Search

More than 75% of patients presenting to level I trauma centers in the United States with suspicion of TBI sufficient to require a clinical computed tomography scan report injury-related symptoms 3 months later. There are currently no approved treatments, and few clinical trials have evaluated possible treatments. Efficient trials will require subject inclusion and exclusion criteria that balance cost-effective recruitment with enrolling individuals with a higher chance of benefiting from the interventions. Using data from the

Obesity is a worldwide epidemic and is associated with an increased risk of hypertension, diabetes, and obstructive sleep apnea. Pregnant patients with obesity experience a higher risk of maternal and fetal complications. Anesthesia also poses higher risks for obese parturients and may be more technically challenging due to body habitus. Safe anesthesia practice for these patients must take into consideration the unique challenges associated with the combination of pregnancy and obesity.

Background Tuberculous meningitis (TBM) is the most severe form of TB. We prospectively documented the treatment outcomes and the risk factors for death in children with TBM from Kandahar, Afghanistan. Methods This prospective observational cohort study was conducted from February 2017 to January 2020 in hospitalised TBM children. All the patients were prospectively followed up for 12 mo. Data were analysed by using descriptive statistics, χ2 and multivariate logistic regression. Results A total of 818 TBM hospitalised patients with median age 4.8 (0.8–14.5) y were recruited. Females accounted for 60.9% (498/818). Upon admission 53.9% (n=441) and 15.2% (n=124) had TBM stages II and III, respectively, and 23.2% (n=190) had focal neurological signs. The case fatality rate was 20.2% (160/794) and 30.6% (243/794) survived with neurological sequelae. Independent risk factors for death were being unvaccinated for BCG (adjusted OR [AOR] 3.8, 95% CI 1.8 to 8.1), not receiving dexamethasone (AOR 2.5, 95% CI 1.5 to 4.2), being male (AOR 2.3, 95% CI 1.5 to 3.6), history of recent weight loss (AOR 2.2, 95% CI 1.3 to 3.9) and having stage III TBM (AOR 2.0, 95% CI 1.2 to 3.3). Conclusions TBM continues to cause high morbidity and mortality in Afghan children. Strategies to reduce mortality should emphasise early diagnosis and treatment, routine use of dexamethasone and increased BCG vaccination.

Many hospitals have been using nutrition support guidelines for patients with coronavirus disease 2019 (COVID-19) as outlined in the April 2020 article released by the American Society for Parenteral and Enteral Nutrition (ASPEN) and the Society of Critical Care Medicine (SCCM). Currently, there are insufficient data on the outcomes of following these guidelines.This was a retrospective, observational study of 131 adult inpatients with COVID-19 admitted to an intensive care unit (ICU) at Banner Health to observe differences in length of stay, mortality, and number of days intubated based on the timing of nutrition support start relative to hours intubated and hours in the ICU.There were no statistically significant differences between length of stay, mortality, or number of days intubated between patients who started nutrition support within12 h of intubation,12 h of intubation and36 h in the ICU, or36 h of intubation and those who were not intubated. Patients who started nutrition support after36 h in the ICU had the longest lengths of stay (median [25th, 75th percentile] = 25.5 [19.25, 35.25] days; P 0.05) and number of days intubated (16.5 [10.0, 24.75] days; P 0.050); however, it was not statistically significant. There was a significant difference between the three intubated groups and the nonintubated group on Sequential Organ Failure Assessment scores (P = 0.01).Prospective, multicenter trials are needed; however, following the SCCM/ASPEN guidelines for nutrition support in patients with COVID-19 may be found to decrease length of stay and number of days intubated.

The objective of this study was to update the association between multivitamin supplementation and total or cause-specific mortality in a population with a high prevalence of undernutrition in China.The Linxian Dysplasia Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial in which 3318 persons aged 40-69 years with esophageal squamous dysplasia were assigned to receive daily multivitamin supplementation or a placebo for 6 years and were followed for 29 years. The primary outcome was esophageal/gastric cardia cancer mortality. The data were analyzed with Cox proportional hazards regression models. Subgroup analyses were performed by common characteristics such as age and gender.The cumulative total mortality was 83.5%. Multivitamin supplementation did not affect total or cause-specific mortality in the participants as a whole (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03). Subgroup analyses showed that no association between multivitamin supplementation and all-cause mortality was observed in men (HR, 0.90; 95% CI, 0.81-1.01), women (HR, 1.01; 95% CI, 0.91-1.12), younger participants (HR, 0.97; 95% CI, 0.87-1.08), or older participants (HR, 0.94; 95% CI, 0.85-1.04). Significant reductions in heart disease mortality (HR, 0.64; 95% CI, 0.47-0.87) and cerebrovascular disease mortality (HR, 0.74; 95% CI, 0.56-1.00) were seen in older men. In a subgroup of younger men and a subgroup of moderate or severe dysplasia, subjects receiving multivitamin supplementation had a lower risk of esophageal/cardia cancer mortality (HR for younger men, 0.76; 95% CI, 0.58-0.99; HR for moderate or severe dysplasia, 0.76; 95% CI, 0.58-1.00). No association between multivitamin supplementation and any cause-specific mortality was observed in a mild dysplasia population.Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial. In light of this and previous trials, multivitamin supplements should be used thoughtfully to improve health status of populations with esophageal squamous dysplasia.Multivitamin supplementation is common, yet its effect on mortality is unclear. The aim of this study was to update the long-term effects of multivitamin supplementation on total and cause-specific mortality during nearly 35 years of follow-up in the Linxian Dysplasia Nutrition Intervention Trial in China. Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial, and this indicates that multivitamin supplements should be used thoughtfully to improve health status.

Prone transpsoas fusion (PTP) is a minimally invasive technique that maximizes the benefit of lateral access interbody surgery and the prone positioning for surgically significant adjacent segment disease. The authors describe the feasibility, reproducibility and radiographic efficacy of PTP when performed for cases of lumbar ASD.Adult patients undergoing PTP for treatment of lumbar ASD at three institutions were retrospectively enrolled. Demographic information was recorded, as was operative data such as adjacent segment levels, operative time, blood loss, laterality of approach, open versus percutaneous pedicle screw instrumentation and need for primary decompression. Radiographic measurements including segmental and global lumbar lordosis, pelvic incidence, pelvic tilt, sacral slope and sagittal vertical axis were recorded both pre- and immediately post-operatively.Twenty-four patients met criteria for inclusion. Average age was 60.4 ± 10.4 years and average BMI was 31.6 ± 5.0 kg/mSingle-position prone transpsoas lumbar interbody fusion is a clinically reproducible minimally invasive technique that can effectively treat lumbar adjacent segment disease.

