66 million (DD) and 5 million (SZ) PHC diagnoses in Europe. A 1% reduction in excess risk assuming causal inference could result in two million fewer PHCs across investigated MHDs.Conclusions This is the first comprehensive study of the physical health burden of serious MHDs in Europe. The methods allow for updates, refinement and extension to other MHDs or geographical areas.Clinical implications The results indicate potential population health benefits achievable through more integrated mental and physical healthcare and prevention approaches.

Background: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) provides risk estimates of postoperative complications. While several studies have examined the accuracy of the ACS-Surgical Risk Calculator (SRC) within a single specialty, the respective conclusions are limited by sample size. We sought to conduct a meta-analysis to determine the accuracy of the ACS-SRC among various surgical specialties. Study design: Clinical studies that utilized the ACS-SRC, predicted complication rates compared to actual rates, and analyzed at least one metric reported by ACS-SRC met the inclusion criteria. Data for each specialty were pooled using the DerSimonian and Laird random-effect models and analyzed with the binary random-effect model to produce risk difference (RD) and 95 % confidence intervals (CIs) using Open Meta[Analyst]. Results: The initial search yielded 281 studies and, after applying inclusion and exclusion criteria, a total of 53 studies remained with a total sample of 30,134 patients spanning 10 surgical specialties. When considering any complication and death, the ACS-SRC significantly underpredicted complications for: Orthopaedic Surgery (RD –0.067, p = 0.008), Spine (RD -0.027, p < 0.001), Urology (RD -0.03, p < 0.001), Surgical Oncology (RD -0.045, p < 0.001), and Gynecology (RD -0.098, p = 0.01). Conclusion: The ACS-SRC proved useful in General, Acute Care, Colorectal, Otolaryngology, and Cardiothoracic Surgery, but significantly underpredicted complication rates in Spine, Orthopaedics, Urology, Surgical Oncology, and Gynecology. These data indicate the ACS-SRC is a reliable predictor in some specialties, but its use should be cautioned in the remaining specialties evaluated here.

Abstract Intrusive memories (IMs) after traumatic events can be distressing and disrupt mental health and functioning. We evaluated the impact of a brief remotely-delivered digital imagery-competing task intervention on the number of IMs for intensive care unit (ICU) staff who faced repeated trauma exposure during the COVID-19 pandemic using a two-arm, parallel-group, single-blind randomised controlled trial, with the comparator arm receiving delayed access to active treatment (crossover). Eligible participants worked clinically in a UK NHS ICU during the pandemic and had at least 3 IMs of work-related traumatic events in the week before recruitment. Participants were randomly assigned (1:1) to immediate (weeks 1–4) or delayed (weeks 5–8) intervention access. Sequential Bayesian analyses to optimise the intervention and increase trial efficiency are reported elsewhere [1]. The primary endpoint for the pre-specified frequentist analysis of the final study population compared the number of IMs experienced in week 4 between the immediate and delayed access arms. Secondary outcomes included clinical symptoms, work functioning and wellbeing. Safety was assessed throughout the trial by scheduled questions and free report. All analyses were undertaken on an intention-to-treat basis (86 randomised participants). There were significantly fewer intrusive memories during week 4 in the immediate (median = 1, IQR = 0–3, n = 43), compared to the comparator delayed arm (median = 10, IQR = 6–17, n = 43), IRR 0.31, 95% CI: 0.20–0.48, p

