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Operating room (OR) fires are rare but devastating events requiring immediate and effective response. Virtual Reality (VR) simulation training can provide a safe environment for practice of skills in such highly stressful situation. This study assessed interprofessional participants’ ability to respond to VR-simulated OR fire scenarios, attitudes, numbers of attempt of the VR simulation do participants need to successfully respond to OR fires and does prior experience, confidence level, or professional role predict the number of attempts needed to demonstrate safety and pass the simulation. 180 surgical team members volunteered to participate in this study at Beth Israel Deaconess Medical Center, Boston, MA. Each participant completed five VR OR simulation trials; the final two trials incorporated AI assistance. Primary outcomes were performance scores, number of attempts needed to pass, and pre- and post-survey results describing participant confidence and experiences. Differences across professional or training role were assessed using chi-square tests and analyses of variance. Differences in pass rates over time were assessed using repeated measures logistic regression. One hundred eighty participants completed simulation testing; 170 (94.4%) completed surveys. Participants included surgeons (17.2%), anesthesiologists (10.0%), allied health professionals (41.7%), and medical trainees (31.1%). Prior to training, 45.4% of participants reported feeling moderately or very confident in their ability to respond to an OR fire. Eight participants (4.4%) responded safely on the first simulation attempt. Forty-three participants (23.9%) passed by the third attempt (VR only); an additional 97 participants (53.9%) passed within the 4–5th attempt (VR with AI assistance). Providers are unprepared to respond to OR fires. VR-based simulation training provides a practical platform for individuals to improve their knowledge and performance in the management of OR fires with a 79% pass rate in our study. A VR AI approach to teaching this essential skill is innovative, feasible, and effective.

Background Traumatic brain injury (TBI) can precipitate new-onset psychiatric symptoms or worsen existing psychiatric conditions. To elucidate specific mechanisms for this interaction, neuroimaging is often used to study both psychiatric conditions and TBI. This systematic review aims to synthesize the existing literature of neuroimaging findings among patients with anxiety after TBI. Methods We conducted a Preferred Reporting Items for Systematic Review and Meta-Analyses–compliant literature search via PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases before May, 2019. We included studies that clearly defined TBI, measured syndromic anxiety as a primary outcome, and statistically analyzed the relationship between neuroimaging findings and anxiety symptoms. Results A total of 5982 articles were retrieved from the systematic search, of which 65 studied anxiety and 13 met eligibility criteria. These studies were published between 2004 and 2017, collectively analyzing 764 participants comprised of 470 patients with TBI and 294 non-TBI controls. Imaging modalities used included magnetic resonance imaging, functional magnetic resonance imaging, diffusion tensor imaging, electroencephalogram, magnetic resonance spectrometry, and magnetoencephalography. Eight of 13 studies presented at least one significant finding and together reflect a complex set of changes that lead to anxiety in the setting of TBI. The left cingulate gyrus in particular was found to be significant in 2 studies using different imaging modalities. Two studies also revealed perturbances in functional connectivity within the default mode network. Conclusions This is the first systemic review of neuroimaging changes associated with anxiety after TBI, which implicated multiple brain structures and circuits, such as the default mode network. Future research with consistent, rigorous measurements of TBI and syndromic anxiety, as well as attention to control groups, previous TBIs, and time interval between TBI and neuroimaging, are warranted. By understanding neuroimaging correlates of psychiatric symptoms, this work could inform future post-TBI screening and surveillance, preventative efforts, and early interventions to improve neuropsychiatric outcomes.

Background Hospital readmissions and outpatient visits contribute to the significant burden on healthcare systems. Obstructive sleep apnea (OSA) is a chronic medical condition that is associated with cardiovascular comorbidities and other chronic conditions. Inpatient and outpatient healthcare utilization rates in patients with OSA following hospitalization are unclear. Methods This. retrospective case-control cohort study utilized a nationwide database to assess if OSA is associated with higher healthcare utilization post-hospitalization. We compared healthcare utilization among patients with OSA versus without OSA between 2009-2014 after matching for demographic variables, geographic location, hospital environment, reason for admission, and severity of illness during hospitalization. We measured future healthcare utilization by the number of ICU admissions, hospital admissions, emergency room visits, and outpatient visits after being discharged from the index hospitalization. Results Two equal-sized cohorts comprised of 85,912 matched pairs were obtained. The OSA cohort demonstrated significantly higher rates of future ICU admissions, hospital admissions, emergency room visits, and outpatient visits. Matching for comorbid cardiovascular conditions continued to demonstrate higher healthcare utilization in the OSA group. Short-term outcomes during the index hospitalization were relatively similar between groups. Conclusions This retrospective database study demonstrated that OSA may be an independent marker of higher future healthcare utilization. On the other hand, the length of stay during the index hospitalization was not elevated. Prospective studies are needed to confirm these findings and investigate the impact of directing additional resources to inpatients with OSA.

BACKGROUND International Statistical Classification of Disease and Related Health Problems, 10th Revision codes (ICD-10) are used to characterize cohort comorbidities. Recent literature does not demonstrate standardized extraction methods. OBJECTIVE Compare COVID-19 cohort manual-chart-review and ICD-10-based comorbidity data; characterize the accuracy of different methods of extracting ICD-10-code-based comorbidity, including the temporal accuracy with respect to critical time points such as day of admission. METHODS Design: Retrospective cross-sectional study. MEASUREMENTS ICD-10-based-data performance characteristics relative to manual-chart-review. RESULTS Discharge billing diagnoses had a sensitivity of 0.82 (95% Confidence Interval [CI]: 0.79-0.85; comorbidity range 0.35-0.96). The past medical history table had a sensitivity of 0.72 (95% CI: 0.69-0.76; range 0.44-0.87). The active problem list had a sensitivity of 0.67 (95% CI: 0.63-0.71; range 0.47-0.71). On day of admission, the active problem list had a sensitivity of 0.58 (95% CI: 0.54-0.63; range 0.30-0.68) and past medical history table had a sensitivity of 0.48 (95% CI: 0.43-0.53; range 0.30-0.56). CONCLUSIONS AND RELEVANCE ICD-10-based comorbidity data performance varies depending on comorbidity, data source, and time of retrieval; there are notable opportunities for improvement. Future researchers should clearly outline comorbidity data source and validate against manual-chart-review. This article is protected by copyright. All rights reserved.

Parkinson's disease (PD) is a neurodegenerative disease that includes motor impairments, such as tremor, bradykinesia, and postural instability. Although eye movement deficits are commonly found in saccade and pursuit tasks, preservation of oculomotor function has also been reported. Here we investigate specific task and stimulus conditions under which oculomotor function in PD is preserved. Sixteen PD patients and 18 healthy, age-matched controls completed a battery of movement tasks that included stationary or moving targets eliciting reactive or deliberate eye movements: pro-saccades, anti-saccades, visually guided pursuit, and rapid go/no-go manual interception. Compared with controls, patients demonstrated systematic impairments in tasks with stationary targets: pro-saccades were hypometric and anti-saccades were incorrectly initiated toward the cued target in ∼35% of trials compared with 14% errors in controls. In patients, task errors were linked to short latency saccades, indicating abnormalities in inhibitory control. However, patients' eye movements in response to dynamic targets were relatively preserved. PD patients were able to track and predict a disappearing moving target and make quick go/no-go decisions as accurately as controls. Patients' interceptive hand movements were slower on average but initiated earlier, indicating adaptive processes to compensate for motor slowing. We conclude that PD patients demonstrate stimulus and task dependency of oculomotor impairments, and we propose that preservation of eye and hand movement function in PD is linked to a separate functional pathway through the superior colliculus-brainstem loop that bypasses the fronto-basal ganglia network. Our results demonstrate that studying oculomotor and hand movement function in PD can support disease diagnosis and further our understanding of disease progression and dynamics.SIGNIFICANCE STATEMENTEye movements are a promising clinical tool to aid in the diagnosis of movement disorders and to monitor disease progression. Although Parkinson's disease (PD) patients show some oculomotor abnormalities, it is not clear whether previously described eye movement impairments are task-specific. We assessed eye movements in PD under different visual (stationary vs moving targets) and movement (reactive vs deliberate) conditions. We demonstrate that PD patients are able to accurately track moving objects but make inaccurate eye movements toward stationary targets. The preservation of eye movements toward dynamic stimuli might enable patients to accurately act on the predicted motion path of the moving target. These results can inform the development of tools for the rehabilitation or maintenance of functional performance.

