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Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Indications for reverse total shoulder arthroplasty (RTSA) have expanded to include primary glenohumeral osteoarthritis (GHOA) with an intact rotator cuff. Limited evidence exists on RTSA in patients with primary GHOA and no posterior glenoid wear (Walch A1, A2, and B1 morphologies). The purpose of this retrospective cohort study was to determine if glenoid morphology is associated with clinical outcomes in patients undergoing RTSA for primary GHOA.A retrospective review of prospectively collected data was performed in patients undergoing primary RTSA for GHOA with a minimum of 2-year clinical follow-up. Preoperative computed tomography and magnetic resonance imaging were used to categorize glenoid morphology as described by the modified Walch classification. Pre- and postoperative American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), Single Assessment Numeric Evaluation (SANE), visual analog scale (VAS) pain scores, and range of motion (ROM) measurements were compared across Walch glenoid subtypes. The percentage of patients that reached previously established clinically significant thresholds for minimal clinically important difference (MCID) and substantial clinical benefit (SCB) was also comparatively assessed. Multivariable analysis was used to evaluate the association between glenoid morphology and postoperative ASES score while controlling for potentially confounding variables.Of the 247 consecutive patients, 197 were available at a minimum 2-year follow-up (80%). Significant improvements were seen in ASES, VAS pain, SANE, and ROM from baseline to final postoperative follow-up in the combined patient cohort (all P.001). Most (98.0%) patients reached MCID, and 90.9% of patients reached SCB for ASES threshold. No significant differences were found among Walch subtypes in terms of preoperative to postoperative improvement in ASES (P = .39), SANE (P = .4), VAS pain (P = .49), forward elevation (P = .77), external rotation (P = .45), or internal rotation (P= 0.1). The only significant difference in postoperative outcomes between Walch glenoid subtypes was higher postoperative ASES scores among type B3 glenoids compared with type A1 glenoids (P = .03) on univariate analysis. However, no individual Walch glenoid subtype was associated with lower postoperative ASES scores on multivariable analysis (P.05).Primary RTSA provides excellent short-term outcomes in patients with glenohumeral arthritis with intact rotator cuff, regardless of the degree of preoperative glenoid deformity. Surgeons can use these data to support the use of RTSA for glenohumeral arthritis in a more standardized way.

Though long-neglected, the right heart (RH) is now widely accepted as a pivotal player in heart failure (HF) either with reduced (HFrEF) or preserved (HFpEF) ejection fraction. The chronic overload of the pulmonary microcirculation results in an initial phase characterized by right ventricular (RV) hypertrophy, right atrial (RA) dilation, and diastolic dysfunction. This progresses to overt right heart failure (RHF) when RV dilation and systolic dysfunction lead to RV-pulmonary arterial uncoupling with low RV output. In the context of its established relevance to progression of HF, clinicians should consider assessment of the right heart with information from clinical assessment, biomarkers, and imaging. Notably, no single parameter can predict prognosis alone in HF. Assessments should simultaneously encompass RV systolic function, pulmonary pressures, an estimation of RV-PA coupling, and right heart morphology. Despite a large volume of evidence indicating the relevance of right heart function to the clinical syndrome of HF, evidence-based management strategies are lacking. Targeting RH dysfunction in HF should be an objective of future investigations, being an unmet need in the current management of HF.

Pulmonary arterial hypertension is a rare disease characterized by pulmonary microvasculature remodeling leading to right ventricular failure and death. Medical management of pulmonary hypertension has grown increasingly complex as more therapeutic agents have been developed. Evolving treatment strategies leveraging the endothelin, nitric oxide, and prostacyclin pathways lead to improved exercise capacity and outcomes in patients; however, significant opportunities for advancement remain.

Objectives The REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study evaluated the effect of macitentan on right ventricular (RV) and hemodynamic outcomes in patie...

The presence of functional somatic syndromes (chronic physical symptoms with no identifiable organic cause) in patients undergoing elective joint arthroplasty may affect the recovery experience. We explored the prevalence of functional somatic syndromes among shoulder arthroplasty patients, as well as their association with postoperative outcomes and costs.We identified 480 patients undergoing elective total shoulder arthroplasty (anatomic or reverse) between 2015 and 2018 in our institutional registry with minimum 2-year follow-up. Medical records were queried for the presence of 4 well-recognized functional somatic syndromes: fibromyalgia, irritable bowel syndrome, chronic headaches, and chronic low-back pain. Multivariable linear regression modeling was used to determine the independent association of these diagnoses with hospitalization time-driven activity-based costs and 2-year postoperative American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE), and pain scores.Nearly 1 in 5 patients (17%) reported at least 1 functional somatic syndrome. These patients were more likely to be women, to be chronic opioid users, to report more allergies, to have a diagnosis of anxiety, and to have shoulder pathology other than degenerative joint disease (all P ≤ .001). After multivariable adjustment, the presence of at least 1 functional somatic syndrome was independently predictive of lower 2-year ASES (-9.75 points) and SANE (-7.63 points) scores and greater residual pain (+1.13 points) (all P ≤ .001). When considered cumulatively, each additional functional disorder was linked to a stepwise decrease in ASES and SANE scores and an increase in residual pain (P.001). These patients also incurred higher hospitalization costs, with a stepwise rise in costs with an increasing number of disorders (P.001).Functional somatic syndromes are common in patients undergoing shoulder arthroplasty and correlate with suboptimal outcomes and greater resource utilization. Efforts to address the biopsychosocial determinants of health that affect the value proposition of shoulder arthroplasty should be prioritized in the redesign of care pathways and bundling initiatives.