Abstract Background Intrusive mental imagery is associated with anxiety and mood instability within bipolar disorder and therefore represents a novel treatment target. Imagery Based Emotion Regulation (IBER) is a brief structured psychological intervention developed to enable people to use the skills required to regulate the emotional impact of these images. Methods Participants aged 18 and over with a diagnosis of bipolar disorder and at least a mild level of anxiety were randomly assigned (1:1) to receive IBER plus treatment as usual (IBER + TAU) or treatment as usual alone (TAU). IBER was delivered in up to 12 sessions overs 16 weeks. Clinical and health economic data were collected at baseline, end of treatment and 16-weeks follow-up. Objectives were to inform the recruitment process, timeline and sample size estimate for a definitive trial and to refine trial procedures. We also explored the impact on participant outcomes of anxiety, depression, mania, and mood stability at 16-weeks and 32-weeks follow-up. Results Fifty-seven (28: IBER + TAU, 27: TAU) participants from two sites were randomised, with 50 being recruited within the first 12 months. Forty-seven (82%) participants provided outcome data at 16 and 32-weeks follow-up. Thirty-five participants engaged in daily mood monitoring at the 32-week follow-up stage. Retention in IBER treatment was high with 27 (96%) attending ≥ 7 sessions. No study participants experienced a serious adverse event. Discussion The feasibility criteria of recruitment, outcome completion, and intervention retention were broadly achieved, indicating that imagery-focused interventions for bipolar disorder are worthy of further investigation.

The ability of gut microbial metabolites to influence the host is increasingly recognized. The microbiota extensively metabolizes the three aromatic amino acids, tryptophan, tyrosine, and phenylalanine. Previously we have found that a metabolite of tyrosine, 4-OH-phenylpropionic acid, can enhance type I interferon (IFN) signaling and protect from influenza pathogenesis in a murine model. Herein we screened 17 related aromatic amino acid metabolites for effects on IFN signaling in human lung epithelial cells and monocytes alone and in the presence of IFN-β, influenza, and LPS. While the tryptophan family metabolites reduced IFN signaling in both cell types, the tyrosine and phenylalanine metabolites had varied effects, which were cell-type dependent. Pooled treatment of all these metabolites reduced IFN signaling in both cell types and suggested a tryptophan metabolite effect dominance. Strikingly, when all the metabolites were pooled together, we found reduced influenza recovery in both cell types. RNA sequencing further validated reduced viral loads and decreased IFN signaling. Single gene silencing of significantly upregulated genes identified by RNA sequencing (EGR2, ATP6VD02, SPOCK1, and IL31RA) did not completely abrogate the metabolite induced decrease in IFN signaling. However, these upregulated targets suggested a mechanistic link to TGF-beta signaling. Treatment with a TGF-beta inhibitor and combined targeted gene silencing led to a significant reversal of metabolite induced IFN signaling suppression. Finally, we demonstrated that intranasal administration of these metabolites prior to influenza infection led to reduced animal morbidity, viral titers, and inflammation. Our work implies that microbial metabolites can alter IFN signaling mechanistically through TGF-beta and promote beneficial outcomes during influenza infection.

Stress is a significant public health burden in the United States, with most Americans reporting unhealthy levels of stress. Stress management techniques include various evidence-based treatments shown to be effective but with heterogeneous treatment responses, indicating a lack of uniform benefits for all individuals. Designed to assess a participant’s response to a specific intervention, personalized (N-of-1) trials provide guidance for which treatment (s) work (s) best for the individual. Prior studies examining the effects of mindfulness meditation, yoga, and walking for stress reduction found all three interventions to be associated with significant reductions in self-reported measures of stress. Delivering these treatments using a personalized trial approach has the potential to assist clinicians in identifying the best stress management techniques for individuals with persistently high stress while fostering treatment decisions that consider their personal condition/barriers. This trial will evaluate a personalized approach compared to standard of care for three interventions (guided mindfulness meditation; guided yoga; and guided brisk walking) to manage perceived stress. Participants will respond to daily surveys and wear a Fitbit device for 18 weeks. After a 2-week baseline period, participants in the personalized trial groups will receive 12 weeks of interventions in randomized order, while participants in the standard-of-care group will have access to all interventions for self-directed stress management. After intervention, all participants will undergo 2 weeks of observation, followed by two additional weeks of the stress management intervention of their choosing while continuing outcome measurement. At study completion, all participants will be sent a satisfaction survey. The primary analysis will compare perceived stress levels between the personalized and standard of care arms. The results of this trial will provide further support for the use of personalized designs for managing stress.Clinical Trial Registration: clinicaltrials.gov, NCT05408832.Protocol version: 9/14/2022, 21-0968-MRB.

