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The emotional attentional blink (EAB), also referred to as emotion-induced blindness, refers to a transient impairment in the ability to discriminate a single target when it is presented closely in time to an emotional distractor. Although the EAB has typically been characterized as representing a complete loss of target information due to attentional capture by the emotional distractors, it is unclear whether the impact of the emotional distractor is in fact discrete or graded. Here, we tested whether the emotional distractor of the EAB interfered with target processing in a continuous or all-or-none manner by measuring changes in both reaction time (RT) and target-vividness ratings in addition to target-discrimination accuracy. Rapid sequences of landscape images were presented centrally, and participants reported the orientation of a ± 90° rotated target as quickly and accurately as possible. Replicating the classic EAB phenomenon, we found a strong impairment in target discrimination when an emotional distractor shortly preceded the target, and we also found a moderate impairment when the target preceded an emotional distractor. This decrement in accuracy at short lags was accompanied by increases in RT to the target as well as lower ratings of subjective target vividness even when the target was detected, indicating that emotional distractors impacted target processing in a lag-dependent, graded manner. We argue that these results are consistent with an interactive race model of the competition between stimulus representations in the conflict between top-down and bottom-up attentional mechanisms. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The objectives of this study were: (1) to determine the incidence of lymphoproliferative disorders in a cohort of patients requiring a biopsy at a tertiary pediatric center; and (2) to elucidate the demographic, clinical, laboratory and diagnostic imaging characteristics associated with a malignant diagnosis.A retrospective review of pediatric cervical lymph node biopsies performed between 2012 and 2019 at a tertiary center was undertaken. Demographic data, clinical presentations, laboratory results, diagnostic imaging findings, and pathology results were compiled and analyzed to identify characteristics associated with a malignant diagnosis.Malignancy was identified in 49.5% of patients (55/111) subjected to a cervical lymph node biopsy. The median age of patients with a benign diagnosis was lower than malignant diagnosis (11.0 vs. 14.0 years, p 0.01). Mediastinal lymphadenopathy based on chest radiography and/or computed tomography scan was identified in 37/49 malignant cases (75.5%) CONCLUSION: In this retrospective study, 49.5% of biopsies performed at a tertiary pediatric setting yielded a malignant diagnosis. Traditional clinical characteristics such as weight loss, night sweats and nodal texture were not informative when derived retrospectively. The most valuable features identified were increased age, increased long and short axis measurements of the involved node(s), and the presence of mediastinal lymphadenopathy.Level III.

In the USA, as many as 20 % of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop Fe deficiency upon completion of training. Fe is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesised Fe deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: Fe-adequate sedentary, Fe-deficient sedentary, Fe-adequate exercise and Fe-deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughness and tibiae mineral composition and morphometry were measured. Fe deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, Fe deficiency further increased bone TRAcP 5b, while in Fe-adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, Fe deficiency increased the rate of bone formation, mineral apposition and Zn content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by Fe deficiency despite a decrease in tibiae Fe content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.

Small bowel cancers are rare gastrointestinal malignancies and tumor location impact on outcomes is unclear.A retrospective review was performed on stage I to IV small bowel cancer cases from 2000 to 2017 in British Columbia, Canada. Baseline patient characteristics, disease-free survival (DFS) and overall survival (OS) were evaluated by tumor location and systemic therapy use patterns were summarized.Of 340 patients included, primary tumor distribution was: duodenum (51.2%), ileum (19.1%), jejunum (18.5%), and unspecified (11.2%). Median DFS for stage I to III disease was 37.7, 49.1, and 26.7 months for duodenal, jejunal, and ileal tumors (P = .018). Median OS was 9.6, 35.2, and 20.1 months for duodenal, jejunal, and ileal tumors (P.0001). Compared to duodenal primaries, both jejunal and ileal tumors were associated with significantly improved OS (HR 0.43, P.001 for jejunal; HR 0.71, P = .035 for ileal). Adjuvant therapy was given to 21.6% of stage II and 50.6% of stage III cancers. Among patients with metastatic disease, median OS was 4.2, 11.4, and 6.9 months for duodenal, jejunal, and ileal tumors (P = .0019). Jejunal tumors had the best prognosis (HR 0.48, P = .001 vs. duodenum).Survival differences exist when small bowel cancers were assessed by tumor location, and jejunal tumors portended better prognosis overall.

The ability to predict patients with stage II colon cancer at high risk of recurrence is currently limited to certain clinicopathologic factors. This population-based study reviewed various prognostic factors to identify those associated with worse time to recurrence (TTR) and improved disease specific survival (DSS), and to subsequently develop a prognostic index (PI) to identify high risk cancers. Multivariate analyses revealed factors significant for TTR and DSS. A PI derived from the TTR risk factors identified 3 risk groups using 5-year rate without relapse: 88% for low-risk, 81% for intermediate-risk, and 59% for high-risk. This model was better at identifying high risk patients than using equally weighted standard risk factors.

Background: The frequency of clinically significant prostate cancer (csPCa) following negative biparametric MRI (bpMRI) and multiparametric MRI (mpMRI) has not been well investigated in direct comparative studies. Objective: To compare the frequency of csPCa after negative prebiopsy bpMRI and mpMRI, and to evaluate factors that predict csPca in the two cohorts. Methods: This retrospective study included 232 men (mean age, 64.5 years) with negative bpMRI from August 2017 to March 2020 and193 men (mean age, 69.0 years) with negative mpMRI from January 2018 to December 2018, defining PI-RADS category of 1 or 2 as negative. Our institution offers bpMRI as a low-cost self-pay option for patients without insurer coverage of prebiospy mpMRI. Patient characteristics and subsequent biopsy results were recorded. csPCa was defined as Gleason score ≥3+4. Multivariable regression analyses were performed to identify independent predictors of csPCa. AUC of prostate specific antigen density (PSAD) for csPCA was computed, and diagnostic performance of PSAD was assessed at a clinically established threshold of 0.15 ng/mL2. Results: Systematic biopsy was performed after negative bpMRI in 41.4% (96/232), versus after negative mpMRI in 30.5% (59/193) (p=.02). Among those undergoing biopsy, csPCa was present in 15.6% (15/96) in the mpMRI cohort versus 13.6% (8/59) in the bpMRI cohort (p=.69). NPV for csPCa was 84% (81/96) for bpMRI and 86% (51/59) for mpMRI. In multivariable analyses, independent predictors of csPCa included smaller prostate volume (OR=0.27, p .05). PSAD had AUC for csPCa of 0.77 (95% CI: 0.64, 0.89) in the bpMRI cohort versus 0.68 (95% CI: 0.42, 0.93) in the mpMRI cohort. For detecting csPCa, PSAD threshold of 0.15 ng/mL2 had NPV of 90% and PPV of 28%, in the bpMRI cohort, versus NPV of 92% and PPV of 44%in the mpMRI cohort. Conclusion: The frequency of csPCa was not significantly different on systematic biopsy performed after negative bpMRI and mpMRI examinations. PSAD had similar diagnostic utility for csPca in both cohorts. Clinical Impact: Either bpMRI or mpMRI, in combination with PSAD, can help avoid negative prostate biopsies.