Funder: British Council; Id: http://dx.doi.org/10.13039/501100000308, Funder: Broad Institute; Id: http://dx.doi.org/10.13039/100013114, Funder: National Institute of Allergy and Infectious Diseases; Id: http://dx.doi.org/10.13039/100000060, Funder: Bill and Melinda Gates Foundation; Id: http://dx.doi.org/10.13039/100000865, Funder: Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Id: http://dx.doi.org/10.13039/100006492, Multiplexed PCR amplicon sequencing (AmpSeq) is an increasingly popular application for cost-effective monitoring of threatened species and managed wildlife populations, and shows strong potential for the genomic epidemiology of infectious disease. AmpSeq data from infectious microbes can inform disease control in multiple ways, such as by measuring drug resistance marker prevalence, distinguishing imported from local cases, and determining the effectiveness of therapeutics. We describe the design and comparative evaluation of two new AmpSeq assays for Plasmodium falciparum malaria parasites: a four-locus panel ("4CAST") composed of highly diverse antigens, and a 129-locus panel ("AMPLseq") composed of drug resistance markers, highly diverse loci for inferring relatedness, and a locus to detect Plasmodium vivax co-infection. We explore the performance of each panel in various public health use cases with in silico simulations as well as empirical experiments. The 4CAST panel appears highly suitable for evaluating the number of distinct parasite strains within samples (complexity of infection), showing strong performance across a wide range of parasitaemia levels without a DNA pre-amplification step. For relatedness inference, the larger AMPLseq panel performs similarly to two existing panels of comparable size, despite differences in the data and approach used for designing each panel. Finally, we describe an R package (paneljudge) that facilitates the design and comparative evaluation of genetic panels for relatedness estimation, and we provide general guidance on the design and implementation of AmpSeq panels for the genomic epidemiology of infectious disease.

People with end-of-life care needs are seen in an increasingly diverse range of health and community settings. Opportunity for continued occupational participation is highly valued by people at the end of life. This scoping review sought to identify the priorities and preferences for participation at the end of life and to map findings using the model of human occupation.A search strategy informed by the research question was developed in collaboration with a research librarian. Data sources used were Ovid Medline(R), CINAHL, Ovid Emcare, Scopus, Web of Science and PsychInfo. Studies that focused on clinician perspectives, clinical care, grief and loss, did not clearly identify end-stage diseases,18 years and written in languages other than English were excluded.Forty-four studies were included with a total of 1,070 study participants. Inductively developed themes were mapped against the model of human occupation constructs of volition (personal causation, values, interests), habituation (habits of occupational performance and routine), performance capacity and the lived body within the physical, social and occupational environment. The majority of findings sat within the construct of volition, particularly around sense of personal capacity, self-efficacy and values. At the end of life, people prioritise ongoing engagement in valued occupations even if participation is effortful. As disease progresses, opportunity to exert influence and control over this participation and engagement increases in importance. Personal causation plays an important role in the experience of occupational participation at this time.This review provides important insights into the occupational priorities of people at the end of life and the importance of supporting agency and volition at this time. The model of human occupation and its client-centred focus offer a framework for a more robust examination of ways to enhance volitional capacity and enable occupational participation for people at the end of life.

The purpose of this study was to arthroscopically evaluate syndesmotic stability after fixation with several combinations of suture buttons (SBs) and suture tape reinforcement in a completely unstable cadaver model.Fifteen cadaver above-knee specimens underwent sequential ligament transection and fixation to create six experimental models: (1) intact model, (2) after complete disruption of the syndesmotic ligaments, and after repair with either suture tape reinforcement (3), suture tape reinforcement with a single SB (4), suture tape reinforcement with two diverging SBs (5), or two diverging SBs alone (6). Instability measurements included anterior and posterior tibiofibular spaces measured arthroscopically under 100 N coronal stress, tibiofibular anteroposterior and posteroanterior translation in sagittal plane measured arthroscopically under sagittal stress of 100 N, and anterior tibiofibular space measured directly with a caliper under external rotation torque of 7.5 N·m. Instability measurements taken after each fixation method were compared with the uninjured model and with the complete unstable model using the Wilcoxon signed-rank test.Fixation using a combination of one SB and singular suture tape reinforcement augmentation provided stability similar to the intact stage (coronal anterior space 1.24 versus 1.15, P = 0.887; coronal posterior space 1.63 versus 1.64, P = 0.8421; anteroposterior translation 0.91 versus 0.46, P = 0.003; posteroanterior translation 0.51 versus 0.57, P = 0.051; external rotation anterior tibiofibular space 1.08 versus 0.55, P = 0.069). Moreover, adding a second SB led to further gains in fixation stability.This study suggests that although a destabilizing syndesmotic injury that includes the anterior inferior tibiofibular ligament, interosseous ligament, and posterior inferior tibiofibular ligament is not adequately stabilized by either one or two SBs, the addition of a suture tape reinforcement to even one SB restores syndesmotic stability to the preinjury level.

The recent introduction of Transcranial Alternating Current stimulation (tACS) in research on memory modulation has yielded some exciting findings. Whilst evidence suggests small but significant modulatory effects of tACS on perception and cognition, it is unclear how effective tACS is at modulating memory, and the neural oscillations underlying memory. The aim of this systematic review was to determine the efficacy with which tACS, compared to sham stimulation, can modify working memory (WM) and long-term memory (LTM) performance in healthy adults. We examined how these effects may be moderated by specific tACS parameters and study/participant characteristics. Our secondary goal was to investigate the neural correlates of tACS' effects on memory performance in healthy adults. A systematic search of eight databases yielded 11,413 records, resulting in 34 papers that included 104 eligible studies. The results were synthesised by memory type (WM/LTM) and according to the specific parameters of frequency band, stimulation montage, individual variability, cognitive demand, and phase. A second synthesis examined the correspondence between tACS' effects on memory performance and the oscillatory features of electroencephalography (EEG) and magnetencephalography (MEG) recordings in a subset of 26 studies. The results showed a small-to-medium effect of tACS on WM and LTM performance overall. There was strong evidence to suggest that posterior theta-tACS modulates WM performance, whilst the modulation of LTM is achieved by anterior gamma-tACS. Moreover, there was a correspondence between tACS effects on memory performance and oscillatory outcomes at the stimulation frequency. We discuss limitations in the field and suggest ways to improve our understanding of tACS efficacy to ensure a transition of tACS from an investigative method to a therapeutic tool.

Bringing evidence into policy and practice discussions is political; more so when evidence from health studies or programme data are deemed controversial or unexpected, or when results are manipulated and misrepresented. Furthermore, opinion and misinformation in recent years has challenged our notions about how to achieve evidence-informed decision-making (EIDM). Health policy and systems (HPS) researchers and practitioners are battling misrepresentation that only serves to detract from important health issues or, worse, benefit powerful interests. This paper describes cases of politically and socially controversial evidence presented by researchers, practitioners and journalists during the Health Systems Research Symposium 2020. These cases cut across global contexts and range from public debates on vaccination, comprehensive sexual education, and tobacco to more inward debates around performance-based financing and EIDM in refugee policy. The consequences of engaging in controversial research include threats to commercial profit, perceived assaults on moral beliefs, censorship, fear of reprisal, and infodemics. Consequences for public health include research(er) hesitancy, contribution to corruption and leakage, researcher reflexivity, and ethical concerns within the HPS research and EIDM fields. Recommendations for supporting researchers, practitioners and advocates include better training and support structures for responding to controversy, safe spaces for sharing experiences, and modifying incentive structures.