Objectives: This study was aimed at understanding the attitudes and positions of key Australian organisational and political stakeholders towards using psychedelic agents in medically supervised environments to treat mental health conditions. Specifically, this research was designed to identify some of the issues that might impede the clinical implementation of psychedelics. Methods: Semi-structured interviews were conducted with four Australian politicians and nine representatives of key stakeholder organisations between September 2022 and January 2023. Data analyses were completed using pattern-based inductive thematic analysis. Results: Participants were cautiously optimistic about using psychedelics to treat mental health conditions, with hesitancy emerging due to the perceived inadequacy of research into the efficacy and feasibility of these treatments. Politicians consistently mentioned that negative stigma prevented them and their peers from supporting the use of psychedelics in Australia. Effective, evidence-based, clear messaging that refutes misconceptions, uses persuasive messaging and provides clear information to inform implementation is needed to improve knowledge and challenge attitudes, biases and emotions that can influence the debate around psychedelics. Conclusions: Stakeholder representatives and politicians agree that insufficient evidence exists to support the widespread clinical implementation of psychedelics in Australia. Politicians also perceive the stigma associated with psychedelics might negatively influence progressive legislation. Additional research and a clear presentation of this research are needed before the clinical use of psychedelics can be supported.

Introduction COMP360 is a synthetic, proprietary, purified form of psilocybin in development for treatment-resistant depression (TRD) with FDA Breakthrough Therapy designation. In a recent phase IIb study, COMP360 psilocybin 25mg was superior to 1mg on change from baseline (CFB) to Week 3 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score (primary efficacy endpoint), when administered alongside psychological support. Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR 16) total score (exploratory efficacy endpoint) showed similar results. Objectives To analyse changes in specific depression symptoms after psilocybin treatment in the aforementioned study, as measured by individual item scores on the MADRS and QIDS-SR 16 (range 0-6 and 0-3). Methods Participants with TRD were randomised to single doses of psilocybin 25mg (n=79), 10mg (n=75), or 1mg (n=79). A remote, blinded rater assessed the MADRS at Baseline, Day 2 (the day post-psilocybin), and Weeks 1, 3, 6, 9, and 12. The QIDS-SR 16 was self-rated at Baseline, Day 1, Day 2, and Weeks 1, 2, 3, 6, 9, and 12. At each time point, descriptive statistics were calculated for each MADRS and QIDS-SR 16 individual item score. Results At Week 3, MADRS items with the largest differences in mean CFB in the 25mg arm were Inability to Feel, Apparent Sadness, Lassitude, and Reported Sadness. Greater improvement in the 25mg arm was apparent from Day 2 and remained to Week 12 (Lassitude remained to Week 6 only). On the QIDS-SR 16, the item with the largest difference in mean CFB at Week 3 in the 25mg arm was in Feeling Sad and remained evident to Week 12 (Table 1). Table 1. Item (mean CFB at Week 3 [standard deviation]) Psilocybin 25mg Psilocybin 10mg Psilocybin 1mg MADRS - Inability to Feel -1.8 [1.81] -0.9 [1.54] -0.8 [1.61] MADRS - Apparent Sadness -1.7 [1.94] -1.1 [1.60] -0.9 [1.62] MADRS - Lassitude -1.6 [1.81] -1.2 [1.83] -0.8 [1.58] MADRS - Reported Sadness -1.6 [1.95] -1.0 [1.52] -0.6 [1.53] QIDS-SR 16 - Feeling Sad -1.1 [1.08] -0.8 [1.07] -0.4 [0.91] Conclusions A single administration of COMP360 psilocybin therapy rapidly and dose-relatedly improved symptoms of depressed mood and anhedonia – the two key symptoms of depression. As anhedonia is predictive of poorer treatment response, and improvements in anhedonia correlate with improvements in functioning, it is important to understand the impact of treatments on this symptom. Disclosure of InterestG. Goodwin Shareolder of: COMPASS Pathways, P1Vital, and P1Vital products , Employee of: COMPASS Pathways, L. Marwood Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, S. Mistry Employee of: COMPASS Pathways, A. Nowakowska Employee of: COMPASS Pathways, H. Simmons Employee of: COMPASS Pathways, J. Tsai Employee of: COMPASS Pathways, S. Williams Employee of: COMPASS Pathways, M. Young Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, E. Malievskaia Employee of: COMPASS Pathways