Background Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. Methods Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. Results Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P, Highlights • We examined psychotic symptoms in adolescents from a population-based birth cohort. • Common positive symptoms were paranoid ideation, visual and auditory hallucinations. • Negative symptoms were correlated with depressive and positive symptoms. • CRP was similarly associated with positive and negative symptom dimension scores. • CRP was specifically associated with auditory hallucinations and anhedonia.

Objective COVID-19 has disproportionately affected low-income communities and people of color. Previous studies demonstrated that race/ethnicity and socioeconomic status (SES) are not independently correlated with COVID-19 mortality. The purpose of our study is to determine the effect of race/ethnicity and SES on COVID-19 30-day mortality in a diverse, Philadelphian population. Methods This is a retrospective cohort study in a single center tertiary care hospital in Philadelphia, PA. The study includes adult patients hospitalized with polymerase-chain-reaction-confirmed COVID-19 between March 1st , 2020 and June 6th , 2020. The primary outcome was a composite of COVID-19 death or hospice discharge within 30 days of discharge. The secondary outcome was intensive care unit (ICU) admission. Results The study included 426 patients. 16.7% died, 3.3% were discharged to hospice, and 20.0% were admitted to the ICU. Using multivariable analysis, race/ethnicity was not associated with the primary nor secondary outcome. In Model 4, age greater than 75 (Odds Ratio [OR], 11.01; 95% confidence interval [CI], 1.96 to 61.97) and renal disease (OR 2.78; 95% CI, 1.31 to 5.90) were associated with higher odds of the composite primary outcome. "Very-low-income area" (OR 0.29; 95% CI, 0.12 to 0.71) and BMI 30-35 (OR 0.24; 95% CI, 0.08 to 0.69) were associated with lower odds of the primary outcome. Conclusions When controlling for demographics, SES, and comorbidities, race/ethnicity was not independently associated with the composite primary outcome. Very-low SES, as extrapolated from census-tract-level income data, were associated with lower odds of the composite primary outcome. This article is protected by copyright. All rights reserved.

Introduction There exists substantial variability in the management of pelvic ring injuries among pelvic trauma surgeons. The objective of this study was to perform a comprehensive survey on the management of pelvic ring injuries among an international group of pelvic trauma surgeons to determine areas of agreement and disagreement. Methods A 45-item questionnaire was developed using an online survey platform and distributed to 30 international pelvic trauma surgeons. The survey consisted of general questions on the acute management of pelvic ring injuries and questions regarding 5 cases: Lateral compression (LC) type 1 injury, LC-3, Anterior-posterior compression (APC) type 3 injury, a combined vertical shear (VS) injury through the sacrum, and VS injury through sacroiliac joint. Respondents were shown blinded anteroposterior pelvis radiographs and axial computed tomography (CT) images for each case and asked if the injury needed fixation, the type of fixation, the order of fixation, and postoperative weight-bearing status. The Kappa statistic was calculated to assess agreement between respondents for each question. Results Nineteen out of 30 pelvic trauma surgeons completed the survey. Respondents practiced in Brazil (n = 1), Germany (n = 1), India (n = 1), Italy (n = 1) United Kingdom (n = 1), and the United States (n = 14). Of the 45 questions in this survey, 38 (84%) had minimal to no agreement among the respondents. There was moderate agreement, for performing lumbopelvic fixation when indicated, for anterior and posterior fixation of the LC-3 injury, and on forgoing EUA or stress X-rays for the APC-3 injury. There was strong agreement for open reduction and internal fixation of the anterior pelvic ring in the APC-3 injury and the VS injury through the SI joint. In contrast, LC-1 injury and combined VS pelvic ring injury through the sacrum had no areas of moderate to strong agreement. Discussion This study identified specific areas of pelvic ring injury management with minimal to no agreement among pelvic trauma surgeons. Future research should target these areas with a lack of agreement to decrease practice variability and improve patient outcomes.

OBJECTIVE To compare immediate quality of open reduction of femoral neck fractures by alternative surgical approaches. DESIGN Retrospective cohort study. SETTING Twelve Level 1 North American trauma centers. PATIENTS Eighty adults 18-65 years of age with isolated, displaced, OTA/AO type 31-B2 or -B3 femoral neck fractures treated with internal fixation. INTERVENTION Thirty-two modified Smith-Petersen anterior approaches versus 48 Watson-Jones anterolateral approaches for open reduction performed by fellowship-trained orthopaedic trauma surgeons. MAIN OUTCOME Reduction quality as assessed by 3 senior orthopaedic traumatologists as "acceptable" or "unacceptable" on AP and lateral postoperative radiographs. RESULTS No difference was observed in the rate of acceptable reduction by modified Smith-Petersen (81%) versus Watson-Jones (81%) approach (risk difference null, 95% confidence interval -17.4% to 17.4%, P = 1.00) with 90.4% panel agreement (Fleiss' weighted κ = 0.63, P < 0.01). Stratified analyses did not identify a significant difference in the rate of acceptable reduction between approaches when stratified by Pauwels angle, basicervical or transcervical fracture location, or posterior comminution. The Smith-Petersen approach afforded a better reduction when preoperative skeletal traction was not applied (RR = 1.67 [95% CI 1.10-2.52] vs. RR = 0.87 [95% CI 0.70-1.08], P = 0.006). CONCLUSIONS No difference was observed in the quality of open reduction of displaced femoral neck fractures in young adults when a Watson-Jones anterolateral approach versus a modified Smith-Petersen anterior approach was performed by orthopaedic trauma surgeons. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Endoprosthetic reconstruction after oncologic resection of bone tumors requires stable fixation between the prosthesis and residual host bone. Compressive osseointegration has been developed as an alternative to traditional stemmed implants to address the challenges and complications of achieving this fixation. Sufficient time has now passed from the advent of compressive implants to allow for an assessment of the intermediate-term and long-term results of this form of fixation. Questions/purposes At a minimum follow-up of 10 years after implantation of a compressive osseointegration device for oncologic reconstruction: (1) What is the risk of periprosthetic fracture, aseptic loosening, or implant breakage resulting in revision surgery for endoprosthesis removal? (2) What is the long-term cortical response at the host-endoprosthesis interface as visualized on plain radiographs? Methods A single-center, retrospective study was performed between 2002 and 2010, in which 110 patients with primary bone sarcoma of the proximal or distal femur were considered for oncologic resection and reconstruction. Patients were considered for a compressive osseointegration endoprosthesis if they were 50 years of age or younger, had not previously received femoral radiation, had no metabolic disease impairing bone healing, were not diagnosed with metastatic disease, and had life expectancy greater than six months. Of the 110 patients, 25 were treated with a compressive osseointegration implant of the proximal or distal femur, and 85 patients were treated with conventional stemmed implants or amputation because of older age, advanced disease, metabolic comorbidities, inability to tolerate a nonweightbearing postoperative period, or in the case of rotationplasty, patient preference. All patients who received this device during the period of study were considered eligible for inclusion in this review. The median (range) age was 18 years (7 to 50), and 13 of 25 patients were men. Five patients died of disease before the minimum follow-up duration of 10 years; two underwent amputation due to local recurrence and three died with the implant in situ, leaving 20 patients for complete analysis. Median follow-up was 144 months, and all 20 surviving patients had a minimum follow-up of 10 years (121 to 230 months). The primary endpoint was reoperation and implant removal for periprosthetic fracture, aseptic loosening, or mechanical breakage of any component of the compressive device in the endoprosthesis. In final analysis, death was considered a competing event to revision surgery, and cumulative incidence was reported after competing-event analysis. A secondary aim was radiographic evaluation of the host-implant interface to assess the long-term cortical response to compressive osseointegration. Results Spindle fracture or loosening was noted in three patients, and the remaining 17 patients maintained the compression device until the final follow-up. The risk of reoperation for aseptic loosening, periprosthetic fracture, or mechanical breakage of the implant using a competing risks estimator was 12% at 10 years (95% CI 0% to 26%). These complications occurred within 29 months of the index surgery; no patients had implant loosening or mechanical breakdown after this initial period. On radiographic assessment, 14 patients demonstrated cortical hypertrophy of the bone-implant interface, six patients had maintenance of the native cortical contour, and no patients had cortical atrophy or narrowing at the implant interface.Conclusion Long-term follow-up in patients with compressive osseointegrative endoprosthetic devices demonstrated no late revisions because of periprosthetic fracture, aseptic loosening, or implant breakage in this cohort with a minimum 10-year follow-up. There was no evidence of late-onset cortical atrophy or stress shielding at the host-implant interface. This study supports the long-term stability of the interface between host bone and the endoprosthesis in compressive osseointegration devices. Level of evidence Level IV, therapeutic study.