Congenital heart disease can lead to notable lymphatic complications such as chylothorax, plastic bronchitis, protein-losing enteropathy, and ascites. Recent improvements in lymphatic imaging and the development of new lymphatic procedures can help alleviate symptoms and improve outcomes.

Lung adenocarcinoma (ADC) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate whether CyTOF identifies cellular and molecular predictors of tumor behavior. We developed and validated a CyTOF panel of 34 antibodies in four ADC cell lines and PBMC. We tested our panel in a set of 10 ADCs, classified into long- (LPS) (n = 4) and short-predicted survival (SPS) (n = 6) based on radiomics features. We identified cellular subpopulations of epithelial cancer cells (ECC) and their microenvironment and validated our results by multiplex immunofluorescence (mIF) applied to a tissue microarray (TMA) of LPS and SPS ADCs. The antibody panel captured the phenotypical differences in ADC cell lines and PBMC. LPS ADCs had a higher proportion of immune cells. ECC clusters (ECCc) were identified and uncovered two ADC groups. ECCc with high HLA-DR expression were correlated with CD4+ and CD8+ T cells, with LPS samples being enriched for those clusters. We confirmed a positive correlation between HLA-DR expression on ECC and T cell number by mIF staining on TMA slides. Spatial analysis demonstrated shorter distances from T cells to the nearest ECC in LPS. Our results demonstrate a distinctive cellular profile of ECC and their microenvironment in ADC. We showed that HLA-DR expression in ECC is correlated with T cell infiltration, and that a set of ADCs with high abundance of HLA-DR+ ECCc and T cells is enriched in LPS samples. This suggests new insights into the role of antigen presenting tumor cells in tumorigenesis.

Background and Purpose: The benefit of endovascular treatment (EVT) for posterior circulation stroke (PCS) remains uncertain, and little is known on treatment outcomes in clinical practice. This study evaluates outcomes of a large PCS cohort treated with EVT in clinical practice. Simultaneous to this observational study, several intervention centers participated in the BASICS trial (Basilar Artery International Cooperation Study), which tested the efficacy of EVT for basilar artery occlusion in a randomized setting. We additionally compared characteristics and outcomes of patients treated outside BASICS in trial centers to those from nontrial centers. Methods: We included patients with PCS from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry: a prospective, multicenter, observational study of patients who underwent EVT in the Netherlands between 2014 and 2018. Primary outcome was a score of 0 to 3 on the modified Rankin Scale at 90 days. Secondary outcomes included reperfusion status and symptomatic intracranial hemorrhage. For outcome comparison between patients treated in trial versus nontrial centers, we used ordinal logistic regression analysis. Results: We included 264 patients of whom 135 (51%) had received intravenous thrombolysis. The basilar artery was most often involved (77%). Favorable outcome (modified Rankin Scale score 0–3) was observed in 115/252 (46%) patients, and 109/252 (43%) patients died. Successful reperfusion was achieved in 178/238 (75%), and symptomatic intracranial hemorrhage occurred in 9/264 (3%). The 154 nontrial patients receiving EVT in BASICS trial centers had similar characteristics and outcomes as the 110 patients treated in nontrial centers (modified Rankin Scale adjusted cOR: 0.77 [95% CI, 0.5–1.2]). Conclusions: Our study shows that high rates of favorable clinical outcome and successful reperfusion can be achieved with EVT for PCS, despite high mortality. Characteristics and outcomes of patients treated in trial versus nontrial centers were similar indicating that our cohort is representative of clinical practice in the Netherlands. Randomized studies using modern treatment approaches are needed for further insight in the benefit of EVT for PCS.

Background Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive. Objective We sought to identify genetic loci associated with EoE. Methods Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE. Results Our study identified 11 new genome-wide significant loci, of which 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10−8; odds ratio [OR], 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 × 10−10; OR, 0.69, RORA), and 15q23 (rs56062135, P = 2.91 × 10−11; OR, 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low-frequency synonymous mutation within the MATN2 gene was identified as the most significant single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 sex-specific loci in the EoE cases, including an inflammatory bowel disease–associated locus at 9p24.1 (rs62541556, P = 4.4 × 10−8; OR, 1.11, JAK2). Conclusions Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases and provide novel candidate genes for therapeutic target identification and prioritization.

Children with vesicoureteral reflux (VUR) are at an increased risk of recurrent urinary tract infections (UTIs) and renal scarring. Gut microbiota are associated with disease phenotypes, but there has been no study that associates urinary microbiota (uMB) and metabolic profiles with VUR pathology. To identify dominant uMB genera and metabolites associated with UTIs in VUR, urine samples collected under sterile conditions underwent 16S ribosomal RNA sequencing (n = 49) and metabolomic analysis by mass spectrometry (n = 96). Alterations in uMB and metabolomic profiles in VUR patients suggest remodeling of urinary bacterial communities after UTIs: Dorea- and Escherichia-dominant uMB profiles were more frequently identified in participants with VUR. Prevotella- and Lactobacillus-dominant uMB profiles were more prevalent in controls (p 0.001). Microbial composition varied based on recurrent febrile UTI status (p = 0.001). A total of 243 urinary metabolites involved in energy, amino acid, nucleotide, and lipid metabolism were altered in VUR patients with UTIs (p 0.05). Importantly, VUR specimens revealed changes in the bacteria-associated metabolic pathways such as glutamate degradation, methyl-citrate cycle, and bile acid metabolism. PATIENT SUMMARY: Differences in urinary commensal bacteria and metabolites exist between children with and without vesicoureteral reflux (VUR). These changes may be utilized to identify patients at risk of VUR-associated kidney damage.

Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences.Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro.TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P.001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P.001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P.001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling.Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

Background The success of pulmonary vein isolation (PVI) is reduced in persistent AF (PsAF) compared to paroxysmal AF. Adjunctive ablation strategies have failed to show consistent incremental benefit over PVI alone in randomized studies. The left atrial posterior wall is a potential source of non-PV triggers and atrial substrate which may promote the initiation and maintenance of PsAF. Adding posterior wall isolation (PWI) to PVI had shown conflicting outcomes, with earlier studies confounded by methodological limitations. Objectives To determine whether combining PWI with PVI significantly improves freedom from AF recurrence, compared to PVI alone, in patients with PsAF. Methods This is a multi-center, prospective, international randomized clinical trial. 338 patients with symptomatic PsAF refractory to anti-arrhythmic therapy (AAD) will be randomized to either PVI alone or PVI with PWI in a 1:1 ratio. PVI involves wide antral circumferential pulmonary vein (PV) isolation, utilizing contact force sensing ablation catheters. PWI involves the creation of a floor line connecting the inferior aspect of the PVs, and a roof line connecting the superior aspect of the PVs. Follow up is for a minimum of 12 months with rhythm monitoring via implantable cardiac device and/or loop monitor, or frequent intermittent monitoring with an ECG device. The primary outcome is freedom from any documented atrial arrhythmia of > 30 seconds off AAD at 12 months, after a single ablation procedure. Conclusions This randomized study aims to determine the success and safety of adjunctive PWI to PVI in patients with persistent AF.