Abstract Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the homeostatic regulation of neuronal activity and synaptic plasticity. However, it remains largely unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 h after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow-wave activity. However, psilocin decreased the recovery rate of sleep slow-wave activity following sleep deprivation in the local field potentials of electrodes targeting the medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.

IntroductionDemonstrated health inequalities persist in the United States. SARS-CoV-2 (COVID) has been no exception, with access to treatment and hospitalization differing across race or ethnic groups. Here, we aim to assess differences in treatment with remdesivir and hospital length of stay across the four waves of the pandemic.Materials and methodsUsing a subset of the Truveta data, we examine the odds ratio (OR) of in-hospital remdesivir treatment and risk ratio (RR) of in-hospital length of stay between Black or African American (Black) to White patients. We adjusted for confounding factors, such as age, sex, and comorbidity status.ResultsThere were statistically significant lower rates of remdesivir treatment and longer in-hospital length of stay comparing Black patients to White patients early in the pandemic (OR for treatment: 0.88, 95% confidence interval [CI]: 0.80, 0.96; RR for length of stay: 1.17, CI: 1.06, 1.21). Rates became close to parity between groups as the pandemic progressed.ConclusionWhile inpatient remdesivir treatment rates increased and length of stay decreased over the beginning course of the pandemic, there are still inequalities in patient care.

Abstract Calibration of the gain and digital conversion factor of an EMCCD is necessary for accurate photon counting. We present a new method to quickly calibrate multiple gain settings of an EMCCD camera. Acquiring gain-series calibration data and analyzing the resulting images with the EMCCD noise model more accurately estimates the gain response of the camera. Furthermore, we develop a method to compare the results from different calibration approaches. Gain-series calibration outperforms all other methods in this self-consistency test.

Cellular phenotype plasticity between the epithelial and mesenchymal states has been linked to metastasis and heterogeneous responses to cancer therapy, and remains a challenge for the treatment of triple‐negative breast cancer (TNBC). Here, we used isogenic human breast epithelial cell lines, D492 and D492M, representing the epithelial and mesenchymal phenotypes, respectively. We employed a CRISPR‐Cas9 loss‐of‐function screen targeting a 2240‐gene ‘druggable genome’ to identify phenotype‐specific vulnerabilities. Cells with the epithelial phenotype were more vulnerable to the loss of genes related to EGFR‐RAS‐MAPK signaling, while the mesenchymal‐like cells had increased sensitivity to knockout of G2‐M cell cycle regulators. Furthermore, we discovered knockouts that sensitize to the mTOR inhibitor everolimus and the chemotherapeutic drug fluorouracil in a phenotype‐specific manner. Specifically, loss of EGFR and fatty acid synthase (FASN) increased the effectiveness of the drugs in the epithelial and mesenchymal phenotypes, respectively. These phenotype‐associated genetic vulnerabilities were confirmed using targeted inhibitors of EGFR (gefitinib), G2‐M transition (STLC), and FASN (Fasnall). In conclusion, a CRISPR‐Cas9 loss‐of‐function screen enables the identification of phenotype‐specific genetic vulnerabilities that can pinpoint actionable targets and promising therapeutic combinations.

