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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.

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.

Allostatic load comprises cardiovascular, metabolic, and inflammatory markers, which is characterized by abdominal obesity, high blood glucose levels, impaired glucose tolerance, dyslipidemia, and hypertension and associated with an increased risk in breast cancer. The study was a 6-month, 3-arm randomized controlled trial of two moderate-intensity exercise interventions (compared with a control group) among obese, physically inactive, postmenopausal Black women aged 45 to 65 years, who were at increased risk for breast cancer based on the CARE model. Two hundred thirteen participants were randomly assigned to (1) supervised, facility-based aerobic exercise intervention (n = 73), (2) home-based exercise intervention (n = 69), or (3) a wait-listed control group (n = 71). The intervention effects of exercise on allostatic load were examined with intent-to-treat analyses using generalized linear models. It was revealed that statistically significant decreases in allostatic load over the 6-month period for both exercise intervention groups (i.e., home-based and supervised arms) compared to the controls were observed among the total population, pc-h = 0.023 and pc-s = 0.035, as well as among women with a family history of breast cancer, pc-h = 0.006 and pc-s = 0.012. Short-term aerobic activity improved allostatic load scores in metabolically unhealthy postmenopausal Black women at increased risk for cancer. Clinical trial registration number NCT02103140.

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.

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

Cholangiocarcinoma (CCA) has poor prognosis due to late‐stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced‐representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin‐fixed, paraffin‐embedded CCA tumors and adjacent hepatobiliary control tissues using methylation‐specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95‐1.0). In the clinical pilot on plasma, a cross‐validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81‐0.95]) but not for primary sclerosing cholangitis–associated eCCA (AUC, 0.54 [0.35‐0.73]). Conclusion: Next‐generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA., Next‐generation DNA sequencing yielded highly‐discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.

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 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.

Single-event multilevel surgery (SEMLS) is frequently used to correct pathological gait patterns in children with bilateral spastic cerebral palsy (BSCP) in a single session surgery. However, in-depth long-term evaluation reports of gait outcomes are limited. Therefore, we investigated if SEMLS is able to correct lower extremity joint and pelvic angles during gait towards typically developing gait patterns (TDC) in children with BSCP, and if so, if this effect is durable over a 10-year period. In total 13 children with BSCP GMFCS level II at time of index-surgery between the ages of 7.7–18.2 years at the time of SEMLS were retrospectively recruited. Three-dimensional gait data were captured preoperatively, as well as at short-, mid-, and long-term post-operatively, and used to analyze: movement analysis profile (MAP), gait profile score (GPS), and lower extremity joint and pelvic angles over the course of a gait cycle using statistical parametric mapping. In agreement with previous studies, MAP and GPS improved towards TDCs after surgery, as did knee extension during the stance phase (ɳ2 = 0.67; p

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.

Objective: The study aim was to compare interictal encephalographic (EEG) functional network topology between people with well-controlled idiopathic generalized epilepsy (WC-IGE) and drug-resistant IGE (DR-IGE). Methods: Nineteen participants with WC-IGE, 18 with DR-IGE, and 20 controls underwent a resting state, 64-channel EEG. An artifact-free epoch was bandpass filtered into the frequency range of high and low extended alpha. Weighted functional connectivity matrices were calculated. Mean degree, degree distribution variance, characteristic path length (L), clustering coefficient, small world index (SWI), and betweenness centrality were measured. A Kruskal–Wallis H-test assessed effects across groups. Where significant differences were found, Bonferroni-corrected Mann–Whitney pairwise comparisons were calculated. Results: In the low alpha band (6–9 Hz), there was a significant difference in L at the three-group level (p