BACKGROUND: Cognitive impairment (CI) is highly prevalent in elderly asthmatics and is associated with worse asthma self-management (SM) and outcomes. CI may also explain why older adults may under-perceive asthma symptoms. We hypothesized that CI would be associated with low medication adherence and asthma symptom under-perception (ASP). We also hypothesized that ASP would mediate the relationship between CI and medication adherence. METHODS: Participants of this longitudinal cohort study were asthmatics (N=334) ≥60 years (51% Hispanic, 25% Black). Cognitive measures assessed general cognition, attention, processing speed, executive functioning, memory, and language. Measures of SM were self-reported and electronically measured adherence to controller medications. ASP was assessed for 6 weeks by participants entering estimates of peak expiratory flow (PEF) into a programmable peak flow meter, followed by PEF blows. Participants were blinded to actual PEF values. Percentage of time that participants were in the over-perception zone was calculated as an average. RESULTS: In regression analyses, those with impairments in memory and general cognition had lower odds ratios (OR) for self-reported non-adherence (OR: 0.96, 95% CI 0.93–0.98 & OR: 0.90, 95% CI 0.83–0.96, respectively). CI was not associated with electronically measured non-adherence or ASP. In structural equation modeling, while CI was associated with adherence (β=0.04, SE = 0.021, p=0.04), ASP did not mediate this relationship. CONCLUSIONS: While results confirmed the importance of cognition in asthma SM, these findings were not linked to ASP. Future analyses are needed to understand the role of confounding factors.

Objective: Examine whether caregiver depressive symptoms at baseline predict longitudinal child asthma outcomes in the two populations with the largest asthma disparities: Mexicans and Puerto Ricans. Methods: 267 Hispanic caregiver-child dyads (Mexican =188, Puerto Rican =79; children 5-12 years) were recruited from clinics and hospitals in Phoenix, AZ and the Bronx, NY. The Center for Epidemiological Studies Depression Scale assessed caregiver depressive symptoms; higher scores indicate greater depressive symptomology. Medical records verified child asthma diagnosis. Assessments for outcome variables occurred at baseline, 3, 6, 9, and 12-month follow-ups. Pulmonary function was measured by spirometry, asthma control was measured by the Asthma Control Test, steroid bursts and acute healthcare utilization were assessed by caregiver report and medical records, and adherence was measured by doser devices on controller medications. Structural equation modeling analyzed baseline caregiver depressive symptoms as a predictor of longitudinal child asthma outcomes, and differences between subgroups. Results: Higher caregiver depressive symptoms predicted better pulmonary function (β = 0.02, p=.001) in Mexican children, and fewer steroid bursts (β= -0.41, p=.01) and better medication adherence (β = 0.02, p=.07) in Puerto Rican children. Caregiver depressive symptoms did not predict pediatric asthma control or acute healthcare utilization in either subgroup. Conclusions: Caregiver depressive symptomology had unexpected effects on child asthma outcomes. Results may be explained by the Hispanic paradox, caregiver resilience, acculturation, and the study's longitudinal nature. Further research is needed on social determinants of health that may influence differences in child asthma outcomes in heterogeneous Hispanic communities.

BACKGROUND AND PURPOSE To explore the prevalence, risk factors, time correlation, characteristics and clinical outcome of dural arteriovenous fistulas (dAVFs) in a cerebral venous thrombosis (CVT) population. METHODS We included patients from the International CVT Consortium registries. Diagnosis of dAVF was confirmed centrally. We assessed the prevalence and risk factors for dAVF among consecutive CVT patients and investigated its impact on clinical outcome using logistic regression analysis. We defined poor outcome as modified Rankin Scale score 3-6 at last follow-up. RESULTS dAVF was confirmed in 29/1218 (2.4%) consecutive CVT patients. The median (interquartile range [IQR]) follow-up time was 8��(5-23) months. Patients with dAVF were older (median [IQR] 53��[44-61] vs. 41��[29-53] years; p��30 days: 39% vs. 7%; p��

INTRODUCTION Large tumors may prove unsuitable for surgical cure or other local therapies due to their size, involvement of critical structures, prior non-ablative treatment failure, or coexisting disease burden. This study was performed to assess the safety and feasibility of percutaneous cryoablation for treatment of large tumors exceeding 6 cm in size, and to highlight the key technical considerations inherent to such cases. MATERIALS AND METHODS This single-institution retrospective study identified 77 patients (42 male, 35 female; median age 55 years) who underwent 96 cryoablation procedures for treatment of 78 tumors (mean diameter 9.8 ± 3.6 cm) from 2008 through 2020. Technical success, procedure-related complications, mortality, oncologic outcomes, and procedural logistics were evaluated. Technical success was defined as ice ball extension at least 5 mm beyond the tumor margins. RESULTS Intentional subtotal ablations were performed in 32% of cases due to tumor encroachment on vulnerable structures or as part of staged/combined therapies. Of the 68% of cases that were planned for complete ablation, the technical success rate was 100%. Major complications occurred after 19/96 (20%) procedures, with hemorrhage and acute kidney injury each occurring in 6/96 (6%). Post-procedural myositis occurred in 24/96 (25%) cases and was not considered a major complication in the absence of acute kidney injury. Local recurrence occurred in 2/23 (8.7%) of patients undergoing ablation for cure or local control at a median follow-up duration of 13 months. CONCLUSION Percutaneous cryoablation may be used to treat large (> 6 cm) tumors with a high degree of technical success and an acceptable safety profile.

Background & Aims Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis. Methods We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA. Results Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer. Conclusions Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy. Lay summary Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.