Abstract Background Lithium is the best documented maintenance treatment in bipolar disorder, but its use varies considerably across and within countries. It is not known whether regional differences in lithium prescription rates translate to differing regional outcomes. Aims To estimate associations between county specific lithium prescription rates and county specific recurrence odds of bipolar disorder in Sweden. Method Data from 14,616 patients with bipolar I disorder, bipolar II disorder, or bipolar disorder not otherwise specified were extracted from the Swedish national quality assurance register for bipolar disorders (BipoläR). Lithium prescription frequencies were calculated for 21 counties. Logistic regression analyses were run adjusted for confounders, with any type of recurrence as primary outcome, and incident elated and depressive episodes as secondary outcomes. Subsets of patients with bipolar I, II and not otherwise specified disorder were also analysed separately. Results Lithium prescription rates for populations with all bipolar subtypes ranged across counties from 37.7 to 84.9% (mean 52.4%). Higher regional prescription rates were significantly associated with lower rate of any type of recurrence. The association was stronger when bipolar I disorder was analysed separately. Conclusions The advantages for lithium use long acknowledged for bipolar I disorder are also seen for the rest of the bipolar spectrum. Results suggest that population level outcomes of bipolar disorder could be improved by increasing the number of patients using lithium.

The steadily rising prevalence of heart failure (HF) and the associated increase in health care expenditures represent a significant burden for patients, caregivers, and society. Ambulatory management of worsening congestion is a complex undertaking that requires diuretic escalation, yet clinical success is often hindered by the progressively declining bioavailability of oral agents. Once beyond a threshold, patients with acute on chronic HF often require hospital admission for intravenous diuresis. A novel, pH neutral formulation of furosemide that is administered by a biphasic drug delivery profile (80 mg total over 5 ​hours) via an automated, on-body infusor was designed to overcome these limitations. Early studies have shown that it has equivalent bioavailability with comparable diuresis and natriuresis to the intravenous formulation, leads to significant decongestion, and improvement in quality of life. It was shown to be safe and is well tolerated by patients. Although there is one ongoing clinical trial, available data have demonstrated the potential to shift hospital-administered, intravenous diuresis to the outpatient setting. Reduction in the need for recurrent hospital admissions would be highly desirable by most patients with chronic HF and would lead to a significant reduction in health care expenditures. In this article, we describe the rationale and evolution of this novel PH neutral formulation of furosemide administered subcutaneously, summarize its pharmacokinetic and pharmacodynamic profiles, and review emerging clinical trials demonstrating its clinical safety, efficacy, and potential to reduce health care expenditures.

Abstract Objective To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls. Methods Peak aerobic capacity (VO2peak) and workload (Wpeak) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% Wpeak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near‐infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X‐ray absorptiometry assessed fat‐free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (FatigueSME) and six‐minute walk test (Fatigue6MWT), respectively. Results ΔHHb‐PEAK, ΔHHb‐SME, VO2peak, Wpeak, FFM%, and 6MWT distance were lower (P

Abstract Psychotic experiences (PE) are associated with poorer functioning, higher distress and the onset of serious mental illness. Environmental exposures (e.g. childhood abuse) are associated with the development of PE. However, which specific exposures convey risk for each type or dimension of PE has rarely been explored. The Oxford Wellbeing Life and Sleep (OWLS) survey includes 22 environmental risk factors for psychosis and was designed to examine how environmental risks are associated with specific dimensions of PE. Multivariate logistic regression models were fit using these risk factors to predict six dimensions of PE (perceptual abnormalities, persecutory ideation, bizarre ideas, cognitive disorganisation, delusional mood and negative symptoms). Models were built using only 70% of the data, and then fit to the remaining data to assess their generalisability and quality. 1789 (27.2% men; mean age = 27.6; SD = 10.9) survey responses were analysed. The risk factors predictive of the most PE were anxiety, social withdrawal during childhood and trauma. Cannabis and depression predicted three dimensions with both predicting bizarre ideas and persecutory ideation. Psychological abuse and sleep quality each predicted two dimensions (persecutory ideation and delusional mood). Risk factors predicting one PE dimension were age (predicting cognitive disorganisation), physical abuse (bizarre ideas), bullying and gender (persecutory ideation); and circadian phase (delusional mood). These results lend support for a continuum of psychosis, suggesting environmental risks for psychotic disorders also increase the risk of assorted dimensions of PE. Furthermore, it advocates the use of dimensional approaches when examining environmental exposures for PE given that environmental risks distribute differently across dimensions.