BACKGROUND The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension. RESEARCH QUESTION What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects? STUDY DESIGN AND METHODS This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019. RESULTS Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001). INTERPRETATION Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov.

Acute pulmonary embolism (PE) is associated with significant morbidity and mortality. The management paradigm for acute PE has evolved in recent years with wider availability of advanced treatment modalities ranging from catheter-directed reperfusion therapies to mechanical circulatory support. This evolution has coincided with the development and implementation of institutional pulmonary embolism response teams (PERT) nationwide and internationally. Because most institutions are not equipped or staffed for advanced PE care, patients often require transfer to centers with more comprehensive resources, including PERT expertise. One of the unmet needs in current PE care is an organized approach to the process of interhospital transfer (IHT) of critically ill PE patients. In this review, we discuss medical optimization and support of patients before and during transfer, transfer checklists, defined roles of emergency medical services, and the roles and responsibilities of referring and receiving centers involved in the IHT of acute PE patients.

Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its role in maintaining glucose homeostasis in vivo has not been fully established. Here we examined whether loss of ARC in FVB background mice exacerbates high fat diet (HFD)-induced hyperglycemia in vivo over 24 weeks. Prior to commencing 24-week HFD, ARC−/− mice had lower body weight than wild type (WT) mice. This body weight difference was maintained until the end of the study and was associated with decreased epididymal and inguinal adipose tissue mass in ARC−/− mice. Non-fasting plasma glucose was not different between ARC−/− and WT mice prior to HFD feeding, and ARC−/− mice displayed a greater increase in plasma glucose over the first 4 weeks of HFD. Plasma glucose remained elevated in ARC−/− mice after 16 weeks of HFD feeding, at which time it had returned to baseline in WT mice. Following 24 weeks of HFD, non-fasting plasma glucose in ARC−/− mice returned to baseline and was not different from WT mice. At this final time point, no differences were observed between genotypes in plasma glucose or insulin under fasted conditions or following intravenous glucose administration. However, HFD-fed ARC−/− mice exhibited significantly decreased β-cell area compared to WT mice. Thus, ARC deficiency delays, but does not prevent, metabolic adaptation to HFD feeding in mice, worsening transient HFD-induced hyperglycemia.

Background: Bradykinesia is the defining motor feature of Parkinson’s disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed. Objective: To develop a quantitative method to track repetitive tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia. Methods: This was a cross-sectional study of 99 participants (early-stage PD = 26, controls = 64, idiopathic anosmia = 9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per second. From each video, amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second) was extracted. Clinical assessment was based on the motor section of the MDS-UPDRS. Results: People in the early stage of PD performed the task with slower velocity (p

Objective To preliminary evaluate the clinical effects of probiotics in individuals with symptomatic oral lichen planus and the possible mechanisms of action. Subjects and Methods A group of 30 individuals with symptomatic oral lichen planus were recruited in a randomised double-blind parallel group controlled (1:1) proof-of-concept pilot trial of probiotic VSL#3 vs placebo. Efficacy outcomes included changes in pain numeric rating scale, oral disease severity score and the chronic oral mucosal disease questionnaire. Adverse effects, home diary and withdrawals were assessed as feasibility outcomes. Mechanistic outcomes included changes in salivary and serum levels of CXCL10 and IFN-γ and in oral microbial composition. Results The probiotic VSL#3 was safe and well tolerated. We observed no statistically significant change in pain, disease activity, quality of life, serum/salivary CXCL10 or oral microbial composition with respect to placebo. Salivary IFN-γ levels demonstrate a trend for a reduced level in the active group (p = 0.082) after 30 days of probiotic consumption. Conclusions The present proof-of-concept study provides some weak not convincing indication of biological and clinical effects of probiotic VSL#3 in individuals with painful oral lichen planus. Further research in this field is needed, with the current study providing useful information to the design of future clinical trials.

INTRODUCTION Pseudoaneurysms are uncommon but potentially life-threatening. Treatment may involve a variety of interventions including observation, manual compression, ultrasound-guided thrombin injection and a variety of endovascular and surgical techniques. Current treatments are largely based on observational data and there is no consensus on management. This study aimed to provide evidence for guiding clinical decisions regarding visceral artery pseudoaneurysm and peripheral artery pseudoaneurysm management. METHODS Retrospective single-centre review of patients diagnosed with visceral and peripheral artery pseudoaneurysms at a tertiary hospital (2010-2020). RESULTS There were 285 patients included in this study. A total of 86 patients were diagnosed with a visceral artery pseudoaneurysm, and 49 of these (57%) were caused by trauma. A total of 199 patients were identified with a peripheral pseudoaneurysm; 76 of these (38%) were caused by trauma and 69 (35%) were due to access site complication during an endovascular procedure. Initial technical success was achieved in 266 patients (93.3%) with 19 requiring an additional treatment to achieve success. Conservative treatment (100% success), endovascular treatment (98.1%) and surgery (100%) were more successful than ultrasound-guided compression (63.6%) and thrombin injection (83.8%). The median time from diagnosis to intervention was

Objective To report a unique case and literature review of post COVID-19 vaccination associated transverse myelitis and with abnormal MRI findings. Background Coronavirus disease have been reported to be associated with several neurological manifestations such as stroke, Guillain-Barré syndrome, meningoencephalitis amongst others. There are only a few reported cases of transverse myelitis with the novel coronavirus (n-CoV-2). Here, we identify a post COVID-19 vaccination patient diagnosed with acute transverse myelitis. Method A retrospective chart review of a patient diagnosed with post SARS-CoV-2 vaccination acute transverse myelitis, and a review of literature of all the reported cases of other post vaccination and transverse myelitis, from December 1st, 2010 till July 15th, 2021, was performed. Conclusion To our knowledge, this is the one of early reported case of transverse myelitis and with post SARS-CoV-2 vaccination, who responded well to plasmapheresis. Further studies would be recommended to identify the underlying correlation between COVID-19 vaccination and transverse myelitis.