Laparoscopic sleeve gastrectomy (LSG) may be complicated by postoperative pain, nausea, and vomiting, with consequent increases in length of stay (LOS), decreased patient satisfaction, and higher costs. While enhanced recovery after surgery (ERAS) protocols have been in circulation for many years, there is no standard ERAS protocol for bariatric surgery. Data were collected prospectively and compared to a historical control. All patients undergoing LSG, ages 18 to 75, were included in the pathway; those with preoperative chronic opioid use were excluded from our results. Statistical analysis was performed using t-statistics and chi-squared test. Ninety patients undergoing LSG, performed by a single surgeon, were included in our ERAS group from November 26, 2018, to April 30, 2019, and were compared to a historical control of 570 patients who underwent LSG over the previous 5 years (pre-ERAS). Measured outcomes included discharge opioid prescriptions issued, hospital length of stay, 30-day readmissions, reoperations, morbidity, and mortality. Ten (11%) ERAS patients vs 100% of pre-ERAS patients received opioid prescriptions upon, or after, discharge (p

Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer­tain. We conducted a “meta‐umbrella” systematic synthesis of umbrella reviews, which are systematic reviews of meta‐analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non‐purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta‐analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta‐analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non‐organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four‐five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention‐deficit/hyperactivity disorder (ADHD), they were maternal pre‐pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer’s disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I‐III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence‐based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders.

Bariatric surgery produces weight loss in part by impacting appetite and eating behavior. Research suggests physical activity (PA) assists with regulation of appetite and eating during non-surgical weight loss, although whether PA carries similar benefits in the context of bariatric surgery is unknown.Evaluate associations of moderate-to-vigorous intensity PA (MVPA) and sedentary time (ST) with appetite sensations (hunger [homeostatic/hedonic], satiety) and eating regulation behaviors (restraint, disinhibition) before and during the initial year following bariatric surgery.Adult bariatric patients received an accelerometer to measure MVPA/ST and a smartphone to complete appetite/eating ratings at four semi-random times daily for 10 days at pre- and 3-, 6-, and 12-months post-surgery. Data were analyzed using generalized linear mixed models.Higher MVPA levels related to more satiety across time (This study is the first to show that MVPA and ST each associate with appetite and eating regulation in daily life before and during post-surgical weight loss. Results, while preliminary and requiring experimental confirmation, highlight potential for targeting bariatric patients' activity behaviors to enhance modulation of appetite, control of food intake, and resistance to overeating.

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that reduces levels of low-density lipoprotein-cholesterol (LDL-C) in the plasma by inhibition of cholesterol synthesis in hepatic cells, which leads to up-regulation of hepatic LDL receptors. Bempedoic acid is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. In this case study, we describe a patient with HeFH who had a prior excellent response to statin but unable to take the same, and a less than expected response to PCSK9i, in whom initiation of bempedoic acid led to a substantial reduction of LDL-C. Our findings suggest that patients who are quite responsive to statins may also be quite responsive to bempedoic acid, a medication that works in the same biochemical pathway as HMG-CoA reductase inhibitors. Additionally, this medication may be particularly effective at lowering LDL-C among individuals not on background statin therapy.

Background The purpose of the study was to identify genetic variants associated with rotator cuff disease by performing a genome-wide association study (GWAS) for shoulder impingement using the UK Biobank (UKB) cohort and then combining the GWAS data with a prior GWAS for rotator cuff tears. The loci identified by the GWAS and meta-analysis were examined for changes in expression following rotator cuff tearing using RNA sequencing. Methods A GWAS was performed using data from UKB with 3864 cases of shoulder impingement. The summary statistics from shoulder impingement and a prior study on rotator cuff tears were combined in a meta-analysis. Also, the previous association of 2 single-nucleotide polymorphisms (SNPs) with shoulder impingement from a published GWAS using the UKB was tested. Rotator cuff tendon biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and differential gene expression was measured by RNA sequencing for genes with variants associated with rotator cuff tearing. Results The shoulder impingement GWAS identified 4 new loci: LOC100506457, LSP1P3, LOC100506207, and MIS18BP1/LINC00871. Combining data with a prior GWAS for rotator cuff tears in a meta-analysis resulted in the identification of an additional 7 loci: SLC39A8/UBE2D3, C5orf63, ASTN2, STK24, FRMPD4, ACOT9/SAT1, and LINC00890/ALG13. Many of the identified loci have known biologic functions or prior associations with diseases, suggesting possible biologic pathways leading to rotator cuff disease. RNA sequencing experiments show that expression of STK24 increases whereas expression of SAT1 and UBE2D3 decreases following rotator cuff tearing. Two SNPs previously reported to show an association with shoulder impingement from a prior UKB GWAS were not validated in our study. Conclusion This is the first GWAS for shoulder impingement in which new data from UKB enabled the identification of 4 loci showing a genetic association. A meta-analysis with a prior GWAS for rotator cuff tearing identified an additional 7 loci. The known biologic roles of many of the 11 loci suggest plausible biologic mechanisms underlying the etiology of rotator cuff disease. The risk alleles from each of the genetic loci can be used to assess the risk for rotator cuff disease in individual patients, enabling preventative or restorative actions via personalized medicine.

Older adults show both age-related decreases in resting state functional connectivity and diminished sensorimotor function. Exercise has emerged as an intervention that may mitigate or even reverse these age-related declines. Here we sought to understand whether exercise impacts resting state functional connectivity, and motor acquisition and learning in older adults. Forty-two healthy older adults rested or completed 3 sets of high-intensity interval exercise (3 minutes at 75% maximal power output and 3 minutes light intensity) for a total of 23 minutes, then immediately practiced a complex, implicit motor task with their non-dominant hand across five separate sessions. Participants completed resting stage functional MRI before the first and after the fifth day of practice; they also returned 24-hours and 35-days following their fifth day of practice to complete short- and long-term retention tests to assess motor learning. Independent component analysis of resting state functional MRI revealed increased connectivity in the frontoparietal, the dorsal attentional, and cerebellar networks in the exercise group relative to the rest group. Seed-based analysis showed strengthened connectivity between the limbic system and right cerebellum, and between the right cerebellum and bilateral middle temporal gyri. There was no motor learning advantage for the exercise group; both rest and exercise groups demonstrated motor learning as measured at the short- and long-term retention tests. Our data suggest that exercise paired with a challenging implicit motor learning task in older adults can augment resting state functional connectivity without enhancing behaviour beyond that stimulated by skilled motor practice.