The aim of this study was to determine if stimulation of sacral spinal nerve roots can induce defecation in cats. In anesthetized cats, bipolar hook electrodes were placed on the S1-S3 dorsal and/or ventral roots. Stimulus pulses (1-50 Hz, 0.2 ms) were applied to an individual S1-S3 root to induce proximal/distal colon contractions and defecation. Balloon catheters were inserted into the proximal and distal colon to measure contraction pressure. Glass marbles were inserted into the rectum to demonstrate defecation by videotaping the elimination of marbles. Stimulation of the S2 ventral root at 7 Hz induced significantly (p

BACKGROUND: Autistic transition-aged youth and young adults face many societal barriers to competitive integrated employment (CIE). Existing evidence-based practices (EBPs) for autistic individuals, such as video modeling (VM), may be a viable on-the-job training method to enhance employment experiences and outcomes for this population. METHODS: The purpose of this meta-analysis was to synthesize VM studies to teach job skills for autistic individuals. We applied the Council for Exceptional Children's (CEC) Standards for Evidence-Based Practices in Special Education to evaluate the methodological rigor of included studies using a weighted coding scheme. We further evaluated methodologically sound studies by calculating an omnibus Tau-U effect size. RESULTS: Twenty articles met our inclusion criteria, and 11 of those studies were classified as methodologically sound according to the CEC's criteria. Results indicate that VM is an EBP to improve job skills of autistic individuals. The overall effect size for methodologically sound studies was strong (0.91), but most studies occurred in contrived or school-based employment settings rather than CIE settings in the local labor market. CONCLUSIONS: Employers, transition professionals, and related service providers can consider VM a viable method to teach job skills to autistic employees. However, additional research conducted in CIE settings is needed to better understand the effects of VM in contexts where autistic employees earn regular wages. LAY SUMMARY: WHY WAS THIS STUDY DONE? Autistic adolescents and adults often experience barriers obtaining employment in their local communities. They may also benefit from on-the-job supports for successful employment. Video modeling is one intervention technique that has been used to teach a variety of skills to autistic individuals. Video modeling involves creating short video clips that show the person how to do specific skills or tasks. We wanted to learn about how video modeling has been used to teach job skills to autistic employees. WHAT WAS THE PURPOSE OF THIS STUDY? The purpose of this study was to evaluate the quality of research studies that used video modeling to teach job skills to autistic employees. Understanding how video modeling interventions can be used in employment settings may help autistic employees have more positive work experiences. WHAT DID THE RESEARCHERS DO? The researchers analyzed the video modeling research studies with autistic participants aged 14 years or older. We evaluated the quality of each study, type of employment setting, type of job skill, and how much the job skills improved. We used a criteria established by a professional organization, the Council for Exceptional Children, to evaluate the quality of the research studies. WHAT WERE THE RESULTS OF THE STUDY? We analyzed 20 research studies and found that video modeling was an overall effective intervention to teach job skills to autistic adolescents and adults. However, most of the studies focused on general job tasks rather than employment-related social skills. In addition, most of the studies were conducted in employment settings where the autistic employees did not earn regular wages, such as school settings or internships. We encourage future researchers to study how video modeling can be used to promote competitive integrated employment in community settings. WHAT DO THESE FINDINGS ADD TO WHAT WAS ALREADY KNOWN? Prior research studies have used video modeling to teach skills such as academic, play, and social skills to autistic children and youth. This study showed us that video modeling is an effective intervention to teach job skills to autistic adolescents and adults. WHAT ARE THE POTENTIAL WEAKNESSES OF THE STUDY? There are disagreements about how to evaluate the quality of research studies in the field of special education. We used a popular criterion by the Council for Exceptional Children organization, but our results may be different from other researchers. We also did not find a large number of studies, so some of our findings should be considered with caution. HOW WILL THESE FINDINGS HELP AUTISTIC ADULTS NOW OR IN THE FUTURE? These findings demonstrate that video modeling is an effective on-the-job training method for autistic employees. Autistic adults can use video modeling at work to learn new job skills. Employers, job coaches, and secondary transition professionals could use brief videos to support autistic employees.

Background Acne is a chronic disease with a varying presentation that requires long-term management. Despite this, the clinical guidelines for acne offer limited guidance to facilitate personalized or longitudinal management of patients. Objectives To generate recommendations to support comprehensive, personalized, long-term patient management that address all presentations of acne and its current and potential future burden. Methods The Personalising Acne: Consensus of Experts panel consisted of 13 dermatologists who used a modified Delphi approach to reach consensus on statements related to longitudinal acne management. The consensus was defined as ≥75% voting "agree" or "strongly agree." All voting was electronic and blinded. Results Key management domains, consisting of distinct considerations, points to discuss with patients, and "pivot points" were identified and incorporated into the Personalised Acne Care Pathway. Long-term treatment goals and expectations and risk of (or fears about) sequelae are highlighted as particularly important to discuss frequently with patients. Limitations Recommendations are based on expert opinion, which could potentially differ from patients' perspectives. Regional variations in health care systems may not have been captured. Conclusions The Personalised Acne Care Pathway provides practical recommendations to facilitate the longitudinal management of acne, which can be used by health care professionals to optimize and personalize care throughout the patient journey.

Objective Decision-making in chronic pain patients involves a combination of subjective and objective criteria, including patient history, physical examination, imaging, and patient response to prior treatments, clinical experience, probabilities, and recognition of patterns. However, there is a distinct lack of objective laboratory biomarkers in use in routine clinical care. The objective was to review the literature to identify and describe specific biomarkers in chronic pain management. Methods This is a narrative review of the literature regarding the use of laboratory biomarkers in chronic pain. A librarian-assisted literature search of the PubMed, Science Direct, and Google Scholar databases was performed and resulted in 304 possible manuscripts. We included manuscripts assessing laboratory collected biomarkers from urine, serum, cerebrospinal fluid, and saliva. After screening and review of the initial literature search results, a total of 75 manuscripts were included in the narrative review. Conclusion The studies reviewed suggested that specific biomarkers may help identify those patients at risk of disease development and function as a prognostic indicator for disease progression and treatment response. However, additional research is necessary before specific recommendations can be made, and current clinical decision-making is modified.

Blood flow restriction (BFR) with low-load resistance exercise (RE) is often used as a surrogate to traditional high-load RE to stimulate muscular adaptations, such as hypertrophy and strength. However, it is not clear whether such adaptations are achieved through similar cellular and molecular processes. We compared changes in muscle function, morphology and signaling pathways between these differing training protocols. Twenty-one males and females (mean ± SD: 24.3 ± 3.1 years) experienced with resistance training (4.9 ± 2.6 years) performed nine weeks of resistance training (three times per week) with either high-loads (75-80% 1RM; HL-RT), or low-loads with BFR (30-40% 1RM; LL-BFR). Before and after the training intervention, resting muscle biopsies were collected, and quadricep cross-sectional area (CSA), muscular strength and power were measured. Approximately 5 days following the intervention, the same individuals performed an additional 'acute' exercise session under the same conditions, and serial muscle biopsies were collected to assess hypertrophic- and ribosomal-based signaling stimuli. Quadricep CSA increased with both LL-BFR (7.4±4.3%) and HL-RT (4.6±2.9%), with no significant differences between training groups (p=0.37). Muscular strength also increased in both training groups, but with superior gains in squat 1RM occurring with HL-RT (p 0.05 for between-group comparisons). Together, these findings validate low-load resistance training with continuous BFR as an effective alternative to traditional high-load resistance training for increasing muscle hypertrophy in trained individuals.