When infants are identified with a difference of sex development (DSD), a thoughtful approach to imaging is essential to appropriate clinical management. This review provides a comprehensive guide for radiologists who are tasked with performing this critical assignment. We review the embryologic basis of DSDs, with attention to the imaging findings that can indicate specific diagnoses. We also discuss techniques for optimal imaging, including strategies for identifying the gonads by US, tactics for performing genitograms with fluoroscopy and contrast-enhanced US, and the appropriate utilization of MRI. Finally, we review the clinical data and imaging findings that characterize some of the most common DSDs, including congenital adrenal hyperplasia, complete androgen insensitivity syndrome and gonadal dysgenesis.

Purpose To examine associations between physiologic stress and delirium in the setting of a direct neurologic injury. Materials and methods We obtained initial neutrophil-to-lymphocyte ratio (NLR), glucose, and troponin in consecutive non-comatose patients with non-traumatic intracerebral hemorrhage (ICH) over 1 year, then used multivariable regression models to determine associations between each biomarker and incident delirium. Delirium diagnoses were established using DSM-5-based methods, with exploratory analyses further categorizing delirium as first occurring 24 h after presentation (“later-onset”). Results Of 284 patients, delirium occurred in 55% (early-onset: 39% [n = 111]; later-onset: 16% [n = 46]). Patients with delirium had higher NLR (mean 9.0 ± 10.4 vs. 6.4 ± 5.5; p = 0.01), glucose (mean 146.5 ± 59.6 vs. 129.9 ± 41.4 mg/dL; p = 0.008), and a higher frequency of elevated troponin (>0.05 ng/mL; 21% vs. 10%, p = 0.02). In adjusted models, elevated NLR (highest quartile: OR 3.4 [95% CI 1.5–7.8]), glucose (>180 mg/dL: OR 3.1 [95% CI 1.1–8.2]), and troponin (OR 3.0 [95% CI 1.2–7.2]) were each associated with delirium, but only initial NLR was specifically associated with later-onset delirium and with delirium in non-mechanically ventilated patients. Conclusions Stress-related biomarkers corresponding to multiple organ systems are associated with ICH-related delirium. Early NLR elevation may also predict delayed-onset delirium, potentially implicating systemic inflammation as a contributory delirium mechanism.

Herpes Zoster Ophthalmicus (HZO) is a rare cause of SIADH (Syndrome of Inappropriate Anti-Diuretic Hormone secretion). It occurs when herpesvirus type 3 activation presents in the first division, or ophthalmic division of the trigeminal nerve.

Background Recent case series have reported early failure with the use of high-viscosity cement (HVC) in total knee arthroplasty (TKA). We evaluated revision risk after TKA with HVC compared with medium-viscosity cement (MVC) in a large cohort. Methods We conducted a cohort study using data from Kaiser Permanente’s Total Joint Replacement Registry. Patients who underwent fully cemented primary TKA for osteoarthritis were identified (2001-2018). Only posterior-stabilized, fixed-mobility designs of the 3 highest-volume implant systems (DePuy PFC, Zimmer NexGen, and Zimmer Persona) were included to mitigate confounding from implant characteristics. Palacos (Zimmer/Heraeus) and Simplex (Stryker) cements comprised the HVC and MVC exposure groups, respectively. Propensity score–weighted Cox proportional hazards regression was used to evaluate risk for any revision during follow-up and risk for revision from aseptic loosening specifically. Results The final cohort comprised 76,052 TKAs, 41.1% using MVC. The crude 14-year cumulative revision probability was 4.55% and 5.12% for TKA with MVC and HVC, respectively. In propensity score–weighted Cox models, MVC compared with HVC had a lower risk of any revision (hazard ratio = 0.82, 95% confidence interval = 0.70-0.95) while no difference was observed for revision from aseptic loosening (hazard ratio = 0.80, 95% confidence interval = 0.56-1.13). Conclusion While we observed a lower risk for any revision with the use of Simplex MVC compared with Palacos HVC, we did not observe a difference in revision for aseptic loosening specifically. Given the widespread use of HVC, additional research to investigate other HVC and potential mechanisms for failure outside of loosening is warranted. Level of Evidence Level III.

Objectives The goal of this study was to describe outcomes of patients with bridge to heart transplantation (BTT) after changes were made to the donor heart allocation system. Background Left ventricular assist devices (LVADs) have been used as a BTT. On October 18, 2018, the donor heart allocation system in the United States was updated. Methods This study identified adults in the United Network for Organ Sharing database with durable, continuous-flow LVAD at listing or implanted while listed between April 2017 and April 2020. Baseline recipient and donor characteristics, waitlist survival, and post-transplantation outcomes were compared pre- and post-allocation system change. Results A total of 1,794 patients met inclusion criteria: 983 in the pre-change period and 814 afterward. The number of patients listed with LVAD decreased nationally over time from 102 in April 2017 to 12 in April 2020 (p Conclusions The number of patients with BTT on the transplant list decreased steadily and dramatically after the allocation system change. Although time to transplant decreased, there was an increase in post-transplant mortality. These data suggest that the risks and benefits of LVAD implantation as a BTT have changed under the new allocation system and that the appropriate indication for this treatment strategy warrants a re-evaluation.