Summary Background In early 2020, the response to the SARS-CoV-2 pandemic focused on non-pharmaceutical interventions, some of which aimed to reduce transmission by changing mixing patterns between people. Aggregated location data from mobile phones are an important source of real-time information about human mobility on a population level, but the degree to which these mobility metrics capture the relevant contact patterns of individuals at risk of transmitting SARS-CoV-2 is not clear. In this study we describe changes in the relationship between mobile phone data and SARS-CoV-2 transmission in the USA. Methods In this population-based study, we collected epidemiological data on COVID-19 cases and deaths, as well as human mobility metrics collated by advertisement technology that was derived from global positioning systems, from 1396 counties across the USA that had at least 100 laboratory-confirmed cases of COVID-19. We grouped these counties into six ordinal categories, defined by the National Center for Health Statistics (NCHS) and graded from urban to rural, and quantified the changes in COVID-19 transmission using estimates of the effective reproduction number (Rt) between Jan 22 and July 9, 2020, to investigate the relationship between aggregated mobility metrics and epidemic trajectory. For each county, we model the time series of Rt values with mobility proxies. Findings We show that the reproduction number is most strongly associated with mobility proxies for change in the travel into counties (0·757 [95% CI 0·689 to 0·857]), but this relationship primarily holds for counties in the three most urban categories as defined by the NCHS. This relationship weakens considerably after the initial 15 weeks of the epidemic (0·442 [−0·492 to −0·392]), consistent with the emergence of more complex local policies and behaviours, including masking. Interpretation Our study shows that the integration of mobility metrics into retrospective modelling efforts can be useful in identifying links between these metrics and Rt. Importantly, we highlight potential issues in the data generation process for transmission indicators derived from mobile phone data, representativeness, and equity of access, which must be addressed to improve the interpretability of these data in public health. Funding There was no funding source for this study.

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation., Oxylipins are lipid mediators generated during infection for regulating inflammatory responses, but how they are removed is not completely clear. Here the authors show that cellular oxylipin removal is linked to mitochondria β-oxidation by CPT1, a mitochondria lipid importer protein, to serve as a metabolic checkpoint for oxylipin homeostasis and inflammation.

BACKGROUND: Thoracic surgery (TS) residency positions are in high demand. There is no study describing the nationwide attributes of successful matriculants in this specialty. We examined the characteristics of TS resident applicants and identified factors associated with acceptance. METHODS: Applicant data from 2014 to 2017 application cycles was extracted from the Electronic Residency Application System and stratified by matriculation status. Medical education, type of general surgery residency, and research achievements were analyzed. The number of peer-reviewed publications and the corresponding impact factor for the journals where they were published were quantified. RESULTS: There were 492 applicants and 358 matriculants. The overall population was primarily male (79.5%), white (55.1%), educated at United States allopathic medical schools (66.5%), and trained at university-based general surgery residencies (59.6%). Education at United States allopathic schools (odds ratio [OR], 2.54; P< .0001), being a member of the American Osteopathic Association (OR, 3.27; P = .021), general surgery residency affiliation with a TS residency (OR, 2.41; P = .0003) or National Cancer Institute designated Comprehensive Cancer Center (OR, 1.76; P = .0172), and being a first-time applicant (OR, 4.71, P< .0001) were independently associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 3 vs 2, P< .0001) and more frequently published in higher impact journals (P< .0001). CONCLUSIONS: Our study includes objective and quantifiable data from recent application cycles and represents an in-depth examination of applicants to TS residency. The type of medical school and residency, as well as academic productivity, correlate with successful matriculation.

In 2021, WHO Member States endorsed a global target of a 40-percentage-point increase in effective refractive error coverage (eREC; with a 6/12 visual acuity threshold) by 2030. This study models global and regional estimates of eREC as a baseline for the WHO initiative.The Vision Loss Expert Group analysed data from 565 448 participants of 169 population-based eye surveys conducted since 2000 to calculate eREC (met need/[met need + undermet need + unmet need]). A binary logistic regression model was used to estimate eREC by Global Burden of Disease (GBD) Study super region among adults aged 50 years and older.In 2021, distance eREC was 79·1% (95% CI 72·4-85·0) in the high-income super region; 62·1% (54·7-68·8) in north Africa and Middle East; 49·5% (45·0-54·0) in central Europe, eastern Europe, and central Asia; 40·0% (31·7-48·2) in southeast Asia, east Asia, and Oceania; 34·5% (29·4-40·0) in Latin America and the Caribbean; 9·0% (6·5-12·0) in south Asia; and 5·7% (3·1-9·0) in sub-Saharan Africa. eREC was higher in men and reduced with increasing age. Global distance eREC increased from 2000 to 2021 by 19·0%. Global near vision eREC for 2021 was 20·5% (95% CI 17·8-24·4).Over the past 20 years, distance eREC has increased in each super region yet the WHO target will require substantial improvements in quantity and quality of refractive services in particular for near vision impairment.WHO, Sightsavers, The Fred Hollows Foundation, Fondation Thea, Brien Holden Vision Institute, Lions Clubs International Foundation.

Glioblastoma is a lethal, diffusely invasive brain cancer that is robustly regulated by the activity of the brain itself, in part through neuron-to-glioma synaptic communication. Venkataramani et al. have conceptually advanced understanding of glioblastoma interactions with neural circuits, demonstrating that conduction of electrochemical signals via neuron-to-glioma synapses drives glioma invasion.

The prognostic role of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) is incompletely understood. Our objectives were to evaluate the evidence for tumor PD-L1 as a prognostic biomarker in MPM through meta-analysis and to determine whether tumor PD-L1 expression is associated with survival in MPM patients undergoing macroscopic complete resection.Meta-analysis was performed to determine the association of PD-L1 with overall survival in MPM (n = 1655) from 14 studies containing overall survival and tumor PD-L1 expression. Univariable and multivariable analyses tested the relationship of tumor PD-L1 with overall survival and recurrence-free survival in an institutional cohort of MPM patients treated by macroscopic complete resection (n = 75). To validate the association of PD-L1 with overall survival, we utilized two independent MPM cohorts (n = 284).Meta-analysis demonstrated that high tumor PD-L1 expression was associated with poor overall survival. Among 75 patients undergoing macroscopic complete resection, 49 tumors (65%) expressed PD-L1 (1% or more), and high PD-L1 (50% or greater) was more commonly expressed on nonepithelial (29%) compared with epithelial tumors (14%). High tumor PD-L1 expression was independently associated with poor overall survival (P.001, hazard ratio 5.67) and recurrence-free survival (P = .003, hazard ratio 3.28). The association of PD-L1 overexpression with unfavorable survival was more significant in epithelial MPMs than nonepithelial MPMs. These findings were validated in RNA sequencing analyses in two independent cohorts. Exploratory transcriptome analysis revealed that MPM tumors with PD-L1 overexpression displayed coexpression of other immune regulatory molecules, programmed cell death 1 ligand 2 and T-cell immunoglobulin mucin receptor 3.Tumor PD-L1 expression is a prognostic biomarker in patients undergoing surgical resection for MPM and may be useful in perioperative decision making.