Importance Complications during pregnancy and birth can impact whether an individual has more children. Individuals experiencing SMM are at a higher risk of general and reproductive health issues after pregnancy, which could reduce the probability of a subsequent birth. Objective To examine whether experiencing SMM during an individual's first birth affects their probability of having an additional birth, and whether this effect varies by maternal factors. Methods This retrospective cohort study US linked vital records and maternal discharges from 1997 to 2017 to identify all California births. The exposure, Severe Maternal Morbidity (SMM) was identified using a Centers for Disease Control and Prevention index. Individuals whose first birth was a singleton live birth were followed until their second birth or December 31, 2017, whichever came first. Hazard ratios for having a subsequent birth were estimated using Cox proportional hazard regression models. This association was assessed overall and stratified by maternal factors of a priori interest: age, race/ethnicity, and payer. Results Of the 3,916,413 individuals in our study, 51,872 (1.3%) experienced SMM at first birth. Compared to those who do not experience SMM, individuals who had SMM had a lower hazard, or instantaneous rate, of subsequent birth (adjusted HR 0.83, 95% CI: 0.82, 0.84); this association was observed in all levels of stratification (for example, adjusted HR range for known race/ethnicity: 0.78, 95% CI: 0.76, 0.80 for non-Hispanic White to 0.90, 95% CI: 0.88, 0.92 for Hispanic) and all indicators of SMM (0.24, 95% CI: 0.17, 0.35 for cardiac arrest/ventricular fibrillation to 0.84, 95% CI: 0.80, 0.87 for eclampsia). Conclusion and Relevance Our findings suggest that individuals who experience SMM at the time of their first birth are less likely to have a subsequent birth as compared to those who do not experience SMM at the time of their first birth. While the reasons for these findings are unclear, they could inform reproductive life planning discussions for individuals experiencing SMM. Future directions include studies exploring the reasons for not having a subsequent birth.

Anemia is a common complication of chronic kidney disease, affecting the quality of life of patients. Among various factors, such as iron and erythropoietin deficiency, reduced red blood cell (RBC) lifespan has been implicated in the pathogenesis of anemia. However, mechanistic data on in vivo RBC dysfunction in kidney disease are lacking. Herein, we describe the development of chronic kidney disease-associated anemia in mice with proteinuric kidney disease resulting from either administration of doxorubicin or an inducible podocin deficiency. In both experimental models, anemia manifested at day 10 and progressed at day 30 despite increased circulating erythropoietin levels and erythropoiesis in the bone marrow and spleen. Circulating RBCs in both mouse models displayed altered morphology and diminished osmotic-sensitive deformability together with increased phosphatidylserine externalization on the outer plasma membrane, a hallmark of RBC death. Fluorescence-labelling of RBCs at day 20 of mice with doxorubicin-induced kidney disease revealed premature clearance from the circulation. Metabolomic analyses of RBCs from both mouse models demonstrated temporal changes in redox recycling pathways and Lands’ cycle, a membrane lipid remodeling process. Anemic patients with proteinuric kidney disease had an increased proportion of circulating phosphatidylserine-positive RBCs. Thus, our observations suggest that reduced RBC lifespan, mediated by altered RBC metabolism, reduced RBC deformability, and enhanced cell death contribute to the development of anemia in proteinuric kidney disease.

Background and ObjectivesThere is accumulating evidence supporting an association between the thrombosis and thrombocytopenia syndrome (TTS) and adenovirus vector-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yet TTS and TTS-associated cerebral venous sinus thrombosis (CVST) remain poorly characterized. We aim to systematically evaluate the proportion of CVST among TTS cases and assess its characteristics and outcomes.MethodsWe performed a systematic review and meta-analysis of clinical trials, cohorts, case series, and registry-based studies with the aim to assess (1) the pooled mortality rate of CVST, TTS-associated CVST, and TTS and (2) the pooled proportion of patients with CVST among patients with any thrombotic event and TTS. Secondary outcomes comprised clinical characteristics of patients with postvaccination thrombotic event. This meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology proposal.ResultsSixty-nine studies were included in the qualitative analysis comprising 370 patients with CVST out of 4,182 patients with any thrombotic event associated with SARS-CoV-2 vector-based vaccine administration. Twenty-three studies were included further in quantitative meta-analysis. Among TTS cases, the pooled proportion of CVST was 51% (95% confidence interval [CI] 36%–66%; I2 = 61%). TTS was independently associated with a higher likelihood of CVST when compared to patients without TTS with thrombotic events after vaccination (odds ratio 13.8; 95% CI 2.0–97.3; I2 = 78%). The pooled mortality rates of TTS and TTS-associated CVST were 28% (95% CI 21%–36%) and 38% (95% CI 27%–49%), respectively. Thrombotic complications developed within 2 weeks of exposure to vector-based SARS-CoV-2 vaccines (mean interval 10 days; 95% CI 8–12) and affected predominantly women (69%; 95% CI 60%–77%) under age 45, even in the absence of prothrombotic risk factors.DiscussionApproximately half of patients with TTS present with CVST; almost one-third of patients with TTS do not survive. Further research is required to identify independent predictors of TTS following adenovirus vector-based vaccination.Registration InformationThe prespecified study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (CRD42021250709).

Adenoviruses cause a range of major diseases across many diverse animal species including ruminants. They are classified into six genera in the family Adenoviridae. In deer species, two adenoviruses are currently recognized: deer adenovirus 1 in the Atadenovirus genus, and deer adenovirus 2 in the Mastadenovirus genus. Deer adenovirus 1 causes adenovirus haemorrhagic disease with high fatality in black-tailed and mule deer in North America. Conversely, deer adenovirus 2 was incidentally detected from a healthy white-tailed deer fawn, but experimentally it has been shown to cause pyrexia, cough and moderate to severe haemorrhage. Here, we detected a novel adenovirus, reindeer adenovirus 1, from lung lesions of a 5-year-old male reindeer (Rangifer tarandus). This animal presented with aspiration pneumonia and necrotizing bronchiolitis following a period of clinical weakness, nasal discharge and wasting. Histopathological examination of the lung revealed large intranuclear basophilic inclusions associated with the areas of necrotizing bronchiolitis. Next generation sequencing of the lung tissue identified a novel mastadenovirus with close similarity to deer adenovirus 2 and bovine adenovirus 3. To our knowledge, this is the first report of a deer mastadenovirus associated with necrotizing bronchiolitis in captive reindeer.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

Background Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD. Methods We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data and IBD-specific outcomes were obtained. Results A total of 396 paediatric patients, including 148 with IBD, were included. Children with IBD were no less likely to have a successful first FMT then the non-IBD affected cohort [76% vs 81%, p = 0.17]. Among children with IBD, patients were more likely to have a successful FMT if they received FMT with fresh stool [p = 0.03], were without diarrhoea prior to FMT [p = 0.03], or had a shorter time from rCDI diagnosis until FMT [p = 0.04]. Children with a failed FMT were more likely to have clinically active IBD post-FMT [p = 0.002] and 19 [13%] patients had an IBD-related hospitalisation in the 3-month follow-up. Conclusions Based on the findings from this large US multicentre cohort, the efficacy of FMT for the treatment of rCDI did not differ in children with IBD. Failed FMT among children with IBD was possibly related to the presence of clinically active IBD.