Abstract Background Bipolar disorder (BD) is associated with excess and premature cardiovascular mortality. Elevated blood pressure (BP) is a leading contributor to cardiovascular risk. However, few studies have examined BP in BD in comparison to other psychiatric disorders. Furthermore, the association between BP and mood instability is not presently clear despite increasing interest in repurposing existing antihypertensive medications as possible novel BD treatments. Thus we examined BP differences between BD and borderline personality disorder (BPD), a disorder with a similar symptom profile through chronic mood instability. Methods A total of 106 adults (38 BD, 25 BPD, and 43 healthy controls), evaluated in the Automated Monitoring of Symptom Severity (AMoSS) study, completed a week-long home blood pressure monitoring assessment and ecological momentary assessment of mood. We examined group-wise differences in mean BP and BP variability and their association with mood instability. Results BD individuals had a significantly wider resting pulse pressure (40.8 ± 7.4, mmHg) compared to BPD (35.7 ± 5.3, mmHg, P = 0.03) and control participants (37.3 ± 6.3, mmHg, P = 0.036). Systolic BP was negatively associated with sad mood instability, and all measures of mean BP (systolic, diastolic, and mean arterial pressure) were negatively associated with positive mood instability. Conclusions This study demonstrates BP differences between BD and healthy and clinical controls that are within a normotensive range. Early pulse pressure widening may be a modifiable pathophysiological feature of BD that confers later cardiovascular risk. BP may be an important transdiagnostic predictor of mood instability and a potential explicit treatment target.

We present a case report of an 84-year-old male who presented with a profunda femoris artery (PFA) pseudoaneurysm 8 years after the index revision total hip arthroplasty procedure. Failure of revision hardware and subsequent migration of implants led to damage of the PFA and pseudoaneurysm formation. The patient was hemodynamically unstable on presentation and required emergent endovascular intervention. Once medically stabilized, the patient underwent extensive debridement of the aneurysm and hematoma bed and broken hardware was removed to prevent further complications. At 6-month follow-up, the patient was able to mobilize independently and had returned to all prior levels of activities of daily living. We discuss the vascular anatomy of the hip, the paucity of literature on PFA pseudoaneurysm, as well as the likely etiology of total hip arthroplasty failures.

Abstract Background Molecular-scale mechanisms of the enzymatic breakdown of cellulosic biomass into fermentable sugars are still poorly understood, with a need for independent measurements of enzyme kinetic parameters. We measured binding times of cellobiohydrolase Trichoderma reesei Cel7A (Cel7A) on celluloses using wild-type Cel7A (WTintact), the catalytically deficient mutant Cel7A E212Q (E212Qintact) and their proteolytically isolated catalytic domains (CD) (WTcore and E212Qcore, respectively). The binding time distributions were obtained from time-resolved, super-resolution images of fluorescently labeled enzymes on cellulose obtained with total internal reflection fluorescence microscopy. Results Binding of WTintact and E212Qintact on the recalcitrant algal cellulose (AC) showed two bound populations: ~ 85% bound with shorter residence times of

The availability of mobile technologies has enabled the efficient collection of prospective longitudinal, ecologically valid self-reported clinical questionnaires from people with psychiatric diagnoses. These data streams have potential for improving the efficiency and accuracy of psychiatric diagnosis as well predicting future mood states enabling earlier intervention. However, missing responses are common in such datasets and there is little consensus as to how these should be dealt with in practice. In this study, the missing-response-incorporated log-signature method achieves roughly 74.8% correct diagnosis, with f1 scores for three diagnostic groups 66% (bipolar disorder), 83% (healthy control) and 75% (borderline personality disorder) respectively. This was superior to the naive model which excluded missing data and advanced models which implemented different imputation approaches, namely, k-nearest neighbours (KNN), probabilistic principal components analysis (PPCA) and random forest-based multiple imputation by chained equations (rfMICE). The log-signature method provided an effective approach to the analysis of prospectively collected mood data where missing data was common and should be considered as an approach in other similar datasets. Because of treating missing responses as a signal, its superiority also highlights that missing data conveys valuable clinical information.