Background Racial disparities among clinical trial participants present a challenge to assess whether trial results can be generalized into patients representing diverse races and ethnicities. The objective of this study was to evaluate the impact of race and ethnicity on treatment response in patients with advanced non‐small cell lung cancer (aNSCLC) treated with programmed cell death‐1 (PD‐1) or programmed cell death‐ligand 1 (PD‐L1) inhibitors through analysis of real‐world data (RWD). Materials and Methods A retrospective cohort study of 11,138 patients with lung cancer treated at hospitals within the Mount Sinai Health System was performed. Patients with confirmed aNSCLC who received anti‐PD‐1/PD‐L1 treatment were analyzed for clinical outcomes. Our cohort included 249 patients with aNSCLC who began nivolumab, pembrolizumab, or atezolizumab treatment between November 2014 and December 2018. Time‐to‐treatment discontinuation (TTD) and overall survival (OS) were the analyzed clinical endpoints. Results After a median follow‐up of 14.8 months, median TTD was 7.8 months (95% confidence interval, 5.4–not estimable [NE]) in 75 African American patients versus 4.6 (2.4–7.2) in 110 White patients (hazard ratio [HR], 0.63). Median OS was not reached (18.4–NE) in African American patients versus 11.6 months (9.7–NE) in White patients (HR, 0.58). Multivariable Cox regression conducted with potential confounders confirmed longer TTD (adjusted HR, 0.65) and OS (adjusted HR, 0.60) in African American versus White patients. Similar real‐world response rate (42.6% vs. 43.5%) and disease control rate (59.6% vs. 56.5%) were observed in the African American and White patient populations. Further investigation revealed the African American patient group had lower incidence (14.7%) of putative hyperprogressive diseases (HPD) upon anti‐PD‐1/PD‐L1 treatment than the White patient group (24.5%). Conclusion Analysis of RWD showed longer TTD and OS in African American patients with aNSCLC treated with anti‐PD‐1/PD‐L1 inhibitors. Lower incidence of putative HPD is a possible reason for the favorable outcomes in this patient population. Implications for Practice There is a significant underrepresentation of minority patients in randomized clinical trials, and this study demonstrates that real‐world data can be used to investigate the impact of race and ethnicity on treatment response. In retrospective analysis of patients with advanced non‐small cell lung cancer treated with programmed cell death‐1 or programmed cell death‐ligand 1 inhibitors, African American patients had significantly longer time‐to‐treatment discontinuation and longer overall survival. Analysis of real‐world data can yield clinical insights and establish a more complete picture of medical interventions in routine clinical practice., Racial disparities in clinical trials affect whether trial results can be generalized for diverse patient populations. This article evaluates real‐world data to assess the impact of race and ethnicity on treatment response in patients with advanced non‐small cell lung cancer treated with PD‐1 or PD‐L1 inhibitors.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P

Background Probiotics have been demonstrated to ameliorate clinical signs of gastrointestinal diseases in dogs in various studies. However, the effect of probiotics in a healthy population, as well as factors contributing individualized responses, remain largely unknown. This trial examined gut microbiota (GM) and health outcomes in household dogs after synbiotic (SN) supplementation containing probiotics and inulin (a prebiotic). Healthy dogs were randomized to receive SN (50 mg/d inulin and 20 billion total CFU/d of L. reuteri, P. acidilactici, E. faecium, L. acidophilus, B. animalis, L. fermentum, L. rhamnosus) or placebo (PL) for 4 weeks. Owners completed a health survey and collected stool samples for GM profiling (shotgun metagenomic sequencing) at baseline and week 4 in both groups, and at week 6 in the SN group. Results A significant shift (p n = 24), but not PL group (n = 19), at week 4 relative to baseline. Forty-five bacterial species, 43 (96%) of which were Lactobacillales, showed an increase in the relative abundances (≥2 fold change, adjusted p E. coli also decreased at week 4 in the SN group (2.8-fold, adjusted p Proteobacteria and lower Lactobacillales responded more robustly to supplementation in terms of the change in β-diversity. Dogs fed SN tended to have lower diarrhea incidence (0% vs 16%, p = 0.08). Conclusions SN supplement had a short-term impact on the gut microbiota in healthy household dogs as characterized by shotgun metagenomic sequencing. Findings warrant further investigation with longer duration and populations at risk of gastrointestinal diseases. The magnitude of response to the supplement was associated with microbial profile at baseline. To our knowledge, this is the first study documenting such association and may provide a basis for personalized nutrition in companion dogs.

Background The association between sexual and physical abuse and subsequent depression is well-established, but the associations with specific depressive symptoms and sex differences remain relatively understudied. We investigated the associations of sexual and physical abuse with depressive symptoms in men and women in a large population cohort. Methods Observational study based on 151,396 UK Biobank participants. Exposures included self-reported experiences of childhood physical abuse and sexual abuse. Mid-life outcomes included current depressive symptoms score, individual depressive symptoms, and lifetime depression. We used logistic regression to test associations of childhood sexual/physical abuse with depressive outcomes. Results Recalled childhood sexual and physical abuse were both associated with current depressive symptoms score in adults. Results for individual symptoms-based analyses suggest that sexual and physical abuse are associated with all depressive symptoms, particularly suicidal behaviours. The associations between lifetime depression and sexual/physical abuse were not fully explained by current depressive symptoms score, indicating that these findings may not be fully attributable to recall bias. There was no indication of differential risk for specific depressive symptoms among men and women. Conclusions Sexual and physical abuse are robust risk factors for depression/depressive symptoms regardless of sex. Higher risk of suicidal behaviours associated with childhood sexual/physical abuse are of particular concern. Longitudinal research into sex-specific associations for individual depressive symptoms is required.

BACKGROUND Graduate medical education is being transformed from a time-based training model to a competency-based training model. While the application of ultrasound in the perioperative arena has become an expected skill set for anesthesiologists, clinical exposure during training is intermittent and nongraduated without a structured program. We developed a formal structured perioperative ultrasound program to efficiently train first-year clinical anesthesia (CA-1) residents and evaluated its effectiveness quantitatively in the form of a proficiency index. METHODS In this prospective study, a multimodal perioperative ultrasound training program spread over 3 months was designed by experts at an accredited anesthesiology residency program to train the CA-1 residents. The training model was based on self-learning through web-based modules and instructor-based learning by performing perioperative ultrasound techniques on simulators and live models. The effectiveness of the program was evaluated by comparing the CA-1 residents who completed the training to graduating third-year clinical anesthesia (CA-3) residents who underwent the traditional ultrasound training in the residency program using a designed index called a "proficiency index." The proficiency index was composed of scores on a cognitive knowledge test (20%) and scores on an objective structured clinical examination (OSCE) to evaluate the workflow understanding (40%) and psychomotor skills (40%). RESULTS Sixteen CA-1 residents successfully completed the perioperative ultrasound training program and the subsequent evaluation with the proficiency index. The total duration of training was 60 hours of self-based learning and instructor-based learning. There was a significant improvement observed in the cognitive knowledge test scores for the CA-1 residents after the training program (pretest: 71% [0.141 ± 0.019]; posttest: 83% [0.165 ± 0.041]; P < .001). At the end of the program, the CA-1 residents achieved an average proficiency index that was not significantly different from the average proficiency index of graduating CA-3 residents who underwent traditional ultrasound training (CA-1: 0.803 ± 0.049; CA-3: 0.823 ± 0.063, P = .307). CONCLUSIONS Our results suggest that the implementation of a formal, structured curriculum allows CA-1 residents to achieve a level of proficiency in perioperative ultrasound applications before clinical exposure.

Background Human milk oligosaccharides (HMOs) are complex glycans that are highly abundant in human milk. While over 150 HMOs have been identified, it is unknown how individual HMOs change in concentration over 24 months of lactation. Objectives To understand how HMO concentrations change over 24 months of lactation. Methods Breast milk samples were collected from participants in a longitudinal cohort study of Hispanic mother-infant pairs at 1, 6, 12, 18, and 24 months postpartum. Concentrations of 19 of the most abundant HMOs were measured using HPLC. Because the parent study is ongoing and not all participants have finished all time points yet, the sample sizes ranged per time point (n = 207 at 1 month; n = 109 at 6 months; n = 83 at 12 months; n = 59 at 18 months; and n = 28 at 24 months). Approximately 88% of participants were classified as HMO secretors-a genetic factor that affects concentrations of HMOs such as 2'fucosyllactose (2'FL) and lacto-N-fucopentaose I-while the remaining 12% were classified as nonsecretors. Mixed models were used to examine changes in HMO concentrations and relative abundances over the course of lactation. Results The majority of HMOs significantly decreased in concentration over the course of lactation. The exceptions were 2'FL, sialyl-lacto-N-tetraose b, and disialyl-lacto-N-tetraose, which did not change with time, and 3-fucosyllactose (3FL) and 3'-sialyllactose (3'SL), which significantly increased. The concentration of 3FL increased 10-fold, from 195 (IQR 138-415) μg/mL at 1 month to 1930 (1100-2630) μg/mL at 24 months, while 3'SL increased 2-fold, from 277 (198-377) μg/mL to 568 (448-708) μg/mL over the same time period. Conclusions These results indicate that HMOs do not decrease in concentration uniformly across lactation. In particular, 3FL and 3'SL increased over the course of lactation in this cohort. Future studies are required to fully understand the functions of these HMOs.