PURPOSE: To explore the relationship between physical activity (PA) and quality of life (QOL) among Hispanic and non-Hispanic white breast cancer (BC) cases and population-based controls from the New Mexico ‘Long-Term Quality of Life Study’. METHODS: Self-reported PA (low, moderate, vigorous MET hours/week) at baseline and follow-up interviews (12–15 years) were available for 391 cases and controls and modeled using multiple linear regressions with SF-36 mean composite scores for physical and mental health. The change in PA from baseline to follow-up and interactions with ethnicity were also examined. Models were adjusted for age at diagnosis/baseline interview, education, comorbidities, body mass index, and change in PA. RESULTS: PA intensities at each timepoint did not differ by case/control status; however, the change in vigorous PA was lower among cases (p = 0.03). At follow-up, low intensity PA increased mental health QOL scores among cases; however, the interaction between low intensity PA and ethnicity was statistically significant among controls indicating decreased mental health among Hispanics (p = 0.02). Change in moderate PA was associated with increased physical and mental health among cases (physical: β = 0.186, p = 0.008; mental: β = 0.225, p = 0.001) and controls (physical: β = 0.220, p < 0.0001; mental: β = 0.193, p = 0.002), when controlling for confounders. CONCLUSION: Our results demonstrate that all levels of PA are important for mental health among BC cases, while activities of higher intensity are important for physical health among women overall. The statistical interaction observed between ethnicity and low intensity PA among controls for mental health warrants further research to provide a meaningful interpretation.

Objective To examine the effectiveness and safety of epidural analgesia in the presurgical period in patients with hip fracture undergoing surgical repair. Design Systematic review. Methods The study protocol was registered with the PROSPERO systematic reviews registry with the (identifier CRD42019140396). Electronic databases were searched for randomized controlled trials comparing preoperative epidural analgesia with other forms of pain management in patients with a hip fracture. The primary outcomes included perioperative cardiac events and death. Pain, noncardiac complications, and adverse effects were also examined as secondary outcomes. The heterogeneity of the included studies was assessed with the I2 statistic, and a random-effects meta-analysis was conducted once sufficient homogeneity was demonstrated. Results Four studies, which included a total of 221 patients, met the inclusion criteria. Preoperative epidural analgesia resulted in fewer cardiac events, which was a reported outcome in two included studies (relative risk 0.30; 95% confidence interval 0.14–0.63; I2=0%). Preoperative epidural analgesia was also associated with a decreased perioperative mortality rate in a meta-analysis of two studies (relative risk 0.13; 95% confidence interval 0.02–0.98; I2 = 0%). Pain was not pooled because of variability in assessment methods, but preoperative epidural analgesia was associated with reduced pain in all four studies. Conclusions Preoperative epidural analgesia for hip fracture may reduce perioperative cardiac events and deaths, but the number of included studies in this systematic review was low. More research should be done to determine the benefit of early epidural analgesia for patients with hip fracture.

The objective of this study was to determine the clinical features that moderate a later age at ASD diagnosis in females in a large sample of females with ASD. Within two large and independent ASD datasets (> 20,000 females), females were first diagnosed with ASD 14-months later relative to males. This later age at diagnosis was moderated by a mild or atypical presentation, wherein repetitive behaviors were limited, IQ and language were broadly intact, and recognized symptoms emerged later in development. Females are at risk for a later age at ASD diagnosis and treatment implementation, and modification of early childhood ASD screening methods for females may be warranted.

We examined cross-sectional associations between arm lymphedema symptoms and health-related quality of life (HRQoL) in the Health, Eating, Activity and Lifestyle (HEAL) Study. 499 women diagnosed with localized or regional breast cancer at ages 35–64 years completed a survey, on average 40 months after diagnosis, querying presence of lymphedema, nine lymphedema-related symptoms, e.g., tension, burning pain, mobility loss, and warmth/redness, and HRQoL. Analysis of covariance models were used to assess HRQoL scores in relation to presence of lymphedema and lymphedema-related symptoms. Lymphedema was self-reported by 137 women, of whom 98 were experiencing lymphedema at the time of the assessment. The most common symptoms were heaviness (52%), numbness (47%), and tightness (45%). Perceived physical health was worse for women reporting past or current lymphedema than those reporting no lymphedema (P-value P-value = 0.31). Perceived physical health, stress, and lymphedema-specific HRQoL scores worsened as number of symptoms increased (P-values ≤ 0.01). Women reporting tension in the arm had lower physical health (P-value = 0.01), and those experiencing burning pain, tension, heaviness, or warmth/redness in the arm had lower lymphedema-specific HRQoL (P-values

The United States is experiencing an opioid epidemic, and there were more than 10 million opioid misusers aged 12 or older each year. Identifying patients at high risk of Opioid Use Disorder (OUD) can help to make early clinical interventions to reduce the risk of OUD. Our goal is to predict OUD patients among opioid prescription users through analyzing electronic health records with machine learning and deep learning methods. This will help us to better understand the diagnoses of OUD, providing new insights on opioid epidemic. Electronic health records of patients who have been prescribed with medications containing active opioid ingredients were extracted from Cerner Health Facts database between January 1, 2008 and December 31, 2017. Long Short-Term Memory (LSTM) models were applied to predict opioid use disorder risk in the future based on recent five encounters, and compared to Logistic Regression, Random Forest, Decision Tree and Dense Neural Network. Prediction performance was assessed using F-1 score, precision, recall, and AUROC. Our temporal deep learning model provided promising prediction results which outperformed other methods, with a F1 score of 0.8023 and AUCROC of 0.9369. The model can identify OUD related medications and vital signs as important features for the prediction. LSTM based temporal deep learning model is effective on predicting opioid use disorder using a patient past history of electronic health records, with minimal domain knowledge. It has potential to improve clinical decision support for early intervention and prevention to combat the opioid epidemic., Comment: 20 pages, 6 figures

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph.