Abstract Objectives To estimate the individual cost and population‐level economic burden of Bipolar Disorder (BD), and explore the impact of clinical and sociodemographic factors on costs in the United Kingdom. Methods Annual UK health care, social care and societal cost data were collected from a prospective cohort of 91 BD patients using digital monitoring of symptoms. Costs (in £) were calculated for the year of resource use collection (2010–2011) and main results inflated to year 2018–2019. A Generalized Estimating Equation framework was used to investigate individual factors influencing costs. An economic burden estimate was derived by multiplying the mean annual cost per patient with literature‐based population prevalence. Results The average annual cost of BD per patient was £12,617 (SE = ±£1085) or £14,938 (SE = ±£1281) at 2018–2019 prices with 68% of the total costs attributed to lost productivity and informal care, 31% to health care costs, 1% to private out‐of‐pocket expenses, and 0.5% to social care costs. A unit increase in average levels of depressive or manic symptoms were associated with 7% and 11% higher societal costs, respectively. The estimated annual prevalence of BD in the United Kingdom was 0.8% resulting in a population‐level economic burden estimate of £5.1 billion for 2010–2011 or £6.43 billion for 2018–2019. Conclusions BD is a disease of substantial costs in the United Kingdom with the majority of the economic burden falling outside the health care system in the form of productivity losses and informal care. These costs highly correlate with patient outcomes highlighting further needs for improved treatment efforts into functionality.

Summary: To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the βIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.

Background: Remote monitoring and digital phenotyping harbor potential to aid clinical diagnosis, predict episode course and recognize early signs of mental health crises. Digital communication metrics, such as phone call and short message service (SMS) use may represent novel biomarkers of mood and diagnosis in Bipolar Disorder (BD) and Borderline Personality Disorder (BPD).Materials and Methods: BD (n = 17), BPD (n = 17) and Healthy Control (HC, n = 21) participants used a smartphone application which monitored phone calls and SMS messaging, alongside self-reported mood. Linear mixed-effects regression models were used to assess the association between digital communications and mood symptoms, mood state, trait-impulsivity, diagnosis and the interaction effect between mood and diagnosis.Results: Transdiagnostically, self-rated manic symptoms and manic state were positively associated with total and outgoing call frequency and cumulative total, incoming and outgoing call duration. Manic symptoms were also associated with total and outgoing SMS frequency. Transdiagnostic depressive symptoms were associated with increased mean incoming call duration. For the different diagnostic groups, BD was associated with increased total call frequency and BPD with increased total and outgoing SMS frequency and length compared to HC. Depression in BD, but not BPD, was associated with decreased total and outgoing call frequency, mean total and outgoing call duration and total and outgoing SMS frequency. Finally, trait-impulsivity was positively associated with total call frequency, total and outgoing SMS frequency and cumulative total and outgoing SMS length.Conclusion: These results identify a general increase in phone call and SMS communications associated with self-reported manic symptoms and a diagnosis-moderated decrease in communications associated with depression in BD, but not BPD, participants. These findings may inform the development of clinical tools to aid diagnosis and remote symptom monitoring, as well as informing understanding of differential psychopathologies in BD and BPD.