Objectives To determine the factors associated with successful union and eradication of infection in the setting of staged procedures to treat obviously infected nonunions of long bones. We hypothesize that patients with positive intraoperative cultures obtained at the time of definitive surgery for infected nonunions are more likely to have persistent nonunion than those with negative cultures. Design Multicenter retrospective review. Setting Eight academic Level 1 trauma centers. Patients/participants Patients who underwent staged management for obviously infected nonunion of a long bone. Main outcome measurements For each patient, initial fracture management, management of retained implants, number of debridements, grafting, bacteriology, antibiotic course, bone defect management, soft-tissue coverage, and definitive surgery performed were reviewed. Results A total of 134 patients were treated with staged procedures for obviously infected nonunion of a long bone (mean age 49 years, 60% open fractures, and mean follow-up 22 months). During definitive procedures, 120 patients had intraoperative cultures taken with 43% having positive cultures. For culture-positive patients, 41 patients achieved eventual union and 10 had persistent nonunion. Of 69 culture-negative patients, 66 achieved eventual union and 3 had persistent nonunion. The number of patients with union versus persistent nonunion was statistically significant between culture-positive and culture-negative groups (P = 0.015). Conclusions Management of infected nonunion in long bones with staged treatments before definitive fixation are beneficial but ultimately less effective when performed in the setting of positive bacterial cultures at the time of definitive management. Level of evidence Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

STUDY OBJECTIVE To compare the Fundamentals of Laparoscopic Surgery (FLS) exam scores between obstetrics and gynecology (OBGYN) and general surgery (GS) providers. DESIGN This is a retrospective cohort study at a single institution from July 2007 to May 2018. Categorical and continuous variables were analyzed with χ2 test, t test, and Wilcoxon rank sum test. SETTING Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, a tertiary care academic medical center. PATIENTS All providers who took the FLS exam at the Carl J. Shapiro Simulation and Skills Center at BIDMC. INTERVENTIONS FLS certification. MEASUREMENTS AND MAIN RESULTS A total of 205 BIDMC trainees and faculty took the FLS exam between July 2007 and May 2018, of which 176 were identified to be OBGYN or GS providers. The FLS certification pass rate was high for both specialties (97.0% OBGYN vs 96.1% sGS, p = .76). When comparing all providers, no significant difference was found in the mean manual skill test scores between surgical specialties (594.9 OBGYN vs 601.0 GS, p = .59); whereas, a significant difference was noted in the mean cognitive scores, with GS providers scoring higher than OBGYN providers (533.8 OBGYN vs 583.4 GS, p

Two cases of primary distal femur osteosarcoma with subsequent metastasis to the abdomen are presented. In both cases, the development of abdominal metastasis was quickly followed by patient decline and death. A review of the literature was performed, assessing the presentation and survival of patients with osteosarcoma metastasized to the abdomen. As illustrated by the current cases and the literature review, abdominal metastasis in osteosarcoma is often a late manifestation and terminal prognostic indicator. Nonetheless, early detection and prompt intervention of this less common site of disease metastasis may improve patient care and palliative therapy.

BACKGROUND: Gastrointestinal symptoms (GIS) are common after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). However, little is known about frequencies of GIS and their co-occurrence with risky eating behaviors. OBJECTIVES: Compare RYGB and SG on GIS and risky eating behaviors, and test associations between GIS and behaviors. SETTING: Two university hospitals in Northeastern United States. METHODS: RYGB (n = 18) and SG (n = 53) patients completed smartphone-based ecological momentary assessment of GIS and risky eating behaviors at 4 semi-random times daily for 10 days preoperatively and at 3, 6, and 12 months postoperatively. Study objectives were evaluated using generalized linear mixed-effects models. RESULTS: All available data from each assessment were included in the analysis: participant attrition was 18%, 30%, and 38% at 3, 6, and 12 months. All GIS were reduced at 12 months postoperative. Bloating decreased consistently whereas cramping, dehydration, and dumping first increased at 3 to 6 months then decreased to 12 months. Diarrhea, nausea, reflux, and vomiting decreased to 12 months for RYGB, but first increased at 3 to 6 months then decreased to 12 months for SG. Consumption of carbonated and sugar-sweetened beverages, fatty meats, and sweets decreased to 6 months then rebounded at 12 months. Eating past the first sign of fullness, drinking liquids with meals, not starting meals with protein, and fried foods consumption decreased to 6 months and then rebounded for RYGB only at 12 months. Alcohol consumption did not change. Sweets consumption and eating past the first sign of fullness were most consistently associated with GIS for both RYGB and SG patients. CONCLUSION: GIS and risky eating behaviors improved postoperatively, although patterns of change were variable and occasionally differed between RYGB and SG. Pending replication, patients may benefit from intervention to limit risky behaviors that are tailored to their surgery type. (Surg Obes Relat Dis 2021;17:475–483.) 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

The etiology of rotator cuff tearing is likely multifactorial, including a potential genetic predisposition. The purpose of the study was to identify genetic variants associated with rotator cuff tearing utilizing the UK Biobank (UKB) cohort, confirm variants using a separate genetic database, and evaluate tissue expression of genes with associated variants following rotator cuff tearing using RNA sequencing.Genome-wide association study (GWAS): A GWAS was performed using data from UKB with 5701 cases of rotator cuff injury. RNA sequencing analyses: rotator cuff biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humerus fracture (controls). Total RNA was extracted and differential gene expression was measured by RNAseq for genes with variants associated with rotator cuff tearing.The results of the UKB GWAS identified 3 loci that reached genome-wide statistical significance: 2 loci on chromosome 7 in GLCCI1 (rs4725069; P = 5.0E-09) and THSD7A (rs575224171; P = 5.3E-09), and 1 locus on chromosome 2 in ZNF804A (rs775583810; P = 3.9E-09). The association with rotator cuff injury of the GLCCI1 single-nucleotide polymorphism (SNP; rs4725069) was confirmed in the Kaiser Permanente Research Bank cohort (P = .008). Twenty previously reported SNPs in 12 genes were evaluated using summary statistics from the UKB GWAS, which confirmed 3 SNPs in TNC with rotator cuff injury (rs1138545, rs72758637, and rs7021589; all P.0024). Of 17 genes with variants associated with rotator cuff injury (14 previously from literature plus 3 new genes from current UKB GWAS), TIMP2, Col5A1, TGFBR1, and TNC were upregulated (P.001 for all) and THSD7A was downregulated (P = .005) in tears vs. controls in the RNA sequencing data set.The UKB GWAS has identified 3 novel loci associated with rotator cuff tearing (ZNF804A, GLCCI1, THSD7A). Expression of the THSD7A gene was significantly downregulated in rotator cuff tears vs. controls supporting a potential functional role. Three previously reported SNPs in the TNC gene were validated in the UKB GWAS, supporting a role for this gene in rotator cuff tearing. Finally, TIMP2, Col5A1, TGFBR1, and TNC genes were found to have significantly upregulated tissue expression in cases vs. controls supporting a biologic role in tearing for these genes.

This study was funded by the Medical Research Council, the European Community’s Seventh Framework Program grant [agreement HEALTH-F2-2009-241909 (Project EU-GEI)], São Paulo Research Foundation (grant 2012/0417-0), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR BRC at University College London and the Wellcome Trust (grant 101272/Z/12/Z)., Tripoli, G., Quattrone, D., Ferraro, L., Gayer-Anderson, C., Rodriguez, V., La Cascia, C., La Barbera, D., Sartorio, C., Seminerio, F., Tarricone, I., Berardi, D., Szöke, A., Arango, C., Tortelli, A., Llorca, P.-M., De Haan, L., Velthorst, E., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., Del-Ben, C.M., Menezes, P.R., Selten, J.-P., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., Lasalvia, A., Tosato, S., Richards, A., O'donovan, M., Rutten, B.P.F., Os, J.V., Morgan, C., Sham, P.C., Murray, R.M., Murray, G.K., Di Forti, M.