Background Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. Methods Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. Results An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. Conclusions Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.

Introduction: To determine the publication rate of registered clinical trials evaluating therapeutic approaches for diabetic macular edema (DME). Methods: Using the search terms “Diabetic Macular Edema,” the National Institute of Health’s ClinicalTrials.gov online registry was searched to identify all clinical trials concerning DME. Non-interventional trials, terminated trials, trials not concerning DME, and those not completed between 2005 and 2015 were excluded. Publication status of each trial was determined using searches of the study title, keywords, author(s), and NCT number on PubMed.gov and Google Scholar. Results: A total of two hundred and forty-seven studies were identified in the primary analysis. Of the 97 trials meeting inclusion criteria, 60 (61.9%) were published. Late-phase trials were published at higher rate (74.5% [35/47]) than early phase trials (50% [25/50]) (p = 0.01). Trial location, date of completion, and industry involvement did not significantly affect the publication rate. Conclusion: Of the registered trials listed in the ClinicalTrials.gov registry investigating DME, 61.9% were published.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Background Routine preoperative allergy testing in patients reporting penicillin and cephalosporin allergies increases the number able to receive cefazolin, which should reduce the risk of infection after total knee and hip arthroplasty (TKA/THA), but it remains unclear whether this practice is cost-effective. Using a break-even analysis, we calculated the cost-effectiveness of routine preoperative allergy testing for infection prevention in total joint arthroplasty patients reporting penicillin and cephalosporin allergies. Methods The cost of a penicillin allergy evaluation, the cost of revision arthroplasty for prosthetic joint infection (PJI), and baseline rates of PJI in patients receiving a noncefazolin antibiotic in the perioperative period were derived from existing literature. A break-even economic model using these variables was constructed to calculate the absolute risk reduction (ARR) in infection rate needed for preoperative allergy testing to be cost-effective. The number needed to treat (NNT) was calculated from the ARR. Results Preoperative allergy testing before TKA and THA in patients reporting penicillin and cephalosporin allergies was cost-effective if the initial infection rate decreased by an ARR of 0.810% (NNT = 123) and 0.655% (NNT = 153) for TKA and THA, respectively. Cost-effectiveness was maintained with varying allergy consultation costs, infection rates, and costs associated with PJI treatment. Conclusion Routine preoperative allergy testing and clearance are cost-effective infection prevention strategies among patients reporting penicillin and cephalosporin allergies in the setting of elective joint arthroplasty. Widespread adoption of this practice may considerably reduce the economic and societal burden associated with prosthetic infections.

The coexistence of coronavirus disease 2019 (COVID-19) and pulmonary embolism (PE), two life-threatening illnesses, in the same patient presents a unique challenge. Guidelines have delineated how best to diagnose and manage patients with PE. However, the unique aspects of COVID-19 confound both the diagnosis and treatment of PE, and therefore require modification of established algorithms. Important considerations include adjustment of diagnostic modalities, incorporation of the prothrombotic contribution of COVID-19, management of two critical cardiorespiratory illnesses in the same patient, and protecting patients and health-care workers while providing optimal care. The benefits of a team-based approach for decision-making and coordination of care, such as that offered by pulmonary embolism response teams (PERTs), have become more evident in this crisis. The importance of careful follow-up care also is underscored for patients with these two diseases with long-term effects. This position paper from the PERT Consortium specifically addresses issues related to the diagnosis and management of PE in patients with COVID-19.

Rationale: Data on the molecular mechanisms that regulate platelet–pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet–pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: Network medicine was used to profile protein–protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography–mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet–endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O(2)) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)–dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9–P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors in vitro and from patients with CTEPH ex vivo. Compared with control mice, platelet–pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9(−/−) mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: The NEDD9–P-selectin protein–protein interaction is a modifiable target with which to inhibit platelet–pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.

Contains fulltext : 229000.pdf (Publisher’s version ) (Open Access) Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the 'antagonistic pleiotropy' hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report - https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18-88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.