BACKGROUND The authors' purpose was to create a nomogram using machine learning models predicting risk of breast reconstruction complications with or without postmastectomy radiation therapy. METHODS Between 1997 and 2017, 1617 breast cancer patients undergoing mastectomy and breast reconstruction were analyzed. Those with autologous, tissue expander/implant, and single-stage direct-to-implant reconstruction were included. Postmastectomy radiation therapy was delivered either with three-dimensional conformal photon or proton therapy. Complication endpoints were defined based on surgical reintervention operative notes as infection/necrosis requiring debridement. For implant-based patients, the authors studied capsular contracture requiring capsulotomy and implant failure. For each complication endpoint, least absolute shrinkage and selection operator-penalized regression was used to select the subset of predictors associated with the smallest prediction error from 10-fold cross-validation. Nomograms were built using the least absolute shrinkage and selection operator-selected predictors, and internal validation using cross-validation was performed. RESULTS Median follow-up was 6.6 years. Among 1617 patients, 23 percent underwent autologous reconstruction, 39 percent underwent direct-to-implant reconstruction, and 37 percent underwent tissue expander/implant reconstruction. Among 759 patients who received postmastectomy radiation therapy, 8.3 percent received proton-therapy to the chest wall and nodes and 43 percent received chest wall boost. Internal validation for each model showed an area under the receiver operating characteristic curve of 73 percent for infection, 75 percent for capsular contracture, 76 percent for absolute implant failure, and 68 percent for overall implant failure. Periareolar incisions and complete implant muscle coverage were found to be important predictors for infection and capsular contracture, respectively. In a multivariable analysis, we found that protons compared to no postmastectomy radiation therapy significantly increased capsular contracture risk (OR, 15.3; p < 0.001). This was higher than the effect of photons with electron boost versus no postmastectomy radiation therapy (OR, 2.5; p = 0.01). CONCLUSION Using machine learning, these nomograms provided prediction of postmastectomy breast reconstruction complications with and without radiation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE Risk, III.

Background Lung cancer is the leading cause of cancer-related death worldwide. Surgical resection remains the definitive curative treatment for early-stage disease offering an overall 5-year survival rate of 62%. Despite careful case selection, a significant proportion of early-stage cancers relapse aggressively within the first year post-operatively. Identification of these patients is key to accurate prognostication and understanding the biology that drives early relapse might open up potential novel adjuvant therapies. Methods We performed an unsupervised interrogation of >1600 serum-based autoantibody biomarkers using an iterative machine-learning algorithm. Results We identified a 13 biomarker signature that was highly predictive for survivorship in post-operative early-stage lung cancer; this outperforms currently used autoantibody biomarkers in solid cancers. Our results demonstrate significantly poor survivorship in high expressers of this biomarker signature with an overall 5-year survival rate of 7.6%. Conclusions We anticipate that the data will lead to the development of an off-the-shelf prognostic panel and further that the oncogenic relevance of the proteins recognised in the panel may be a starting point for a new adjuvant therapy.

Headache disorders and trigeminal neuralgia are common conditions representing the types of craniofacial pain syndrome that can significantly impact quality of life. Many cases are refractory to traditional pharmacologic treatments, whether oral or intravenous. Radiofrequency ablation has been increasingly used as a tool to treat resistant, chronic pain of both of these disorders. Multiple studies have been reported that illustrate the efficacy of radiofrequency ablation in the treatment of the numerous headache subtypes and trigeminal neuralgia.

Background Higher flavonoid intakes are hypothesised to confer protection against type 2 diabetes mellitus. Objective We aimed to 1) investigate associations between flavonoid intakes and diabetes, 2) examine the mediating impact of body fat, and 3) identify subpopulations that may receive the greatest benefit from higher flavonoid intakes in participants of the Danish Diet, Cancer, and Health Study followed-up for 23 years. Design Cross-sectional associations between baseline flavonoid intake, estimated using food frequency questionnaires and the Phenol Explorer database, and body fat estimated by bioelectrical impedance, were assessed using multivariable-adjusted linear regression models. Non-linear associations between flavonoid intake and incident diabetes were examined using restricted cubic splines with multivariable-adjusted Cox proportional hazards models. Results Among 54,787 participants (median [IQR] age of 56 [52-60] years; (47.3%) men), 6700 individuals were diagnosed with diabetes. Participants in the highest total flavonoid intake quintile (median, 1,202 mg/d) had a 1.52 kg lower body fat (95%CI: -1.74, -1.30) and a 19% lower risk of diabetes [hazard ratio (95%CI): 0.81 (0.75, 0.87)] after multivariable adjustments and compared to participants in the lowest intake quintile (median, 174 mg/d). Body fat mediated 57% (95% CI: 42%, 83%) of the association between flavonoid intake and incident diabetes. Of the flavonoid subclasses, moderate to high intakes of flavonols, flavanol monomers, flavanol oligo + polymers, and anthocyanins were significantly associated with a lower risk of diabetes. While associations were not modified by sex, smoking status, BMI or physical activity (pinteraction > 0.05 for all), findings on an absolute scale suggest that those at a higher risk (those with obesity) may benefit the most from a higher flavonoid intake. Conclusions These findings suggest that a diet abundant in flavonoid-rich foods may help to ameliorate diabetes risk, in part through a reduction in body fat.

Objectives This study sought to describe expected changes in a mirror-image prone electrocardiogram (ECG) compared with normal supine, including a range of cardiac conditions. Background Unwell COVID-19 patients are at risk of cardiac complications. Prone ventilation is recommended but poses practical challenges to acquisition of a 12-lead ECG. The effects of prone positioning on the ECG remain unknown. Methods 100 patients each underwent 3 ECGs: standard supine front (SF); prone position with precordial leads attached to front (PF); and prone with precordial leads attached to back in a mirror image to front (PB). Results Prone positioning was associated with QTc prolongation (PF 437 ± 32 ms vs. SF 432 ± 31 ms; p, Central Illustration

Background: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. Methods: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7–90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. Findings: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73–83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21–74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0–3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7–21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2–20·8]; adjusted hazard ratio 1·05 [95% CI 0·48–2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. Interpretation: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. Funding: Dutch Heart Foundation (grant 2012T077).