Purpose The innovative capacity of an organization is typically realized through unit-level teams. Previous studies correlate innovation performance with cultural diversity of teams, but note that team dynamics need to be optimized to derive maximum benefit. Herein, this study offers an assessment of available team building instruments through the lens of diverse innovation teams. In a demonstration project in the pharmaceutical industry, this study then outlines specific tools and approaches which can be successfully deployed through team coaching and mentoring. Design/methodology/approach A cluster of nine innovation teams with varying degrees of cultural diversity was provided with assessment and management instruments which had been identified and field tested by a mentoring team. Content included cultural awareness tools, innovation team profiling methods and Team Science (SciTS) ideology. Teams were funded, coached and mentored through a six-month performance period and assessed at regular intervals. Findings Team assessments provided correlations between performance (measured by project completion and new intellectual property generated) and diversity together with wealth of information on intra-team culture and dynamics. Concrete recommendations from the study include adoption of appropriate communication standards to promote inclusivity, use of SciTS operational tracking metrics to enhance engagement, use of the FourSight group profiling methodology and cultural quotient scale cultural awareness instruments at team-forming stage to promote effective dynamics and enhance inclusivity. Practical implications Cultural diversity has a positive impact on innovation teams. This said, for maximum benefit cultural awareness of team members should be optimized to avoid unintended conflicts developing. Such issues can be exacerbated when teams are deployed remotely and preventative measures should be established. These issues became of heightened significance as a result of telecommuting imposed by the COVID-19 pandemic and have longer-term implications, as corporations consider global air travel reduction through environmental concerns. A tracking tool is described to monitor team engagement and promote inclusivity. It is expected that the learnings can influence how teams can best form, normalize and operate within corporate innovation programs and form the basis of long-term impact studies. Originality/value This represents the first systematic study on the impact of cultural diversity and team dynamics within innovation programs in the pharmaceutical industry. The tools and methodologies deployed are widely available and can be adopted by innovation teams in many adjacent industries with established innovation ecosystems.

BackgroundThe clinical course of psychotic disorders is highly variable. Typically, researchers have captured different course types using broad pre-defined categories. However, whether these adequately capture symptom trajectories of psychotic disorders has not been fully assessed. Using data from AESOP-10, we sought to identify classes of individuals with specific symptom trajectories over a 10-year follow-up using a data-driven approach.MethodAESOP-10 is a follow-up, at 10 years, of 532 incident cases with a first episode of psychosis initially identified in south-east London and Nottingham, UK. Using extensive information on fluctuations in the presence of psychotic symptoms, we fitted growth mixture models to identify latent trajectory classes that accounted for heterogeneity in the patterns of change in psychotic symptoms over time.ResultsWe had sufficient data on psychotic symptoms during the follow-up on 326 incident patients. A four-class quadratic growth mixture model identified four trajectories of psychotic symptoms: (1) remitting-improving (58.5%); (2) late decline (5.6%); (3) late improvement (5.4%); (4) persistent (30.6%). A persistent trajectory, compared with remitting-improving, was associated with gender (more men), black Caribbean ethnicity, low baseline education and high disadvantage, low premorbid IQ, a baseline diagnosis of non-affective psychosis and long DUP. Numbers were small, but there were indications that those with a late decline trajectory more closely resembled those with a persistent trajectory.ConclusionOur current approach to categorising the course of psychotic disorders may misclassify patients. This may confound efforts to elucidate the predictors of long-term course and related biomarkers.

Medicated chewing gum has been recognised as a new advanced drug delivery method, with a promising future. Its potential has not yet been fully exploited because currently there is no gold standard for testing the release of agents from chewing gum in vitro . This study presents a novel humanoid chewing robot capable of closely replicating the human chewing motion in a closed environment, incorporating artificial saliva and allowing measurement of xylitol release from the gum. The release of xylitol from commercially available chewing gum was quantified following both in vitro and in vivo mastication. The chewing robot demonstrated a similar release rate of xylitol as human participants. The greatest release of xylitol occurred during the first 5 minutes of chewing and after 20 minutes of chewing only a low amount of xylitol remained in the gum bolus, irrespective of the chewing method used. Saliva and artificial saliva solutions respectively were collected after 5, 10, 15 and 20 minutes of continuous chewing and the amount of xylitol released from the chewing gum determined. Bioengineering has been implemented as the key engineering strategy to create an artificial oral environment that closely mimics that found in vivo. These results demonstrate the chewing robot with built-in humanoid jaws could provide opportunities for pharmaceutical companies to investigate and refine drug release from gum, with reduced patient exposure and reduced costs using this novel methodology.

The current management of patients with primary psychosis worldwide is often remarkably stereotyped. In almost all cases an antipsychotic medica­tion is prescribed, with second-generation antipsychotics usually preferred to first-generation ones. Cognitive behavioral therapy is rarely used in the vast majority of countries, although there is evidence to support its efficacy. Psychosocial interventions are often provided, especially in chronic cases, but those applied are frequently not validated by research. Evidence-based family interventions and supported employment programs are seldom implemented in ordinary practice. Although the notion that patients with primary psychosis are at increased risk for cardiovascular diseases and diabetes mellitus is widely shared, it is not frequent that appropriate measures be implemented to address this problem. The view that the management of the patient with primary psychosis should be personalized is endorsed by the vast majority of clinicians, but this personalization is lacking or inadequate in most clinical contexts. Although many mental health services would declare themselves “recovery-oriented”, it is not common that a focus on empowerment, identity, meaning and resilience is ensured in ordinary practice. The present paper aims to address this situation. It describes systematically the salient domains that should be considered in the characterization of the individual patient with primary psychosis aimed at personalization of management. These include positive and negative symptom dimensions, other psychopathological components, onset and course, neurocognition and social cognition, neurodevelopmental indicators; social functioning, quality of life and unmet needs; clinical staging, antecedent and concomitant psychiatric conditions, physical comorbidities, family history, history of obstetric complications, early and recent environmental exposures, protective factors and resilience, and internalized stigma. For each domain, simple assessment instruments are identified that could be considered for use in clinical practice and included in standardized decision tools. A management of primary psychosis is encouraged which takes into account all the available treatment modalities whose efficacy is supported by research evidence, selects and modulates them in the individual patient on the basis of the clinical characterization, addresses the patient’s needs in terms of employment, housing, self-care, social relationships and education, and offers a focus on identity, meaning and resilience.

There is a high prevalence of obesity and type 2 diabetes in the United States, particularly among Hispanic women, which may be partly explained by failure to lose gestational weight during the postpartum period. Previous work indicates that protein and amino acids may protect against weight gain; therefore, this study examined the impact of dietary protein and amino acid intake on changes in postpartum weight and the percent of women meeting the Estimated Average Requirement (EAR) for these dietary variables among Hispanic women from the Southern California Mother's Milk Study (n = 99). Multivariable linear regression analysis was used to examine the associations between protein and amino acid intake with change in weight after adjusting for maternal age, height, and energy intake. Women's weight increased from prepregnancy to 1‐month and 6‐months postpartum (71.1 ± 14.6 vs. 73.1 ± 13.1 vs. 74.5 ± 14.6 kg, p, Among 99 Hispanic women from the Southern California Mother's Milk Study, dietary protein was not associated with postpartum weight change; however, several amino acids (i.e., phenylalanine, tryptophan, valine, isoleucine, and cysteine) were inversely associated with change in weight from 1‐ to 6‐months postpartum. Additionally, less than 50% of women were consuming the recommended amounts of dietary protein, tyrosine, and cysteine. These results suggest that dietary protein and amino acids should be considered when developing obesity prevention strategies for Hispanic women during the postpartum period.

Background The disease course of adult immunoglobulin A (IgA) vasculitis (IgAV; Henoch–Schönlein purpura) has not been well defined. Methods In a retrospective survey, we studied 85 adult IgAV patients with extended follow-up (median 43 months) for 67 patients. Results Only 33 of 67 (49%) achieved complete remission. Ongoing renal disease was the most common persistent organ manifestation, but extra-renal disease activity was also present in >50% of patients not achieving complete remission. Twenty-nine of 67 (43%) had relapsing disease, with 18/67 (27%) experiencing several relapses. Skin disease was the most common feature in relapsing patients, followed by nephritis. At 4 years of follow-up, 6 of 29 (21%) experienced progressive disease and 10/29 (34%) relapsing disease. Five of 67 (7%) developed nephritis after diagnosis, within the first 6 months of follow-up. At final follow-up, 10 of 67 (15%) had chronic kidney disease Stage ≥G3a, 18 (27%) haematuria and 13 (19%) proteinuria. No therapy appeared particularly effective and only 6/17 patients treated with mycophenolate mofetil experienced a good response. Conclusions The disease course of adult IgAV is different from that seen in children, with higher frequency of persisting and relapsing disease. Renal disease is the main determinant of ongoing disease activity, but extra-renal features were seen in >50% of patients with chronic disease activity. No clear conclusions on use or choice of immunosuppressive agent could be made based on our experience.