Background With a multimodal treatment strategy, cytoreductive surgery extends survival in malignant pleural mesothelioma. Improving the accuracy of staging can refine patient selection. Our objective was to determine whether diagnostic laparoscopy (DL) improves staging for patients with malignant pleural mesothelioma with the routine use of positron emission tomography (PET). Methods We performed a retrospective review of our prospectively maintained database from February 2014 to May 2019. Inclusion criteria were patients who had disease in the chest that was deemed potentially resectable by radiographic criteria and who underwent DL as part of the staging evaluation before surgery. Results Of 187 patients (71% men, 80% epithelial) who underwent DL during staging, 76% proceeded to surgery; 22% were unresectable at exploratory thoracotomy and 78% underwent resection (pleurectomy and decortication, 68%; extrapleural pneumonectomy, 32%). Also, 89% had a PET computed tomography (CT), and 11% had a preoperative CT without PET. DL revealed peritoneal disease in 17%. Among patients with pathologically proven disease at DL, 77% had negative PET-CT imaging. Based on the pathologic findings at DL the sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 23%, 78%, 17%, and 83%, respectively. The accuracy of PET-CT was 68%. Conclusions PET-CT has low sensitivity and diagnostic accuracy to identify peritoneal disease in malignant pleural mesothelioma. DL as part of the preoperative staging defines an important subset of patients with bicavitary disease. We recommend DL as a component of staging before surgery.

Purpose of review Liquid biopsies have emerged as a noninvasive alternative to tissue biopsy with potential applications during all stages of pediatric oncology care. The purpose of this review is to provide a survey of pediatric cell-free DNA (cfDNA) studies, illustrate their potential applications in pediatric oncology, and to discuss technological challenges and approaches to overcome these hurdles. Recent findings Recent literature has demonstrated liquid biopsies' ability to inform treatment selection at diagnosis, monitor clonal evolution during treatment, sensitively detect minimum residual disease following local control, and provide sensitive posttherapy surveillance. Advantages include reduced procedural anesthesia, molecular profiling unbiased by tissue heterogeneity, and ability to track clonal evolution. Challenges to wider implementation in pediatric oncology, however, include blood volume restrictions and relatively low mutational burden in childhood cancers. Multiomic approaches address challenges presented by low-mutational burden, and novel bioinformatic analyses allow a single assay to yield increasing amounts of information, reducing blood volume requirements. Summary Liquid biopsies hold tremendous promise in pediatric oncology, enabling noninvasive serial surveillance with adaptive care. Already integrated into adult care, recent advances in technologies and bioinformatics have improved applicability to the pediatric cancer landscape.

The National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH-NINDS) Traumatic Brain Injury (TBI) Imaging Common Data Elements (CDEs) are standardized definitions for pathological intracranial lesions based on their appearance on neuroimaging studies. The NIH-NINDS TBI Imaging CDEs were designed to be as consistent as possible with the U.S. Food and Drug Administration (FDA) definition of biomarkers as "an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention." However, the FDA qualification process for biomarkers requires proof of reliable biomarker test measurements. We determined the interrater reliability of TBI Imaging CDEs on subacute brain magnetic resonance imaging (MRI) performed on 517 mild TBI patients presenting to 11 U.S. level 1 trauma centers. Three U.S. board-certified neuroradiologists independently evaluated brain MRI performed 2 weeks post-injury for the following CDEs: traumatic axonal injury (TAI), diffuse axonal injury (DAI), and brain contusion. We found very high interrater agreement for brain contusion, with prevalence- and bias-adjusted kappa (PABAK) values for pairs of readers from 0.92 [95% confidence interval, 0.88-0.95] to 0.94 [0.90-0.96]. We found intermediate agreement for TAI and DAI, with PABAK values of 0.74-0.78 [0.70-0.82]. The near-perfect agreement for subacute brain contusion is likely attributable to the high conspicuity and distinctive appearance of these lesions on T1-weighted images. Interrater agreement for TAI and DAI was lower, because signal void in small vascular structures, and artifactual foci of signal void, can be difficult to distinguish from the punctate round or linear areas of slight hemorrhage that are a common hallmark of TAI/DAI on MRI.

Background. Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for selected Parkinson's disease (PD) patients. Gait characteristics are often altered after surgery, but quantitative therapeutic effects are poorly described. Objective. The goal of this study was to systematically investigate modifications in asymmetry and dyscoordination of gait 6 months postoperatively in patients with PD and compare the outcomes with preoperative baseline and to asymptomatic controls without PD. Methods. A convenience sample of thirty-two patients with PD (19 with postural instability and gait disorder (PIGD) type and 13 with tremor dominant disease) and 51 asymptomatic controls participated. Parkinson patients were tested prior to the surgery in both OFF and ON medication states, and 6-months postoperatively in the ON stimulation condition. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I to IV and medication were compared to preoperative conditions. Asymmetry ratios, phase coordination index, and walking speed were assessed. Results. MDS-UPDRS I to IV at 6 months improved significantly, and levodopa equivalent daily dosages significantly decreased. STN-DBS increased step time asymmetry (hedges' g effect sizes [95% confidence interval] between pre- and post-surgery: .27 [-.13, .73]) and phase coordination index (.29 [-.08, .67]). These effects were higher in the PIGD subgroup than the tremor dominant (step time asymmetry: .38 [-.06, .90] vs .09 [-.83, 1.0] and phase coordination index: .39 [-.04, .84] vs .13 [-.76, .96]). Conclusions. This study provides objective evidence of how STN-DBS increases asymmetry and dyscoordination of gait in patients with PD and suggests motor subtypes-associated differences in the treatment response., Neurorehabilitation and Neural Repair, 35 (11), ISSN:1545-9683, ISSN:0888-4390, ISSN:1552-6844

Background and Aims We previously identified a 5 methylated DNA marker (MDM) panel for the detection of nonendoscopic Barrett’s esophagus (BE). In this study, we aimed to recalibrate the performance of the 5 MDM panel using a simplified assay in a training cohort, validate the panel in an independent test cohort, and explore the accuracy of an MDM panel with only 3 markers. Methods Participants were recruited from 3 medical centers. The sponge on a string device (EsophaCap; CapNostics, Concord, NC, USA) was swallowed and withdrawn, followed by endoscopy, in BE cases and control subjects. A 5 MDM panel was blindly assayed using a simplified assay. Random forest modeling analysis was performed, in silico cross-validated in the training set, and then locked down, before test set analysis. Results The training set had 199 patients: 110 BE cases and 89 control subjects, and the test set had 89 patients: 60 BE cases and 29 control subjects. Sensitivity of the 5 MDM panel for BE diagnosis was 93% at 90% specificity in the training set and 93% at 93% specificity in the test set. Areas under the receiver operating characteristic curves were .96 and .97 in the training and test sets, respectively. Model accuracy was not influenced by age, sex, or smoking history. Multiple 3 MDM panels achieved similar accuracy. Conclusions A 5 MDM panel for BE is highly accurate in training and test sets in a blinded multisite case-control analysis using a simplified assay. This panel may be reduced to only 3 MDMs in the future. (Clinical trial registration number: NCT 02560623.)