Previous studies have identified increased expression of members of the nuclear transport protein family in cancer cells. Recently, certain nuclear transport proteins have been reported to be secreted by cells and found in the serum. The aims of our study were to investigate the levels of multiple nuclear transport proteins secreted from cancer cells, and to determine their potential as diagnostic markers for cervical and oesophageal cancer. Mass spectrometry identified 10 nuclear transport proteins in the secretome and exosomes of cultured cancer cells, and Western blot analysis confirmed increased secreted levels in cancer cells compared to normal. To investigate their presence in patient serum, enzyme-linked immunosorbent assays were performed and revealed significantly increased levels of KPNβ1, CRM1, CAS, IPO5 and TNPO1 in cervical and oesophageal cancer patient serum compared to non-cancer controls. Significantly elevated KPNα2 and RAN levels were also identified in oesophageal cancer serum samples. Logistics regression analyses revealed IPO5 and TNPO1 to be the best performing individual candidate biomarkers in discriminating between cancer cases and controls. The combination of KPNβ1, CRM1, KPNα2, CAS, RAN, IPO5 and TNPO1 as a panel of biomarkers had the highest diagnostic capacity with an area under the curve of 0.944 and 0.963, for cervical cancer and oesophageal cancer, and sensitivity of 92.5% at 86.8% specificity and 95.3% sensitivity at 87.5% specificity, respectively. These results suggest that nuclear transport proteins have potential as diagnostic biomarkers for cervical and oesophageal cancers, with a combination of protein family members being the best predictor.

Background Excessive electronic health record (EHR) alerts reduce the salience of actionable alerts. Little is known about the frequency of interruptive alerts across health systems and how the choice of metric affects which users appear to have the highest alert burden. Objective (1) Analyze alert burden by alert type, care setting, provider type, and individual provider across 6 pediatric health systems. (2) Compare alert burden using different metrics. Materials and Methods We analyzed interruptive alert firings logged in EHR databases at 6 pediatric health systems from 2016–2019 using 4 metrics: (1) alerts per patient encounter, (2) alerts per inpatient-day, (3) alerts per 100 orders, and (4) alerts per unique clinician days (calendar days with at least 1 EHR log in the system). We assessed intra- and interinstitutional variation and how alert burden rankings differed based on the chosen metric. Results Alert burden varied widely across institutions, ranging from 0.06 to 0.76 firings per encounter, 0.22 to 1.06 firings per inpatient-day, 0.98 to 17.42 per 100 orders, and 0.08 to 3.34 firings per clinician day logged in the EHR. Custom alerts accounted for the greatest burden at all 6 sites. The rank order of institutions by alert burden was similar regardless of which alert burden metric was chosen. Within institutions, the alert burden metric choice substantially affected which provider types and care settings appeared to experience the highest alert burden. Conclusion Estimates of the clinical areas with highest alert burden varied substantially by institution and based on the metric used.

Introduction Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. Aim To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. Methods Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. Results Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. Conclusion Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.

Introduction Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. Aim To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. Methods Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. Results Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. Conclusion Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.

Context Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. Objective Assess plasma metabolome changes mediated by tirzepatide. Design Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. Setting Post hoc analysis. Participants 259 subjects with T2D. Intervention(s) Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. Main Outcome Measure(s) Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. Results At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. Conclusions Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.

Objective Traditional iliac (TI) screws require extensive dissection, involve offset-connectors, and have prominent screw heads that may cause patient discomfort. S2 alar-iliac (S2AI) screws require less dissection, do not need offset connectors, and are less prominent. However, the biomechanical consequences of S2AI screws crossing the alar-iliac joint is unknown. The present study investigates the fixation strength of a modified iliac (MI) screw, which has a more medial entry point and reduced screw prominence, but does not cross the alar-iliac joint. Methods Eighteen sacropelvic spines were divided into 3 groups (n = 6): TI, S2AI, and MI. Each specimen was fixed unilaterally with S1 pedicle screws and pelvic fixation according to its group. Screws were loaded at ±10 Nm at 3Hz for 1000 cycles. Motion of each screw and rod strain above and below the S1 screw was measured. Results Toggle of the S1 screw was lowest for the TI group, followed by the MI and S2AI groups, but there were no significant differences (P = 0.421). Toggle of the iliac screw relative to the pelvis was also lowest for the TI group, followed by the MI group, and was greatest for the S2AI group, without significant differences (P = 0.179). Rod strain was similar across all groups. Conclusions No statistically significant differences were found between the TI, S2AI, and MI techniques with regard to screw toggle or rod strain. Advantages of the MI screw include its lower profile and a medialized starting point eliminating the need for offset-connectors.

Understanding acid-base disorders using weak-acid concepts learned in general chemistry class is challenging for pre-nursing and pre-professional biology students enrolled in anatomy/physiology and biochemistry classes. We utilized a graphic seesaw model of carbonic acid-bicarbonate equilibrium using the Henderson-Hasselbalch (H-H) equation of a weak acid. We then used real-world clinical case studies for students to identify acid-base disorders and the appropriate compensatory responses of the lungs and kidneys. Students developed a working knowledge of how the bicarbonate blood buffer system maintains a physiological pH of 7.4 using a “seesaw” with metabolic [HCO3−] on one side, and respiratory PCO2 on the other at a ratio of 20:1 in the H-H equation. When the dysfunction of either the kidneys or lungs causes the seesaw to tip, homeostasis pH is disrupted, causing an acid-base disorder classified as metabolic or respiratory acidosis or alkalosis. The functioning organ can “level the seesaw” by compensating for the dysfunction of the opposite organ to regain homeostasis. Unlike traditional ways of explaining acid-base disorders, this graphic seesaw method is a simple and easy way to achieve understanding.

This review summarizes the current state of non-invasive diagnosis of non-alcoholic fatty liver disease (NAFLD). This begins with a brief discussion of blood-based analysis (serum biomarkers) then progresses through various imaging modalities (imaging biomarkers) including magnetic resonance (MR), computed tomography (CT), and ultrasound-based imaging methods. The review concludes with comment on the advantages, disadvantages, and prospects of commercially available modalities and the impact they may have on diagnosis and management of patients with NAFLD.