Background: Manual wheelchair (MWC) users with spinal cord injuries (SCI) are at a significantly higher risk of experiencing rotator cuff pathology than able-bodied individuals. A deeper understanding of where the arm is used dynamically within the humeral workspace during daily life may help explain why MWC users have higher shoulder pathology rates than able-bodied individuals. The purpose of this study was to report the daily percentage and consecutive durations MWC users and matched able-bodied individuals (controls) spent static and dynamic across the humeral elevation workspace.Methods: MWC users with SCI and controls wore three inertial measurement units on their bilateral arms and torso for 1 or 2 days. The percentages of time and average consecutive duration individuals were static or dynamic while in five humeral elevation ranges (0–30°, 30–60°, 60–90°, 90–120°, and >120°) were calculated and compared between cohorts.Results: Forty-four MWC users (10 females, age: 42.8 ± 12.0, time since injury: 12.3 ± 11.5) and 44 age- and sex-matched controls were enrolled. The MWC cohort spent significantly more time dynamic in 60–90° (p = 0.039) and 90–120° (p = 0.029) and had longer consecutive dynamic periods in 30–60° (p = 0.001), 60–90° (p = 0.027), and 90–120° (p = 0.043) on the dominant arm. The controls spent significantly more time dynamic in 0–30° of humeral elevation (p < 0.001) on both arms. Although the average consecutive static durations were comparable between cohorts across all humeral elevation ranges, the MWC cohort spent a significantly higher percentage of their day static in 30–60° of humeral elevation than controls (dominant: p = 0.001, non-dominant: p = 0.01). The MWC cohort had a moderate association of increased age with decreased time dynamic in 30–60° for both arms.Discussion: Remote data capture of arm use during daily life can aid in understanding how arm function relates to shoulder pathology that follows SCI and subsequent MWC use. MWC users spent more time dynamic in higher elevations than controls, and with age, dynamic arm use decreased in the 30–60° humeral elevation range. These results may exemplify effects of performing activities from a seated position and of age on mobility.

Background: Adult acquired flatfoot (AAFD) is commonly treated by foot and ankle surgeons. Despite how commonly this disease presents, its incidence and economic impact have yet to be defined. We hypothesized that the operative incidence of AAFD and its economic burden would increase over the time period 1996 to 2014. Methods: The South Carolina database was queried for data from acute care and ambulatory surgery centers. Bivariate descriptive statistics were used to analyze the data. Operative incidence was calculated and demographics and medical comorbidities of patients who progressed to operative intervention were analyzed. Costs associated with operative care episodes were calculated to determine the economic burden. Results: A total of 1299 patients underwent AAFD corrective surgery between 1996 and 2014. Patients who underwent surgery for AAFD were most likely to be white, female, and in their fourth, fifth, and sixth decade of life. Operative incidence for AAFD rose from 0.26 per 100 000 covered lives in 1996 to 3.04 in 2014. The total health care costs associated with patients who underwent surgery for AAFD increased from $57 395.33 in 1996 to $6 859 723.60 in 2014. Conclusions: This data demonstrate that patients most commonly undergoing operative intervention for AAFD were white, female, and in their fourth, fifth, or sixth decade of life. There has been a significant increase in operative incidence, which may help direct attention to further exploration of outcome data in these patient populations, associated treatment costs, and preventative treatment options. Level of Evidence: Level III, retrospective comparative study.

Shoulder pain and pathology are extremely common for individuals with spinal cord injuries (SCI) who use manual wheelchairs (MWC). Although risky humeral kinematics have been measured during wheelchair-based activities performed in the lab, little is known about arm kinematics in the free-living environment. The purpose of this study was to measure the humeral elevation workspace throughout a typical day for individuals with SCI who use a MWC and matched able-bodied controls. Thirty-four individuals with SCI who use a MWC (42.7±12.7 years of age, 28 males/6 females, C6-L1) and 34 age-and sex-matched controls were enrolled. Participants wore three inertial measurement units (IMU) on their upper arms and torso for one to two days. Humeral elevation angles were estimated and the percentage of time individuals spent in five elevation bins (0-30°, 30-60°, 60-90°, 90-120°, and 120-180°) were calculated. For both arms, the SCI cohort spent a significantly lower percentage of the day in 0-30° of humeral elevation (Dominant: SCI = 15.7±12.6%, Control = 32.1±15.6%, p