BACKGROUND Prophylactic administration of doxycycline is regarded as a potential new public health strategy to combat the rising rates of Chlamydia trachomatis infections and syphilis among men who have sex with men. We conducted a survey-based study to evaluate how community members and health care providers in Southern California would perceive doxycycline preexposure/postexposure prophylaxis (PrEP/PEP) to predict its acceptability and identify potential areas of concern. METHODS We conducted an online cross-sectional survey among community members who identify as men who have sex with men and health care providers with prescribing authority in Southern California to investigate the current attitudes toward doxycycline PrEP/PEP, including their willingness to accept. We analyzed the data using descriptive statistics and binary logistic regression. RESULTS Among 212 enrolled community member participants, 67.5% indicated they would take doxycycline PrEP/PEP if offered by their provider. Higher acceptability was significantly associated with several characteristics, including recent history of bacterial sexually transmitted infection diagnosis and current use of HIV PrEP. For health care providers, 89.5% of 76 enrolled participants expressed willingness to prescribe doxycycline PrEP/PEP to their patients if recommended by the Centers for Disease Control and Prevention, but only 43.4% were willing if not. Both community members and health care providers demonstrated high levels of concern toward possible drug resistance. CONCLUSIONS Doxycycline PrEP/PEP as a preventive strategy against chlamydial infections and syphilis would likely be accepted among community members and health care providers. Clear guidelines from public health officials and further clarification on the strategy's potential impact on developing drug resistance may be necessary to ensure successful implementation.

Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to develop various endocrine and non-endocrine tumors. Over 90% of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic tumors. The goal of this study was to investigate the molecular aspects of MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing (RNA-Seq) to identify genes associated with tumor development and potential targeted therapy. A retrospective chart review of 294 patients with MEN1 germline mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism for thymic tumor development. Unsupervised principal component analysis and hierarchical clustering of RNA-Seq data showed that thymic NETs formed a homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was abundantly expressed in thymic NETs, a potential therapeutic target. The molecular insights gained from our study about thymic tumors combined with similar data from other MEN1-associated tumors may lead to better surveillance and treatment of these rare tumors.

Pseudomonas aeruginosa is a human pathogen that relies on quorum sensing to establish infections. The PqsE quorum-sensing protein is required for P. aeruginosa virulence factor production and infection. PqsE has a reported enzymatic function in the biosynthesis of the quorum-sensing autoinducer called PQS. However, this activity is redundant because, in the absence of PqsE, this role is fulfilled by alternative thioesterases. Rather, PqsE drives P. aeruginosa pathogenic traits via a protein-protein interaction with the quorum-sensing receptor/transcription factor RhlR, an interaction that enhances the affinity of RhlR for target DNA sequences. PqsE catalytic activity is dispensable for interaction with RhlR. Thus, the virulence function of PqsE can be decoupled from its catalytic function. Here, we present an immunoprecipitation-mass spectrometry method employing enhanced green fluorescent protein-PqsE fusions to define the protein interactomes of wild-type PqsE and the catalytically inactive PqsE(D73A) variant in P. aeruginosa and their dependence on RhlR. Several proteins were identified to have specific interactions with wild-type PqsE while not forming associations with PqsE(D73A). In the Δ

Cataract surgery is a safe, effective and common elective procedure in Australia but access is inequitable. True waiting times for cataract care are undisclosed or inconsistently reported by governments. Estimates of true waiting times range from 4 to 30 months and have been extended during the coronavirus disease 2019 (COVID-19) pandemic. Comparative analysis revealed that reducing waiting periods from 12 to 3 months would result in estimated public health system cost savings of $6.6 million by preventing 50 679 falls. Investment in public cataract services to address current unmet needs would prevent avoidable vision impairment and associated negative consequences.

BACKGROUND The prevalence of myopia is increasing globally including in Europe and parts of Asia but Australian data are lacking. This study aim described the change in myopia prevalence in middle-aged Australian adults over approximately a 20-year period. METHODS Two contemporary Western Australian studies (conducted in mid-late 2010s): the coastal-regional Busselton Healthy Ageing Study (BHAS) and the urban Gen1 of the Raine Study (G1RS) were compared to two earlier studies (early-mid 1990s) in Australia: the urban Blue Mountains Eye Study (BMES) and urban/regional Melbourne Visual Impairment Project (MVIP). Refractive error was measured by autorefraction, vertometry, or subjective refraction. Participants (49-70 years) of European descent without self-reported/diagnosed cataract, corneal disease, or refractive or corneal surgery were included. RESULTS After exclusions, data were available from 2217, 1760, 700, 2987 and 756 participants from BMES, urban MVIP, regional MVIP, BHAS, and G1RS, respectively. The mean age ranged from 57.1 ± 4.6 years in the G1RS to 60.1 ± 6.0 years in the BMES; 44-48% of participants were male. When stratified by location, the contemporary urban G1RS cohort had a higher age-standardised myopia prevalence than the urban MVIP and BMES cohorts (29.2%, 16.4%, and 23.9%, p

The Glasgow Outcome Scale (GOS) in its original or extended (GOSE) form is the most widely used assessment of global disability in traumatic brain injury (TBI) research. Several publications have reported concerns about assessor scoring inconsistencies, but without documentation of contributing factors. We reviewed 6801 GOSE assessments collected longitudinally, across 18 sites in the 5-year, observational Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We recorded error rates (i.e., corrections to a section or an overall rating) based on site assessor documentation and categorized scoring issues, which then informed further training. In cohort 1 (n = 1261; February 2014 to May 2016), 24% of GOSEs had errors identified by central review. In cohort 2 (n = 1130; June 2016 to July 2018), acquired after curation of cohort 1 data, feedback, and further training of site assessors, the error rate was reduced to 10%. GOSE sections associated with the most frequent interpretation and scoring difficulties included whether current functioning represented a change from pre-injury (466 corrected ratings in cohort 1; 62 in cohort 2), defining dependency in the home and community (163 corrections in cohort 1; three in cohort 2) and return to work/school (72 corrections in cohort 1; 35 in cohort 2). These results highlight the importance of central review in improving consistency across sites and over time. Establishing clear scoring criteria, coupled with ongoing guidance and feedback to data collectors, is essential to avoid scoring errors and resultant misclassification, which carry potential to result in "failure" of clinical trials that rely on the GOSE as their primary outcome measure.

According to the social domains hypothesis, we reduce the information-processing demands of\ud complex social cues by classifying them into a limited number of domains, each with distinct sets\ud of expectations. This requires rapid identification of violations of the boundaries between\ud domains. We hypothesised that these violations are likely to be associated with neural activation\ud of the salience system. Using fMRI we compared responses of 20 adults to expected and\ud unexpected everyday social scenarios in personal and work interactions. The vignettes\ud exemplified different kinds of scenarios presented in the work setting, i.e., task-focused scenarios\ud which are expected at work and scenarios with a personal focus which are unexpected at work.\ud The key contrast between task and personal focussed scenarios presented in the work setting\ud was associated with fronto-insular activation. Perceived inappropriateness of the unexpected\ud scenarios, and shorter response time to judgement of inappropriateness, were also associated\ud with fronto-insular activation, after controlling for unpleasantness. This study indicates specific\ud neural responses to violations of expectations in different social situations. Our findings suggest\ud that the fronto-insular region is implicated in rapid detection of behaviours that cross the\ud boundaries of social domains which are hypothesised to be necessary for efficient social\ud information processing.