Purpose: We aimed to assess the concordance of colorectal cancer–associated methylated DNA markers (MDM) in primary and metastatic colorectal cancer for feasibility in detection of distantly recurrent/metastatic colorectal cancer in plasma. Experimental Design: A panel of previously discovered colorectal cancer–associated MDMs was selected. MDMs from primary and paired metastatic colorectal cancer tissue were assayed with quantitative methylation-specific PCR. Plasma MDMs were measured blindly by target enrichment long-probe quantitative-amplified signal assays. Random forest modeling was used to derive a prediction algorithm of MDMs in archival plasma samples from primary colorectal cancer cases. This algorithm was validated in prospectively collected plasma samples from recurrent colorectal cancer cases. The accuracy of the algorithm was summarized as sensitivity, specificity, and area under the curve (AUC). Results: Of the 14 selected MDMs, the concordance between primary and metastatic tissue was considered moderate or higher for 12 MDMs (86%). At a preset specificity of 95% (91%–98%), a panel of 13 MDMs, in plasma from 97 colorectal cancer cases and 200 controls, detected stage IV colorectal cancer with 100% (80%–100%) sensitivity and all stages of colorectal cancer with an AUC of 0.91 (0.87–0.95), significantly higher than carcinoembryonic antigen [AUC, 0.72 (0.65–0.79)]. This panel, in plasma from 40 cases and 60 healthy controls, detected recurrent/metastatic colorectal cancer with 90% (76%–97%) sensitivity, 90% (79%–96%) specificity, and an AUC of 0.96 (0.92–1.00). The panel was positive in 0.30 (0.19–0.43) of 60 patients with no evidence of disease in post-operative patients with colorectal cancer. Conclusions: Plasma assay of novel colorectal cancer–associated MDMs can reliably detect both primary colorectal cancer and distantly recurrent colorectal cancer with promising accuracy.

Extended pleurectomy and decortication (ePD) is a difficult operation performed for the surgical resection of malignant pleural mesothelioma that can achieve a macroscopic complete resection with preservation of the lung. With lower perioperative mortality, similar long-term survival, and better tolerance in patients with lower performance status, ePD has become the preferred operation rather than extrapleural pneumonectomy despite lack of a direct comparison. As ePD has become more popular, international collaboration is underway to create surgical guidelines based on collection of operative data. These efforts will improve the safety and standardization of this operation.

Background Lymphedema affects many women who are treated for breast cancer. We examined the effectiveness of an education-only (EO) versus education plus sleeve compression/exercise intervention (lymphedema education and prevention [LEAP]) on lymphedema incidence and range of motion (ROM) in a group-randomized trial across 38 cooperative group sites. Methods The treating institution was randomly assigned to either EO or LEAP by a study statistician. All patients at a treating institution participated in the same intervention (EO or LEAP) to minimize contamination bias. Participants completed surveys, arm volume measurements, and self-reported ROM assessments before surgery and at 12 and 18 months after surgery. Lymphedema was defined as a ≥10% difference in limb volume at any time post-surgery up to 18 months after surgery or diagnosis by a health provider. Cochran-Mantel-Haenszel tests were used to compare lymphedema-free rates between groups, stratified by lymph node surgery type. Self-reported ROM differences were compared between groups. Results A total of 554 participants (56% LEAP) were included in the analyses. At 18 months, lymphedema-free rates were 58% (EO) versus 55% (LEAP) (P = .37). ROM for both arms was greater in LEAP versus EO at 12 months; by 18 months, most women reported full ROM, regardless of group. In LEAP, only one-third wore a sleeve ≥75% of the time; 50% performed lymphedema exercises at least weekly. Conclusion Lymphedema incidence did not differ by intervention group at 18 months. Poor adherence in the LEAP group may have contributed. However, physical therapy may speed recovery of ROM. Further research is needed to effectively reduce the incidence and severity of lymphedema in patients who have breast cancer.