Adults with major depressive disorder (MDD) with psychotic features (delusions and/or hallucinations) have more severe symptoms and a worse prognosis. Subclinical psychotic symptoms are more common in adolescents than adults. However, the effects of psychotic symptoms on outcome of depressive symptoms have not been well studied in adolescents. Depressed adolescents aged 11–17 with and without psychotic symptoms were compared on depression severity scores at baseline and at 28- or 42-week follow-up in two large UK cohorts. Psychotic symptoms were weakly associated with more severe depression at baseline in both cohorts. At follow-up, baseline psychotic symptoms were only associated with depressive symptoms in one sample; in the other, the effect size was close to zero. This supports the DSM5 system of psychotic symptoms being a separate code to severity rather than the ICD10 system which only allows the diagnosis of psychotic depression with severe depression. There was no clear support for psychotic symptoms being a baseline marker of treatment response.

Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on

Over the last decade, the microbiome has received increasing attention as a key factor in macroorganism fitness. Sustainable pest management requires an understanding of the complex microbial endophyte communities existing symbiotically within plants and the way synthetic pesticides interact with them. Fungal endophytes are known to benefit plant growth and fitness and may deter pests and diseases. Recent advances in high-throughput sequencing (HTS) have enabled integrative microbiome studies, especially in agricultural contexts. Here, we profile the fungal endophyte community in the phyllosphere of two barley (Hordeum vulgare) cultivars exposed to two systemic foliar fungicides using metabarcoding, an HTS tool that constructs community profiles from environmental DNA. We studied the fungal nuclear ribosomal large subunit D2 and internal transcribed spacer 2 (ITS2) DNA markers through a bioinformatics pipeline introduced here. We found 88 and 128 unique amplicon sequence variants (ASVs) using the D2 and ITS2 metabarcoding assays, respectively. With principal coordinate analysis and permutational analysis of variance, ASV diversity did not change in response to barley cultivar or fungicide treatment; however, the community structure of unsprayed plants did change between two collection times 8 days apart. The workflow described here can be applied to other microbiome studies in agriculture and we hope it encourages further research into crop microbiomes to improve agroecosystem management.

Black Girls Dive Foundation (BGDF) was established to empower and inspire young girls to explore their STEM (Science, Technology, Engineering and Mathematics) identities through aquatic-based STEM activities and ocean stewardship. BGDF’s STREAMS program integrates aquatic-based recreation of SCUBA with scientific diving, ocean science, and stewardship. STREAMS explores ways to have broader reach and impact on STEM identity and STEM interest for individuals who are historically underserved and underrepresented in the sciences and provides research informed ways to close the divide and bring about equity.

Although Directed Energy Deposition (DED) has more than a two and a half decade history, the difficulty of consistently controlling this process is still limiting its adoption. Achieving robust printing of arbitrary shapes with high-fidelity (macro-scale) geometry and uniform pre-determined micro structure throughout relies on careful coordination of many factors (some of which still rely on the knowledge of the system user). Key to this endeavor is controlling the activity of the melt pool and managing its influence on surrounding material (including due to reheating cycles). Even with emerging in-process melt pool control methods, translating ideal steady state melt pool models into practical use while creating arbitrary shapes on-the-fly can be difficult to visualize and validate. Despite recent advances in the field of melt pool control, intuitive visualization of melt pool signatures and confirmation of how they affect the quality of the deposition is yet to be found. A process control indicating possible flaws or defective regions in the material component, as well as certifying the uniformity of characteristics during deposition would be of great help to improve the process itself and further diffuse its application. This study presents the development of a novel and innovative method for acquiring, processing and visually showing DED process signatures to assess progress toward fully automated melt pool control. This methodology relies on incrementally building a map of actual process conditions by merging multiple data streams collected during the deposition process for each layer and then plotting the recorded signatures along the 2D toolpath position. This concept has been realized with a new software application called HeatMAP. This application uses data supplied by the AMBIT™ Melt Pool Measurement ‘MPM’ system wherein images from the melt pool are acquired by a CMOS camera and processed. A second data stream is simultaneously collected directly from the CNC including the actual feed speed and the nozzle positions by using the DTConnect software (an application developed in this study based on FANUC FOCAS library). A visualization of the merged data sets in the HeatMAP software then imparts to the user an intuitive way of assessing the process quality using visualization as an indicator of metallurgical quality. To demonstrate the utility of this approach, two sets of experiments were undertaken: one as a benchmark, where process signatures were captured by the MPM system in monitoring only mode and another with active closed-loop laser control. When the melt pool measurement system is used in closed loop mode, the laser power is varied in order to maintain a target melt pool area within a specific range. At present, image data was acquired and processed throughout two deposition strategies, which were used to prove the mapping concept, its capabilities and methodology. The methods behind HeatMAP and DTConnect presented in this study, demonstrate the potential for these applications to accelerate the development of more stable deposition parameters, and process planning and control in the future. Using the proposed control, improvements to material quality are expected in the DED process.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.

Background High-quality and high-utility feedback allows for the development of improvement plans for trainees. The current manual assessment of the quality of this feedback is time consuming and subjective. We propose the use of machine learning to rapidly distinguish the quality of attending feedback on resident performance. Methods Using a preexisting databank of 1925 manually reviewed feedback comments from 4 anesthesiology residency programs, we trained machine learning models to predict whether comments contained 6 predefined feedback traits (actionable, behavior focused, detailed, negative feedback, professionalism/communication, and specific) and predict the utility score of the comment on a scale of 1-5. Comments with ≥4 feedback traits were classified as high-quality and comments with ≥4 utility scores were classified as high-utility; otherwise comments were considered low-quality or low-utility, respectively. We used RapidMiner Studio (RapidMiner, Inc, Boston, MA), a data science platform, to train, validate, and score performance of models. Results Models for predicting the presence of feedback traits had accuracies of 74.4%-82.2%. Predictions on utility category were 82.1% accurate, with 89.2% sensitivity, and 89.8% class precision for low-utility predictions. Predictions on quality category were 78.5% accurate, with 86.1% sensitivity, and 85.0% class precision for low-quality predictions. Fifteen to 20 hours were spent by a research assistant with no prior experience in machine learning to become familiar with software, create models, and review performance on predictions made. The program read data, applied models, and generated predictions within minutes. In contrast, a recent manual feedback scoring effort by an author took 15 hours to manually collate and score 200 comments during the course of 2 weeks. Conclusions Harnessing the potential of machine learning allows for rapid assessment of attending feedback on resident performance. Using predictive models to rapidly screen for low-quality and low-utility feedback can aid programs in improving feedback provision, both globally and by individual faculty.