Supplemental Digital Content is available in the text., Rationale: Pyroptosis is a morphologically and mechanistically distinct form of cell death and is characterized by GSDMD (gasdermin D) or GSDME (gasdermin E)-mediated necrosis with excessive inflammatory factor release. Cardiomyocyte necrosis and inflammation play key roles in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. However, whether cardiomyocytes undergo pyroptosis and the underlying mechanism in myocardial I/R injury remain unclear. Objective: We aimed to investigate the role of pyroptosis in myocardial I/R injury. Methods and Results: In vivo and in vitro experiments were used to investigate pyroptosis of cardiomyocyte and the associated mechanisms during I/R injury. Wild-type, Myh6-Cre, and cardiomyocyte-specific GSDMD-deficient male mice were subjected to I/R. Human peripheral blood samples were collected from patients with acute ST-segment–elevation myocardial infarction or control patients at 0, 1, and 24 hours after percutaneous coronary intervention in our department. The serum levels of GSDMD were measured by ELISA. Hypoxia/reoxygenation induced cardiomyocyte pyroptosis and the release of mature IL (interleukin)-18 but not IL-1β, which mechanistically resulted from GSDMD cleavage by caspase-11 in cardiomyocytes. Furthermore, GSDMD gene deletion blocked hypoxia/reoxygenation-induced cardiomyocyte pyroptosis and IL-18 release. GSDMD and its pyroptosis-inducing N-terminal fragment were upregulated in myocardial tissues after I/R injury. Immunofluorescence analysis showed that GSDMD was mainly localized in cardiomyocytes. GSDMD deficiency in cardiomyocytes significantly reduced the I/R-induced myocardial infarct size. Moreover, increased GSDMD serum levels were detected in patients exhibiting I/R injury 1 hour after percutaneous coronary intervention for ST-segment–elevation myocardial infarction. Conclusions: Our results show that GSDMD-mediated cardiomyocyte pyroptosis is a key event during myocardial I/R injury and that the caspase-11/GSDMD pathway may be essential to this process. Additionally, GSDMD inhibition significantly reduces cardiomyocyte pyroptosis and I/R-induced myocardial injury. Graphic Abstract: A graphic abstract is available for this article.

(1) describe imaging features of CIA, (2) compare dilation rate and wall thickening of aortic aneurysms in patients with CIA versus those with giant cell arteritis/aortitis (GCA), (3) present clinical outcomes of CIA patients. Retrospective search of electronic records from 2004 to 2018 yielded 71 patients, 52 of whom were female, with a mean age of 67.5 ± 9.0 years old, with a new clinical diagnosis of cranial or extracranial GCA (GCA group), and giant cell aortitis revealed by the aortic biopsy (CIA group). Comparisons between groups were conducted using the Wilcoxon rank-sum and Fisher’s exact tests. Survival from the date of initial diagnosis to the end of data collection was compared between the two groups through a log-rank test. CIA patients (n = 23; 32%) presented with cardiovascular symptoms, and none had systemic inflammatory symptoms. Inflammatory markers were significantly higher among GCA patients than among CIA patients (p < 0.0001). The CIA group demonstrated thoracic aortic aneurysms without wall thickening. None of the GCA patients (n = 48; 68%) had aneurysmal dilation in the aorta at the time of diagnosis. None of the four CIA patients had FDG uptake in the aorta, while nine out of 13 GCA patients had FDG uptake in the vessels. There was no statistically significant difference in the survival between the two groups (p = 0.12). CIA patients presented with cardiovascular symptoms and was characterized by aneurysm of the aorta without the involvement of the infrarenal aortic segment. The role of FDG-PET/CT in CIA is less certain, though none of the patients in this cohort had FDG uptake in the vessels.

Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.

Physical activity is recommended for most cancer patients as a nonpharmacological therapy to improve prognosis. Few studies have investigated the association between physical activity and breast cancer prognosis by ethnicity, biological, and modifiable risk factors for mortality. We investigated the association between physical activity and long-term survival among breast cancer survivors. A total of 397 survivors (96 Hispanic and 301 non-Hispanic White (NHW)) from the New Mexico HEAL study contributed baseline and biological data approximately 6 months after diagnosis. Study outcomes included all-cause, breast cancer-specific, and non-breast cancer mortality. The exposure was self-reported physical activity within the past month. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox Proportional Hazards regression. A total of 133 deaths (53 breast cancer-specific deaths) were observed after a median follow-up time of 13 years. Engaging in >6.9 metabolic equivalent hours/week (MET-h/week) of moderate to vigorous physical activity (active) was inversely associated with all-cause mortality among all women (HR 0.66, 95% CI 0.43–0.99) and NHWs (HR 0.58, 95% CI 0.36–0.94). Active NHW women also had a reduced risk of non-breast cancer mortality (HR 0.56, 95% CI 0.31–0.99), compared to inactive women (0 MET-h/week). In subgroups, we observed the inverse associations with all-cause mortality among women >58 years old (p-interaction= 0.03) and with localized stage (p-interaction = 0.046). Our results confirm the protective association between physical activity and mortality after breast cancer diagnosis, and demonstrate that this association significantly differs by age and cancer stage. Larger studies are warranted to substantiate our findings.

Summary Background Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF–IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. Methods This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50–85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF–IND (320 μg, 150 μg) or medium-dose MF–IND (160 μg, 150 μg) once daily via Breezhaler; high-dose MF (800 μg [400 μg twice daily]) or medium-dose MF (400 μg once daily) via Twisthaler; or high-dose fluticasone propionate–salmeterol xinafoate (FLU–SAL; 500 μg, 50 μg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF–IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF–IND once daily was compared with high-dose FLU–SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of −90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov , NCT02554786 , and is completed. Findings Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF–IND, n=445; medium-dose MF–IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU–SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF–IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p Interpretation Once-daily FDC of ICS and LABA (MF−IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF–IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU–SAL) for improvement in trough FEV1. The combination of MF–IND provides a novel once-daily dry powder option for asthma control. Funding Novartis Pharmaceuticals.