The critical clinical and scientific insights achieved through knowledge of in vivo musculoskeletal soft tissue strains has motivated the development of relevant measurement techniques. This review provides a comprehensive summary of the key findings, limitations, and clinical impacts of these techniques to quantify musculoskeletal soft tissue strains during dynamic movements. Current technologies generally leverage three techniques to quantify in vivo strain patterns, including implantable strain sensors, virtual fibre elongation, and ultrasound. (1) Implantable strain sensors enable direct measurements of tissue strains with high accuracy and minimal artefact, but are highly invasive and current designs are not clinically viable. (2) The virtual fibre elongation method tracks the relative displacement of tissue attachments to measure strains in both deep and superficial tissues. However, the associated imaging techniques often require exposure to radiation, limit the activities that can be performed, and only quantify bone-to-bone tissue strains. (3) Ultrasound methods enable safe and non-invasive imaging of soft tissue deformation. However, ultrasound can only image superficial tissues, and measurements are confounded by out-of-plane tissue motion. Finally, all in vivo strain measurement methods are limited in their ability to establish the slack length of musculoskeletal soft tissue structures. Despite the many challenges and limitations of these measurement techniques, knowledge of in vivo soft tissue strain has led to improved clinical treatments for many musculoskeletal pathologies including anterior cruciate ligament reconstruction, Achilles tendon repair, and total knee replacement. This review provides a comprehensive understanding of these measurement techniques and identifies the key features of in vivo strain measurement that can facilitate innovative personalized sports medicine treatment., Annals of Biomedical Engineering, 49 (1), ISSN:1573-9686, ISSN:0191-5649, ISSN:0090-6964

Background: Accumulating evidence has shown that serum calcium and vitamin D may be associated with or influence various cancer risks. However, no prospective studies have evaluated the independent and joint associations between prediagnostic levels of serum calcium and vitamin D and future risk of incident primary liver cancer. Methods: We used a nested case–control design to evaluate subjects over 22 years of follow-up. Serum calcium, 25-hydroxy vitamin D [25(OH)D], and three markers of hepatitis B virus and hepatitis C virus were measured in baseline serum from 226 incident primary liver cancer cases and 1,061 matched controls. We calculated ORs and 95% confidence intervals (CI) using logistic regression to estimate the associations between calcium, 25(OH)D, and primary liver cancer risk. Results: Multivariable adjusted models showed that subjects with both low (ORLow/Medium = 1.48, 95% CI = 1.01–2.17) or high (ORHigh/Medium = 1.92, 95% CI = 1.34–2.76) calcium had an increased primary liver cancer risk, while those with high 25(OH)D had a decreased risk of primary liver cancer (ORHigh/Medium = 0.54, 95% CI = 0.35–0.82). In joint analyses, when compared with subjects with medium calcium and 25(OH)D, subjects with high calcium and medium 25(OH)D had elevated odds of developing primary liver cancer (OR = 1.89, 95% CI = 1.17–3.05); those with medium calcium and high 25(OH)D had reduced odds of developing primary liver cancer (OR = 0.34, 95% CI = 0.17–0.67); and subjects in other classifications of calcium and serum 25(OH)D levels had no change in the odds of developing primary liver cancer (all P > 0.05). Conclusions: In a nutrient-deficient population, we found that serum calcium and serum 25(OH)D could potentially be modifiable risk or protective factors. Impact: Our findings provide potential targets for primary liver cancer prevention and control.

AIM: To determine the prevalence and associations of non-retinopathy ocular conditions among older Australian adults with diabetes. METHODS: Multistage random-cluster sampling was used to select 3098 non-indigenous Australians aged 50y or older (46.4% male) and 1738 indigenous Australians aged 40y or older (41.1% male) from all levels of geographic remoteness in Australia. Participants underwent a standardised questionnaire to ascertain diabetes history, and a clinical examination to identify eye disease. We determined the prevalence of uncorrected refractive error, visually significant cataract, cataract surgery, age-related macular degeneration, glaucoma, ocular hypertension, retinal vein occlusion and epiretinal membrane among those with and without self-reported diabetes. RESULTS: Participants with self-reported diabetes had a higher prevalence of cataract surgery than those without diabetes (28.8% vs 16.9%, OR 1.78, 95%CI: 1.35-2.34 among non-indigenous Australians, and 11.3% vs 5.2%, OR 1.62, 95%CI: 1.22-2.14 among indigenous Australians). Diabetic retinopathy (DR) increased the odds of cataract surgery among self-reported diabetic indigenous and non-indigenous Australians (OR 1.89, P=0.004 and OR 2.33, P