ObjectiveTo examine the incidence, characteristics, treatment, and predictors of late seizures (LS) after cerebral venous thrombosis (CVT), we described these features in a registry of 1,127 patients with CVT.MethodsWe included consecutive adult patients from an international consortium of 12 hospital-based CVT registries. We excluded patients with a history of epilepsy or with 7 days after diagnosis of CVT. We used multivariable Cox regression to identify predictors of LS.ResultsWe included 1,127 patients with CVT. During a median follow-up of 2.0 years (interquartile range [IQR] 1.0–6.3), 123 patients (11%) experienced ≥1 LS (incidence rate for first LS 30 per 1,000 person-years, 95% confidence interval [CI] 25–35). Median time to first LS was 5 months (IQR 1–16 months). Baseline predictors of LS included status epilepticus in the acute phase (hazard ratio [HR] 7.0, 95% CI 3.9–12.6), decompressive hemicraniectomy (HR 4.2, 95% CI 2.4–7.3), acute seizure(s) without status epilepticus (HR 4.1, 95% CI 2.5–6.5), subdural hematoma (HR 2.3, 95% CI 1.1–4.9), and intracerebral hemorrhage (HR 1.9, 95% CI 1.1–3.1). Eighty-five patients (70% of patients with LS) experienced a recurrent seizure during follow-up, despite the fact that 94% received antiepileptic drug treatment after the first LS.ConclusionDuring a median follow-up of 2 years, ≈1 in 10 patients with CVT had LS. Patients with baseline intracranial bleeding, patients with acute symptomatic seizures, and those who underwent decompressive hemicraniectomy were at increased risk of developing LS. The high recurrence risk of LS justifies epilepsy diagnosis after a first LS.

Children with neurofibromatosis type 1 (NF1) often experience executive dysfunction, attention deficit/hyperactivity disorder (ADHD) symptoms and poor social skills, however, the nature of the relationships between these domains in children with NF1 is unclear. This study investigated these relationships using primary caregiver ratings of executive functions, ADHD symptoms and social skills in children with NF1. Participants were 136 children with NF1 and 93 typically developing (TD) controls aged 3-15 years recruited from 3 multidisciplinary neurofibromatosis clinics in Melbourne and Sydney, Australia, and Washington DC, USA. Mediation analysis was performed on primary outcome variables: parent ratings of executive functions (Behavior Rating Inventory of Executive Function, Metacognition Index), ADHD symptoms (Conners-3/Conners ADHD Diagnostic and Statistical Manual for Mental Disorders Scales) and social skills (Social Skills Improvement System-Rating Scale), adjusting for potential confounders (full scale IQ, sex, and social risk). Results revealed significantly poorer executive functions, elevated ADHD symptoms and reduced social skills in children with NF1 compared to controls. Poorer executive functions significantly predicted elevated ADHD symptoms and poorer social skills. Elevated ADHD symptoms significantly mediated the relationship between executive functions and social skills problems although did not fully account for social dysfunction. This study provides evidence for the importance of targeting ADHD symptoms as part of future interventions aimed at promoting prosocial behaviors in children with NF1.

Mild parkinsonian signs (MPS) have been widely studied during the past 3 decades and proposed as a risk marker for neurodegenerative disease. This systematic review explores the epidemiology, clinical and prognostic associations, radiological features, and pathological findings associated with MPS in older adults free from neurodegenerative disease. We find that MPS as currently defined are strongly associated with increasing age and increased risk of development of Parkinson's disease (PD), all-cause dementia, disability, and death. Positive associations with later PD are found mainly in younger populations and those with other features of prodromal PD. There are currently no consistent radiological findings for MPS, and pathological studies have shown that MPS, at least in the oldest old, are often underpinned by mixed neuropathologies, including those associated with Alzheimer's disease, cerebrovascular disease, nigral neuronal loss, and Lewy bodies. Different subcategories of MPS appear to convey varying risk and specificity for PD and other outcomes. MPS overall are not specific for parkinsonian disorders and, although associated with increased risk of PD, can reflect multiple pathologies, particularly in older individuals. "Mild motor signs" appears a more appropriate term to avoid prognostic and pathological implications, and larger future studies to prospectively examine outcomes and associations of specific MPS subcategories are required. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVE To describe a population of dogs with hops toxicosis, including clinical signs observed, treatments performed, patient outcome, and overall prognosis. Clinical findings and treatment interventions were evaluated for their potential effects on outcome. This study also aims to review hops toxicosis and treatment options. DESIGN Retrospective observational study. SETTING Poison Control Center. ANIMALS Seventy-one dogs presenting for hops ingestion. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Records of 71 dogs with known hops ingestion from the ASPCA - Animal Poison Control Center (ASPCA-APCC) database and the Tufts University medical record system were reviewed. Fifty-nine (77%) of the dogs survived. The most common clinical signs on presentation were hyperthermia and tachycardia, with presenting temperatures and heart rates significantly higher in nonsurvivors. There was no significant difference between survivors and nonsurvivors in regard to signalment. Time to presentation was shorter in survivors (5.0 vs 5.5 h; P

Background: Crisaborole is a nonsteroidal anti-inflammatory phosphodiesterase 4 inhibitor that is approved for the treatment of patients with mild-to-moderate atopic dermatitis (AD); however, the efficacy and safety of crisaborole in patients with AD and other atopic comorbidities have not been investigated. Objective: This post hoc pooled analysis of the pivotal phase III studies (CrisADe CORE 1 and CORE 2) assessed the efficacy and safety of crisaborole versus vehicle in patients aged ≥ 2 years with mild-to-moderate AD and other atopic comorbidities. Methods: Patients with mild-to-moderate AD and a medical history of asthma, allergic rhinitis, or food allergies were identified. Efficacy assessments included the proportion of patients who achieved Investigator's Static Global Assessment (ISGA) success at day 29, ISGA clear or almost clear at day 29, and improvement in the Severity of Pruritus Scale score at week 4. Safety was assessed via treatment-emergent adverse events (TEAEs). Results: This analysis included 1522 patients (crisaborole, 1016; vehicle, 506); 26.2, 15.9, and 16.5% had a medical history of asthma, allergic rhinitis, and food allergies, respectively. The mean age was 12.2 years. A significantly greater proportion of patients treated with crisaborole achieved ISGA success at day 29 compared with patients treated with vehicle for most subgroups analyzed. Furthermore, a significantly greater proportion of patients treated with crisaborole achieved ISGA clear or almost clear at day 29 across all subgroups and demonstrated improvement in the Severity of Pruritus Scale score at week 4 versus patients treated with vehicle in most of the subgroups. Overall, most TEAEs were mild or moderate in severity; the most common treatment-related TEAE in patients with atopic comorbidities was application-site pain (crisaborole, 5.1%; vehicle, 1.7%). Conclusion: Crisaborole was efficacious and well tolerated in patients with mild-to-moderate AD and other atopic comorbidities, which suggested that crisaborole should be considered for the management of AD in this population. Clinical Trials NCT02118766 (CrisADe CORE 1) and NCT02118792 (CrisADe CORE 2), www.clinicaltrials.gov