BACKGROUND: Our prior studies revealed that infant somatic growth is influenced by fructose in breast milk, and fructose in breast milk is increased in response to maternal sugar-sweetened beverage (SSB) intake in lactation. It is unknown whether infant neurodevelopmental outcomes are also influenced by maternal SSBs in lactation. OBJECTIVES: To determine whether infant cognitive development at 24 postnatal months was influenced by maternal fructose consumption during lactation, and whether this relation persisted after accounting for maternal SSB and juice (SSB + J) intake. METHODS: Hispanic mother–infant pairs (n = 88) were recruited across the spectrum of prepregnancy BMI. Mothers completed two 24-h dietary recalls at 1 and 6 postnatal months, and reported breastfeedings per day. The Bayley-III Scales of Infant Development were administered at 24 postnatal months to assess infant cognition. Linear regressions were used to examine associations, reported as unstandardized (B) coefficients, 95% CIs, and P values. RESULTS: Mothers consumed 1656 ± 470 kcal, 21.8 ± 12 g fructose, and 2.5 ± 2.6 servings SSBs + J, and reported 6.9 ± 2.1 breastfeedings per day at 1 postnatal month. Controlling for maternal age, prepregnancy BMI, education level, kilocalories, infant age, sex, and birthweight revealed that infant cognitive development scores at 24 postnatal months correlated inversely with maternal fructose consumption at 1 postnatal month (B = −0.08; 95% CI = −0.13, −0.03; P

Introduction Clinicians, payers, guideline committees, and policymakers support the use of high-intensity statins in patients at high risk for complications of cardiovascular disease (CVD). Guidelines and recommendations provide guidance on next steps for patients with inadequate low-density lipoprotein cholesterol (LDL-C) control on maximally tolerated statin or for those who are statin-intolerant. Ezetimibe and evolocumab improve CV outcomes when added to statins in high-CV-risk populations. The aim of the study was to compare evolocumab and ezetimibe for lipid-lowering efficacy and safety. Methods We summarized data from 1427 patients from three phase 3 evolocumab studies comparing double-blinded evolocumab vs. ezetimibe. These studies evaluated four distinct populations: those free of CVD receiving each agent as monotherapy, patients with CVD receiving add-on therapy to low- or high-intensity statin, and statin-intolerant patients. Lipid efficacy and safety were reported at week 12. Results Across the studies, evolocumab reduced LDL-C by a mean 55–61% from baseline to week 12; ezetimibe lowered LDL-C by 18–20% from baseline (mean difference = 38–43% favoring evolocumab; p, Plain language summary A statin is a type of medication that is used, with diet and exercise, to lower cholesterol levels and help prevent a heart attack or stroke caused by atherosclerosis. Atherosclerosis is the hardening and narrowing of blood vessels known as arteries from a buildup of plaque, usually made up of cholesterol and other fatty substances. LDL cholesterol, also known as “bad” cholesterol, is one of the most important risk factors for having a heart attack, and can be lowered. Patients with a high risk of heart disease may benefit from the additional lowering of LDL cholesterol beyond that achieved by statins alone. The medication evolocumab reduced LDL cholesterol levels and improved other risk factors more than the medication ezetimibe in four studies. These studies included patients who were receiving statins and those who were not, including those who did not receive statins because of statin-related side effects. Both evolocumab and ezetimibe had good safety profiles.

Introduction Heart failure remains a substantive contributor to patient morbidity and mortality rates worldwide and represents a significant burden on the healthcare ecosystem. Faced with persistent physical symptoms and debilitating social consequences, patients follow complex treatment regimens and often have difficulty adhering to them. Purpose In this manuscript, we review factors which contribute to low adherence rates and advance potential single- and multi-factor-based interventions. It is hoped that these observations can lead to improvements in managed care of this vulnerable population of patients. Methods A narrative review of the primary literature was performed on contributing factors with primary focus on the period 2015–2020 using available databases and search engines. Adherence pain points identified were mapped against a series of potential solutions which are presented. Results Enhancement of treatment adherence relies on two approaches viz. single-factor and multi-factor solutions. Single factors identified include electronic reminders, enhanced health education, financial incentives, gamification strategies, community drivers, persona-based modeling, and burden relief of poly pharmacy. Multi-factor solutions combine two or more of the seven approaches offering the potential for flexible interventions tailored to the individual. Discussion and Conclusion Heart failure patients with poor adherence have increased mortality, hospitalization needs, and healthcare costs. This review highlights current single-factor and multi-factor adherence methods. Against a backdrop of diversity of approaches, multi-factor solutions cast the widest net for positively influencing adherent behaviors. A key enabler lies in the development and leveraging of patient personas in the synthesis of successful intervention methods. Deployable solutions can also be envisioned in clinical trials where adherence tracking represents an essential component.

BackgroundChildhood infections are associated with adult psychosis and depression, but studies of psychotic experiences (PEs) and depressive symptoms in childhood, adolescence, and early-adulthood are scarce. Previous studies have typically examined severe infections, but studies of common infections are also scarce.MethodsUsing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, we examined associations of the number of infections in childhood from age 1.5 to 7.5 years with depressive symptom scores at age 10, 13, 14, 17, 18, and 19 years, and with PEs at 12 and 18 years. We performed additional analysis using infection burden (‘low’ = 0–4 infections, ‘medium’ = 5–6, ‘high’ = 7–9, or ‘very high’ = 10–22 infections) as the exposure.ResultsThe risk set comprised 11 786 individuals with childhood infection data. Number of childhood infections was associated with depressive symptoms from age 10 (adjusted beta = 0.14; standard error (s.e.) = 0.04; p = s.e. = 0.08; p = 0.04), and with PEs at age 12 (suspected/definite PEs: adjusted odds ratio (OR) = 1.18; 95% confidence interval (CI) = 1.09–1.27). These effect sizes were larger when the exposure was defined as very high infection burden (depressive symptoms age 17: adjusted beta = 0.79; s.e. = 0.29; p = 0.01; suspected/definite PEs at age 12: adjusted OR = 1.60; 95% CI = 1.25–2.05). Childhood infections were not associated with depressive/psychotic outcomes at age 18 or 19.ConclusionsCommon early-childhood infections are associated with depressive symptoms up to mid-adolescence and with PEs subsequently in childhood, but not with these outcomes in early-adulthood. These findings require replication including larger samples with outcomes in adulthood.

ObjectivesThe enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis.MethodsUsing the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA.ResultsGlobal deletion of 11β-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11β-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11β-HSD1.ConclusionsWe identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and amplification by 11β-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.

Background Nontuberculous mycobacteria (NTM) are a rare cause of infectious tenosynovitis of the upper extremity. Using molecular methods, clinical microbiology laboratories are increasingly reporting identification down to the species level. Improved methods for speciation are revealing new insights into the clinical and epidemiologic features of rare NTM infections. Methods We encountered 3 cases of epidemiologically linked upper extremity NTM tenosynovitis associated with exposure to hurricane-damaged wood. We conducted whole-genome sequencing to assess isolate relatedness followed by a literature review of NTM infections that involved the upper extremity. Results Despite shared epidemiologic risk, the cases were caused by 3 distinct organisms. Two cases were rare infections caused by closely related but distinct species within the Mycobacterium terrae complex that could not be differentiated by traditional methods. The third case was caused by Mycobacterium intracellulare. An updated literature review that focused on research that used modern molecular speciation methods found that several species within the M. terrae complex are increasingly reported as a cause of upper extremity tenosynovitis, often in association with environmental exposures. Conclusions These cases illustrate the importance of molecular methods for speciating phenotypically similar NTM, as well as the limitations of laboratory-based surveillance in detecting point-source outbreaks when the source is environmental and may involve multiple organisms.

Individuals diagnosed with schizophrenia are often assigned other psychiatric diagnoses during their lives. The significance of changing diagnosis has not been widely studied.Our aim was to examine the association between diagnostic change and later outcome.Individuals' diagnostic history, clinical and social outcomes were extracted from the AESOP-10 study, a 10-year follow-up of first episode psychosis cases. The association between outcome and different patterns of diagnosis over time were assessed using linear or logistic regression.Individuals always diagnosed with schizophrenia (Individuals always and never diagnosed with schizophrenia had different outcomes. In cases of diagnostic instability participants had similar outcomes to those always assigned the diagnosis they changed to irrespective of initial diagnosis.

Background Enhancing cognitive load while performing a bimanual surgical task affects performance. Whether repeated training under this condition could benefit performance in an operating room was tested using a virtual reality simulator with cognitive load applied through two-digit math multiplication questions. Method 11 subjects were randomized to Control, VR and VR + CL groups. After a pre-test, VR and VR + CL groups repeated the peg transfer task 150 times over 15 sessions with cognitive load applied only for the last 100 trials. After training, all groups took a post-test and two weeks later the retention test with and without cognitive load and the transfer task on a pig intestine of 150 cm long under cognitive load. Results and conclusion Mixed ANOVA analysis showed significant differences between the control and VR and VR + CL groups (p = 0.013, p = 0.009) but no differences between the VR + CL and the VR groups (p = 1.0). GOALS bimanual dexterity score on transfer test show that VR + CL group outperformed both Control and VR groups (p = 0.016, p = 0.03). Training under cognitive load benefitted performance on an actual surgical task under similar conditions.