Background: Patients with asthma who are inadequately controlled on inhaled corticosteroid–long-acting β2-adrenoceptor agonist (ICS–LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF–IND–GLY) versus ICS–LABA in patients with inadequately controlled asthma. Methods: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS–LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF–IND–GLY (80 μg, 150 μg, 50 μg; 160 μg, 150 μg, 50 μg) or MF–IND (160 μg, 150 μg; 320 μg, 150 μg) once daily via Breezhaler, or high-dose fluticasone–salmeterol (FLU–SAL; 500 μg, 50 μg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV1 with MF–IND–GLY versus MF–IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed. Findings: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF–IND–GLY, n=620; high-dose MF–IND–GLY, n=619; medium-dose MF–IND, n=617; high-dose MF–IND, n=618; high-dose FLU–SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF–IND–GLY (treatment difference [Δ] 76 mL [95% CI 41–111]; p1 versus corresponding doses of MF–IND at week 26. Improvements in trough FEV1 were greater for both medium-dose MF–IND–GLY (99 mL [64–133]; p

Bretylium, with an extensive pharmacologic and medicinal history, was approved by the United States Food and Drug Administration in 1986 for "short-term prevention and treatment of ventricular fibrillation (VF) and treatment of life-threatening ventricular arrhythmias and ventricular tachycardia (VT) unresponsive to adequate doses of a first-line antiarrhythmic agent, such as lidocaine." The NDA sponsor withdrew bretylium from the market in 2011, largely due to unavailability of raw materials required for its production; prior to this, bretylium was removed from the 2000 ACLS Guidelines algorithm for VF/pulseless VT given the challenges obtaining raw materials for drug manufacture. Recently, bretylium has been reintroduced into the US market by a generic pharmaceutical company with the same indications as before. This article provides a history of the salient trials evaluating the efficacy and safety of bretylium and looks to the future as bretylium finds its place in the modern day management of ventricular arrhythmia.

NEW FINDINGS What is the central question of this study? Delayed cardiovascular responses occur following a single bout of remote ischaemic preconditioning (RIPC). Is heart rate variability (HRV), a surrogate marker of cardiac vagal control, able to detect a delayed effect after a single bout of RIPC? Do repeated bouts of RIPC further alter HRV? What is the main finding and its importance? Indices of HRV indicated a shift in sympathovagal balance toward greater parasympathetic activity following 2 weeks of RIPC but not after a single bout of RIPC. Thus, repeated bouts of RIPC were necessary to elicit changes in autonomic function. ABSTRACT Remote ischaemic preconditioning (RIPC), induced by brief periods of ischaemia followed by reperfusion, protects against ischaemia-reperfusion injury and improves microvascular function. However, the effect of RIPC on autonomic function remains unclear. We hypothesized that RIPC, administered as a single bout or repeated over a 2-week period, will increase markers of cardiac vagal control measured by heart rate variability (HRV). Thirty-two young adults performed a single bout (n = 13), repeated bouts (n = 11), or served as a time control (n = 8). RIPC sessions consisted of four repetitions of 5 min unilateral brachial artery occlusion interspersed by 5 min of reperfusion. For the single bout protocol, resting lead II electrocardiogram (ECG) was collected before and 24, 48, 72 and 168 h post-RIPC. The repeated bout protocol consisted of three 4-day periods of RIPC training, each interspersed by a 1-day break. Similar to time controls, ECG was collected before and 24 h after the last RIPC bout. HRV was analysed by power spectral density and symbolic dynamics using 350-beat ECG segments. After a single bout of RIPC, no changes in HRV were observed at any time point (P > 0.05). After 2 weeks of repeated RIPC, the percentage of zero-variation fragments (baseline = 13.1 ± 1.9%, post-RIPC = 6.9 ± 1.5%, P

Objectives Compare longitudinal trajectories of youth with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Bipolar Disorder (BD), grouped at baseline by presence/absence of increased energy during their worst lifetime mood episode (required for DSM-5). Methods Participants from the parent Course and Outcome of Bipolar Youth study (N = 446) were assessed utilizing The Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), KSADS Mania Rating Scale (KMRS), and KSADS Depression Rating Scale (KDRS). Youth were grouped at baseline into those with increased energy (meeting DSM-5 Criteria A for mania) vs. without increased energy (meeting DSM-IV, but not DSM-5, Criteria A for mania), for those who had worst lifetime mood episode recorded (n = 430). Youth with available longitudinal data had the presence/absence of increased energy measured, as well as psychiatric symptomatology/clinical outcomes (evaluated via the Adolescent Longitudinal Interval Follow-Up Evaluation), at each follow-up for 12.5 years (n = 398). Results At baseline, the increased energy group (based on endorsed increased energy during worst lifetime mood episode; 86% of participants) vs. the without increased energy group, were more likely to meet criteria for BD-I and BD Not Otherwise Specified, had higher KMRS/KDRS total scores, and displayed poorer family/global psychosocial functioning. However, frequency of increased energy between groups was comparable after 5 years, and no significant group differences were found on clinical/psychosocial functioning outcomes after 12.5 years. Limitations Secondary data limited study design; groupings were based on one time point. Conclusions Results indicate no clinically relevant longitudinal group differences.

Background Incorrect inhaler use is associated with poorer health outcomes, reduced quality of life, and higher healthcare utilisation in patients with asthma and COPD. Methods We performed an observational study of pressurized metered-dose inhaler technique in patients with asthma or COPD. Patients were assessed using a six-point inhaler checklist to identify common critical inhaler technique errors. An inadequate inhaler technique was defined as the presence of one or more critical errors. A multivariate logistic regression model was used to determine the odds of an inadequate inhaler technique. Results During the 14-month study period, 357 patients were enrolled. At least one critical error was executed by 66.7% of participants, and 24.9% made four or more critical errors. The most common errors were failure to exhale completely prior to pMDI activation and inhalation (49.6%), failure to perform a slow, deep inhalation following device activation (48.7%), and failure to perform a breath-hold at the end of inspiration (47.3%). The risk of a critical error was higher in COPD patients (aOR 2.25, 95% CI 1.13-4.47). Prior training reduced error risk specifically when trained by a doctor (aOR 0.08, 95% CI 0.1-0.57) or a pharmacist (aOR 0.02, 95% CI 0.01-0.26) compared to those with no training. Previous clinical trial participation significantly reduced error risk and rate