BACKGROUND AND AIM Previous studies suggest that serum ferritin may be associated with higher risk of liver cancer. However, additional studies of the association are needed. It is also not clear whether serum ferritin is associated with mortality from chronic liver disease (CLD). METHODS We performed a nested case-control study in the Linxian Nutrition Intervention Trials. Baseline serum ferritin was measured for 226 incident primary liver cancer cases, 281 CLD mortalities diagnosed, and 1061 age-matched, gender-matched, and trial-matched controls. We used multivariable logistic regression models to calculate odds ratios and 95% confidence intervals. Subgroup analysis and interaction tests were performed by age, gender, alcohol drinking, hepatitis B virus seropositivity (HBV+)/hepatitis C virus seropositivity (HCV+), and trial. RESULTS Participants with serum ferritin in the highest quartile, as compared with those in the lowest quartile, had an increased risk of CLD mortality (odds ratio = 1.72, 95% confidence interval = 1.12, 2.64, P-trend

BACKGROUND: This study aimed to understand the prevalence of prediabetes and diabetes in patients with cancer overall, by tumor site, by cancer treatment, and by time point in the cancer continuum. METHODS: This cohort study has been conducted at the Huntsman Cancer Institute, Salt Lake City, Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible for this analysis. The prevalence of prediabetes and diabetes is based on ICD code, laboratory tests for HbA1c (%), fasting plasma glucose (mg/dl), non-fasting blood glucose (mg/dl), or insulin prescription. RESULTS: The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of prediabetes was 6.0% (95% CI: 5.3–6.8) and of diabetes 12.2% (95% CI: 11.2–13.3). One year after diagnosis the prevalences were 16.6% for prediabetes (95% CI: 15.4–17.9) and 25.0% for diabetes (95% CI: 23.6–26.4). At the end of the observation period, the prevalence of prediabetes was 21.2% (95% CI: 20.4–23.0) and of diabetes was 32.6% (95% CI: 29.2–32.1). Patients with myeloma (39.2%; 95% CI: 32.6–46.2) had the highest prevalence of prediabetes and patients with pancreatic cancer the highest prevalence of diabetes (65.1%; 95% CI: 57.0–72.3). In patients who underwent chemotherapy (prediabetes: 29.1% vs 15.6%; diabetes: 37.6% vs 29.0%), radiation therapy (prediabetes: 24.3% vs. 19.9%; diabetes: 33.7% vs 32.1%), or immunotherapy (diabetes: 29.2% vs 20.4; prediabetes: 36.0% vs 32.2%), the prevalence of prediabetes and diabetes was higher compared to patients not undergoing those therapies. CONCLUSIONS: Every second patient with cancer suffers from prediabetes or diabetes. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of prediabetes and diabetes remains critical.

Background Women who engage in higher levels of exercise while trying to quit smoking have been shown to be less likely to relapse and to sustain their smoking abstinence longer. This study sought to examine the benefits of exercise for improving smoking cessation among Black women. Methods We evaluated the feasibility of a 12-week smoking and exercise intervention, Quit and Fit, tailored for Black women. All participants (intervention and control) received 12 weeks of smoking cessation counseling via telephone and 9 weeks of nicotine lozenges. Participants who were randomly assigned to the intervention condition were also assigned to a 12-week exercise group. Results Thirty-eight women were enrolled and 27 completed a 12-week follow-up assessment. Women from the intervention group were more likely to complete the 12-week follow-up assessment compared to participants in the control group (80% vs. 61%). Overall, 7 of the 38 participants (18%) were abstinent at 12 weeks (biochemically verified by expired carbon monoxide). Among the 25 women who completed the 12-week follow-up, abstinence was reported in 33% of the intervention group and 20% of the control group. Using an intent-to-treat approach, 25% of women in the intervention group were abstinent at 12 weeks (n = 5), compared to 11.1% for the control group (n = 2). These differences were not statistically significant. Conclusions The overall retention rate was 71% (27/38) at 12 weeks with higher among the intervention group (16/20; 80%) compared to the control group (11/18; 61%). The study demonstrates that it is feasible to retain African-American women in a short-term study of smoking cessation and exercise.

The objective of this project is to evaluate the usefulness of the asynchronous or standardized video interview (SVI) for selecting integrated interventional radiology residents. All selected interviewees were asked to provide a brief recorded video answering 2 standardized questions. The applicants were interviewed in the virtual real-time format by 8 interviewers and ranked by group consensus. The SVIs were independently reviewed by a separate group of 4 interviewers and ranked by group consensus. These consensus ranks were compared to each other to determine similarities and differences in rank order. The results show that the SVIs are not statistically reliable as compared to the real-time interviews. There was a trend for an agreement for the lowest tiers in ranking; however, this was not statistically significant. The asynchronous interview is not equivalent to the virtual real-time interview and would not represent an equivalent replacement. However, the SVI may be useful for screening applicants to interview.

The opportunistic pathogen

Importance: Responsive communication is critical to ensuring family-centered care in early intervention (EI). The Intentional Relationship Model (IRM) offers a framework for examining therapist–parent communication and offers strategies for supporting therapist responsiveness. Objective: To explore family-centered care and therapists’ communication in EI using the IRM. Design: Prospective descriptive study. Setting: Illinois EI program. Participants: Convenience sample of 101 therapists and 19 parents enrolled in an EI program. Therapist disciplines included developmental (n = 24), occupational (n = 32), physical (n = 17), and speech (n = 28) therapy. Outcomes and Measures: Demographic questionnaire, Early Interventionist Self-Efficacy Scale, Early Intervention Parenting Self-Efficacy Scale, Measure of Processes of Care (MPOC)–Short Form, MPOC–Service Provider, Clinical Assessment of Modes (CAM), and Clinical Assessment of Suboptimal Interaction–Short Form (CASI–SF). Results: Therapists used family-centered practices specific to relationship building more frequently than information sharing (especially sharing of general information). Therapists used the empathizing, encouraging, and instructing modes most frequently in their interactions with families. Participants’ scores on the MPOC, CAM, and CASI–SF were significantly correlated. Conclusions and Relevance: Therapist–parent interactions were aligned with family-centered care. Opportunities for practitioners were identified in (1) sharing specific and general information and (2) expanding the use of collaborating, problem-solving, and advocating modes. What This Article Adds: In this study, we explored how the IRM can inform family-centered practices in EI through examination of therapists’ interpersonal competency and therapeutic mode use.

Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of pre-invasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune microenvironment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from pre-invasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multi-dimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1-expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy.

A growing body of literature has emphasized the importance of biobehavioral processes – defined as the interaction of behavior, psychology, socioenvironmental factors, and biological processes – for clinical outcomes among transplantation and cellular therapy (TCT) patients. TCT recipients are especially vulnerable to distress associated with pandemic conditions and represent a notably immunocompromised group at greater risk for SARS-CoV-2 infection with substantially worse outcomes. The summation of both the immunologic and psychologic vulnerability of TCT patients renders them particularly susceptible to adverse biobehavioral sequelae associated with the Covid-19 pandemic. Stress and adverse psychosocial factors alter neural and endocrine pathways through sympathetic nervous system and hypothalamic-pituitary-adrenal axis signaling that ultimately affect gene regulation in immune cells. Reciprocally, global inflammation and immune dysregulation related to TCT contribute to dysregulation of neuroendocrine and central nervous system function, resulting in the symptom profile of depression, fatigue, sleep disturbance, and cognitive dysfunction. In this article, we draw upon literature on immunology, psychology, neuroscience, hematology and oncology, Covid-19 pathophysiology, and TCT processes to discuss how they may intersect to influence TCT outcomes, with the goal of providing an overview of the significance of biobehavioral factors in understanding the relationship between Covid-19 and TCT, now and for the future. We discuss the roles of depression, anxiety, fatigue, sleep, social isolation and loneliness, and neurocognitive impairment, as well as specific implications for sub-populations of interest, including pediatrics, caregivers, and TCT donors. Finally, we address protective psychological processes that may optimize biobehavioral outcomes affected by Covid-19.

Sustained complement activation is an underlying pathologic driver in many inflammatory and autoimmune diseases. Currently approved anti-complement therapies are directed at the systemic blockade of complement. Consequently, these therapies provide widespread inhibition of complement pathway activity, beyond the site of ongoing activation and the intended pharmacodynamic (PD) effects. Given the essential role for complement in both innate and adaptive immunity, there is a need for therapies that inhibit complement in diseased tissue while limiting systemic blockade. One potential approach focuses on the development of novel fusion proteins that enable tissue-targeted delivery of complement negative regulatory proteins. These therapies are expected to provide increased potency and prolonged tissue PD, decreased dosing frequency, and the potential for improved safety profiles. We created a library of bifunctional fusion proteins that direct a fragment of the complement negative regulator, complement receptor type 1 (CR1) to sites of tissue injury. Tissue targeting is accomplished through the binding of the fusion protein to complement C3 fragments that contain a surface-exposed C3d domain and which are covalently deposited on tissues where complement is being activated. To that end, we generated a fusion protein that contains an anti-C3d monoclonal antibody recombinantly linked to the first 10 consensus repeats of CR1 (CR11-10) with the intention of delivering high local concentrations of this complement negative regulatory domain to tissue-bound complement C3 fragments iC3b, C3dg and C3d. Biochemical and in vitro characterization identified several fusion proteins that inhibit complement while maintaining the C3d domain binding properties of the parent monoclonal antibody. Preclinical in vivo studies further demonstrate that anti-C3d fusion proteins effectively distribute to injured tissue and reduce C3 fragment deposition for periods beyond 14 days. The in vitro and in vivo profiles support the further evaluation of C3d mAb-CR11-10 as a novel approach to restore proper complement activation in diseased tissue in the absence of continuous systemic complement blockade.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

Diabetic retinopathy (DR) is a global health burden. Screening for sight-threatening DR (STDR) is the first cost-effective step to decrease this burden. We analyzed the similarities and variations between the recent country-specific and the International Council of Ophthalmology (ICO) DR guideline to identify gaps and suggest possible solutions for future universal screening. We selected six representative national DR guidelines, one from each World Health Organization region, including Canada (North America), England (Europe), India (South- East Asia), Kenya (Africa), New Zealand (Western Pacific), and American Academy of Ophthalmology Preferred Practice Pattern (used in Latin America and East Mediterranean). We weighed the newer camera and artificial intelligence (AI) technology against the traditional screening methodologies. All guidelines agree that screening for DR and STDR in people with diabetes is currently led by an ophthalmologist; few engage non-ophthalmologists. Significant variations exist in the screening location and referral timelines. Screening with digital fundus photography has largely replaced traditional slit-lamp examination and ophthalmoscopy. The use of mydriatic digital 2-or 4-field fundus photography is the current norm; there is increasing interest in using non-mydriatic fundus cameras. The use of automated DR grading and tele-screening is currently sparse. Country-specific guidelines are necessary to align with national priorities and human resources. International guidelines such as the ICO DR guidelines remain useful in countries where no guidelines exist. Validation studies on AI and tele-screening call for urgent policy decisions to integrate DR screening into universal health coverage to reduce this global public health burden.摘要: 糖尿病视网膜病变(DR)是全球性的健康负担。筛查威胁视力的DR (STDR)是降低这一负担的第一个具有成本效益的步骤。我们分析了不同国家特有的指南和国际眼科理事会(ICO)指南之间的共同点和差异点, 以确定差距, 并为未来的普遍筛查提出可能的解决方案。我们选择了六个具有代表性国家的DR指南, 每个世界卫生组织区域各一个, 包括加拿大 (北美) 、英国 (欧洲) 、印度 (东南亚) 、肯尼亚 (非洲) 、新西兰 (西太平洋) 和美国眼科学会首选的临床模式 (拉丁美洲和东地中海) 。我们考量了较新的照相技术、人工智能 (AI) 技术与传统筛查方法之间的差别。所有指南都认为糖尿病患者的DR和STDR筛查应该由眼科医生主导进行, 仅少量主张非眼科医生参与。但筛选地点和转诊时间不同指南之间存在显著差异。数字眼底照相筛检在很大程度上取代了传统的裂隙灯检查和检眼镜。散瞳后的数字眼底照相视野2个或4个视野范围是目前的标准, 但免散瞳的眼底照相也逐渐兴起。目前很少使用自动进行DR分级和远程筛查。根据各国的重点政策和人力资源情况制定相应的具体指南必不可少。但国际指南如ICO-DR指南在没有具体指南的国家仍然可以使用。为了减轻这一全球公共卫生负担, 有关AI和远程筛查的有效性研究需要立刻进行政策决策, 以将DR筛查纳入全民健康的覆盖范围。.

Background Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC). Methods We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer. Results Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07–1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P P = 0.13). Conclusions This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.

Objectives The clinical parameter of morning stiffness is widely used to assess the status of RA, but its accurate quantitative assessment in a clinical setting has not yet been successful. This lack of individual quantification limits both personalized medication and efficacy evaluation in the treatment of RA. Methods We developed a novel technology to assess passive resistance of the MCP III joint (stiffness) and its passive range of motion (PRoM). Within this pilot study, 19 female postmenopausal RA patients and 9 healthy controls were examined in the evening as well as the morning of the following day. To verify the specificity of the biomechanical quantification, 11 patients with RA were assessed both prior to and ∼3 h after glucocorticoid therapy. Results While the healthy controls showed only minor changes between afternoon and morning, in RA patients the mean PRoM decreased significantly by 18% (s.d. 22) and stiffness increased significantly by 20% (s.d. 18) in the morning compared with the previous afternoon. We found a significant positive correlation between RA activity and biomechanical measures. Glucocorticoids significantly increased the mean PRoM by 16% (s.d. 11) and reduced the mean stiffness by 23% (s.d. 22). Conclusion This technology allowed mechanical stiffness to be quantified in MCP joints and demonstrated high sensitivity with respect to disease status as well as medication effect in RA patients. Such non-invasive, low-risk and rapid assessment of biomechanical joint stiffness opens a novel avenue for judging therapy efficacy in patients with RA and potentially also in other non-RA inflammatory joint diseases.