Introduction Japanese encephalitis (JE) vaccine is an inactivated vaccine that has shown no risks in pregnancy in animal models, but epidemiologic studies are lacking. U.S. military service members located in JE endemic regions are required to be vaccinated; understanding the potential adverse events (AEs), including AEs that may occur in pregnancy, is needed. Here, we assessed pregnancy and infant health outcomes in association with JE vaccination in pregnancy. Methods The study population consisted of 192,570 pregnancies to active duty women (2003–2014), captured in the Department of Defense Birth and Infant Health Research program. JE vaccine in pregnancy, vaccine count, formulation, trimester, and whether first career dose coincided with pregnancy were compared with unexposed pregnancies to assess risk of pregnancy and infant health outcomes. Adjusted risk estimates and 95% confidence intervals (CIs) were calculated by multivariable models. Results Of the 192,570 identifed pregnancies, 513 were exposed to the JE vaccine; 474 exposures occurred in the first trimester. For all outcomes, elevated risk estimates ranging from 1.53 to 1.70, were observed with receipt of >1 JE vaccine in pregnancy, though 95% CIs were wide and encompassed the null. First dose of JE vaccination in pregnancy was associated with a 1.87 (95% CI: 1.12–3.13) times increased risk of low birthweight (LBW) when excluding pregnancies exposed to other non-routinely recommended vaccinations in pregnancy. All other associations were null in both main and subset analyses. Conclusions The overall results of these analyses provide reassuring findings for the safety of JE vaccination in pregnancy. Higher counts of JE vaccine received in pregnancy yielded large yet non-statistically significant risk estimates for all outcomes, though likely driven by lack of pregnancy awareness. An association was observed with LBW in subset analyses, but it was limited to women receiving their first JE vaccine and not observed in the larger main analyses.

Nonclassical monocytes maintain vascular homeostasis by patrolling the vascular endothelium, responding to inflammatory signals, and scavenging cellular debris. Nonclassical monocytes also prevent metastatic tumor cells from seeding new tissues, but whether the patrolling function of nonclassical monocytes is required for this process is unknown. To answer this question, we utilized an inducible-knockout mouse that exhibits loss of the integrin-adaptor protein Kindlin-3 specifically in nonclassical monocytes. We show that Kindlin-3-deficient nonclassical monocytes are unable to patrol the vascular endothelium in either the lungs or periphery. We also find that Kindlin-3-deficient nonclassical monocytes cannot firmly adhere to, and instead “slip” along, the vascular endothelium. Loss of patrolling activity by nonclassical monocytes was phenocopied by ablation of LFA-1, an integrin-binding partner of Kindlin-3. When B16F10 murine melanoma tumor cells were introduced into Kindlin-3-deficient mice, nonclassical monocytes showed defective patrolling towards tumor cells and failure to ingest tumor particles in vivo. Consequently, we observed a significant, 4-fold increase in lung tumor metastases in mice possessing Kindlin-3-deficient nonclassical monocytes. Thus, we conclude that the patrolling function of nonclassical monocytes is mediated by Kindlin-3 and essential for these cells to maintain vascular endothelial homeostasis and prevent tumor metastasis to the lung.

The sensu lato (s.l.) complexes of Borrelia burgdorferi and Anaplasma phagocytophilum include pathogenic genospecies each with distinct ecologies in northern California, yet, most work conflates the genospecies of each pathogen into one sensu lato species. Detailed understanding of the differences in geographic distributions and ecology among genospecies is lacking. We aimed to evaluate whether two B. burgdorferi and two A. phagocytophilum genospecies in high-risk locations in coastal northern California were spatially clustered and if presence of a particular genospecies was associated with geographical site, host species, or other demographic or ecological variables. DNA sequencing was performed to differentiate genospecies of Borreliae and Anaplasma from PCR-positive dusky-footed woodrats (Neotoma fuscipes) and sciurids (chipmunks, Tamias spp., and Douglas squirrels, Tamiasciurus douglasii) at four sites in northwestern California. Logistic regression was performed to assess associations of genospecies with the predictor variables host species, host sex, site, season, and year. Spatial clustering was assessed using a Poisson spatial scan statistic in SaTScan. Host species was a significant predictor for Borrelia bissettiae, B. burgdorferi sensu stricto (s.s.), A. phagocytophilum s.s., and the DU1 Anaplasma genospecies. Woodrats were significantly more likely to be PCR-positive for B. bissettiae and A. phagocytophilum DU1 genospecies, while A. phagocytophilum s.s. and B. burgdorferi s.s. were significantly associated with sciurids. We report a single Borrelia lanei in an Allen's chipmunk (Tamias senex) from the Hoopa Valley Tribal Reservation. A significant spatial cluster of A. phagocytophilum s.s. was detected at Hendy Woods State Park in Mendocino County. These results highlight the need to better understand genospecies partitioning according to host species to further assess human risks, aid in future surveillance, and inform targeted research.

CITATION: Allwood, B. W., et al. Transition from restrictive to obstructive lung function impairment during treatment and follow-up of active tuberculosis. International Journal of Chronic Obstructive Pulmonary Disease, 2020(15):039-1047, doi:10.2147/COPD.S219731.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.