Gastric cancer shows a strong male predominance, and sex steroid hormones have been hypothesized to explain this sex disparity. Previous studies examining the associations between sex hormones and sex hormone binding globulin (SHBG) and risk of gastric cancer come primarily from western populations and additional studies in diverse populations will help us better understand the association. We performed a nested case–control study in Linxian Nutrition Intervention Trials cohorts to evaluate the associations among Chinese men, where we had sufficient cases to perform a well-powered study. Using radioimmunoassays and immunoassays, we quantitated androgens, estrogens, and SHBG in baseline serum from 328 men that developed noncardia gastric cancer and matched controls. We used multivariable unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) and explored interactions with body mass index (BMI), age, alcohol drinking, smoking, and follow-up time. Subjects with SHBG in the highest quartile, as compared with those in the lowest quartile, had a significantly increased risk of gastric cancer (OR = 1.87; 95% CI, 1.01–3.44). We found some evidence for associations of sex steroid hormones in men with lower BMI. Our study found a novel association suggesting that higher serum concentrations of SHBG may be associated with risk of gastric cancer in men. We found no overall associations with sex hormones themselves, but future studies should expand the scope of these studies to include women and further explore whether BMI modifies a potential association. Prevention Relevance: It was the first study to investigate the association of gastric cancer with prediagnostic sex steroid hormones and SHBG in an Asian male population. Although there were no overall associations for sex steroid hormone concentrations, higher concentrations of SHBG was associated with increased risk of noncardia gastric cancer.

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. Peripheral blood mononuclear cells from this patient were unable to mount a cytokine (tumor necrosis factor, interleukin 6) response to Aspergillus fumigatus, and this first identified Dectin-2–deficient patient died of complications of invasive aspergillosis., We identified a Dectin-2 N170I mutation in an immunocompromised patient who died of complications of invasive aspergillosis. This mutation results in an early stop codon and poor receptor expression and renders Dectin-2 functionally defective.

Protein intake has been shown to lower risk of aging-related functional decline. The goal of this study was to assess long-term effects of weight-adjusted animal (AP) and plant protein (PP) intakes on aging-related change in functional status and grip strength.Framingham Offspring Study participants (n = 1896, 891 men and 1005 women), ≥age 50, were followed for an average of 14.4 years. Protein intake derived from two sets of 3-day diet records (exams 3 and 5) was expressed as both weight-adjusted intake (from residuals) and per kilogram of body weight (g/kg/d). Seven tasks from two standardized assessments (Nagi and the Rosow-Breslau scales) were selected to determine functional status at exams 5-9. Functional impairment was defined as failure to complete (or having a lot of difficulty completing) a given task. Grip strength was assessed by dynamometer at exams 7-9.Participants with higher (vs. lower) weight-adjusted intakes of AP and PP maintained higher functional scores (p = 0.001 and p 0.001, respectively). After accounting for baseline skeletal muscle mass (SMM) and physical activity, only AP was linked with lower risks of functional impairment. Higher AP intake among sedentary individuals led to 29% (95% CI: 0.51-1.00) reduced risks of impairment; among subjects with lower SMM, higher AP was associated with 30% (95% CI: 0.49-0.98) reduced risks. Physical activity and SMM were independently associated with reduced risks of functional impairment, regardless of protein intake. Finally, higher AP intake led to 34% and 48% greater preservation of grip strength in men (p = 0.012) and women (p = 0.034). Results were similar for protein intake expressed as g/kg/d.Higher AP intake and higher levels of physical activity and SMM were independently associated with lower risks of functional impairment and greater preservation of grip strength in adults over the age of 50 years.

Social rewards or punishments motivate human learning and behaviour, and alterations in the brain circuits involved in the processing of these stimuli have been linked with several neuropsychiatric disorders. However, questions still remain about the exact neural substrates implicated in social reward and punishment processing. Here, we conducted four Anisotropic Effect Size Signed Differential Mapping voxel-based meta-analyses of fMRI studies investigating the neural correlates of the anticipation and receipt of social rewards and punishments using the Social Incentive Delay task. We found that the anticipation of both social rewards and social punishment avoidance recruits a wide network of areas including the basal ganglia, the midbrain, the dorsal anterior cingulate cortex, the supplementary motor area, the anterior insula, the occipital gyrus and other frontal, temporal, parietal and cerebellar regions not captured in previous coordinate-based meta-analysis. We identified decreases in the BOLD signal during the anticipation of both social reward and punishment avoidance in regions of the default-mode network that were missed in individual studies likely due to a lack of power. Receipt of social rewards engaged a robust network of brain regions including the ventromedial frontal and orbitofrontal cortices, the anterior cingulate cortex, the amygdala, the hippocampus, the occipital cortex and the brainstem, but not the basal ganglia. Receipt of social punishments increased the BOLD signal in the orbitofrontal cortex, superior and inferior frontal gyri, lateral occipital cortex and the insula. In contrast to the receipt of social rewards, we also observed a decrease in the BOLD signal in the basal ganglia in response to the receipt of social punishments. Our results provide a better understanding of the brain circuitry involved in the processing of social rewards and punishment. Furthermore, they can inform hypotheses regarding brain areas where disruption in activity may be associated with dysfunctional social incentive processing during disease

The American Association for the Surgery of Trauma (AAST) recently developed a classification system to standardize outcomes analyses for several emergency general surgery conditions. To highlight this system's full potential, we conducted a study integrating prospective AAST grade assignment within the electronic medical record.Our institution integrated AAST grade assignment into our clinical workflow in July 2018. Patients with acute diverticulitis were prospectively assigned AAST grades and modified Hinchey classes at the time of surgical consultation. Support vector machine-a machine learning algorithm attuned for small sample sizes-was used to compare the associations between the two classification systems and decision to operate and incidence of complications.67 patients were included (median age of 62 y, 40% male) for analysis. The decision for operative management, hospital length of stay, intensive care unit admission, and intensive care unit length of stay were associated with both increasing AAST grade and increasing modified Hinchey class (all P 0.001). AAST grade additionally showed a correlation with complication severity (P = 0.02). Compared with modified Hinchey class, AAST grade better predicted decision to operate (88.2% versus 82.4%).This study showed the feasibility of electronic medical record integration to support the full potential of AAST classification system's utility as a clinical decision-making tool. Prospectively assigned AAST grade may be an accurate and pragmatic method to find associations with outcomes, yet validation requires further study.

Purpose:We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case–control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC.Experimental Design:Thirteen MDMs (GRIN2D, CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated.Results:The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89–0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87–0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98–1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76–0.92), CA19-9 alone was 0.87 (0.79–0.94), and combined MDM-CA19-9 panel was 0.90 (0.84–0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%–99%) for stage I disease and 82% (68%–92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86–0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84–0.93) versus 0.97 (0.94–0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%–98%), with an observed specificity of 92% at the preset specificity of 97.5%.Conclusions:Plasma MDMs in combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.