Background To investigate oral leukoplakia (OL) and risk of upper gastrointestinal (UGI) cancer deaths in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort. Methods A total of 3318 subjects with esophageal squamous dysplasia enrolled on 1 May 1985, and were followed up until 30 September 2015. Participants with OL at baseline were treated as an exposed group, while the remainder was selected as a control group. All subjects were followed monthly and reviewed quarterly by the Linxian Cancer Registry. Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results During the 30‐year follow‐up, a total of 902 UGI cancer deaths occurred, including 541 esophageal squamous cell carcinoma (ESCC) related, 284 gastric cardia carcinoma (GCC) related, and 77 gastric noncardia carcinoma (GNCC) related deaths. Relative to subjects without OL, the long‐term risk of ESCC mortality in participants with OL increased by 26.1% (HR = 1.26, 95% CI: 1.05–1.52). In the subgroup analyses, adverse effects of OL on ESCC mortality were observed especially in younger subjects (HR = 1.48, 95% CI: 1.11–1.97), females (HR = 1.44, 95% CI: 1.11–1.89), non‐smokers (HR = 1.44, 95% CI: 1.15–1.81), nondrinkers (HR = 1.28, 95% CI: 1.04–1.57), and individuals with a family history of cancer (HR = 1.37, 95% CI: 1.05–1.79). No associations were observed between OL and risk of GCC and GNCC mortality. Conclusions OL may increase the long‐term risk of ESCC mortality, especially in younger subjects, females, nondrinkers, non‐smokers, and subjects with a family cancer history. Future studies are needed to explore the potentially etiological mechanism., OL could increase the long‐term risk of ESCC mortality, especially in younger subjects, females, nondrinkers, non‐smokers, and subjects with a family cancer history. The specific etiological mechanism needs to be further explored.

A simplified grading system for trachoma was published by the World Health Organization (WHO) in 1987. Intended for use by non-specialist personnel working at community level, the system includes five signs, each of which can be present or absent in any eye: (i) trachomatous trichiasis; (ii) corneal opacity; (iii) trachomatous inflammation-follicular; (iv) trachomatous inflammation-intense; and (v) trachomatous scarring. Though neither perfectly sensitive nor perfectly specific for trachoma, these signs have been essential tools for identifying populations that need interventions to eliminate trachoma as a public health problem. In 2018, at WHO's 4th global scientific meeting on trachoma, the definition of one of the signs, trachomatous trichiasis, was amended to exclude trichiasis that affects only the lower eyelid. This paper presents the amended system, updates its presentation, offers notes on its use and identifies areas of ongoing debate.En 1987, l'Organisation mondiale de la Santé a publié un système de codage simplifié du trachome. Destiné au personnel non qualifié travaillant au sein des communautés, il comporte cinq signes, chacun pouvant être présent ou absent dans l'un ou l'autre œil: (i) le trichiasis trachomateux; (ii) l'opacité cornéenne; (iii) l'inflammation trachomateuse — folliculaire; (iv) l'inflammation trachomateuse — intense; et enfin, (v) la cicatrice trachomateuse. Bien qu'ils ne soient ni parfaitement précis, ni totalement spécifiques au trachome, ces signes constituent des outils essentiels pour identifier les populations qui nécessitent une intervention afin d'éliminer le trachome en tant que problème de santé publique. En 2018, lors de la quatrième réunion scientifique mondiale sur le trachome, la définition de l'un des signes, le trichiasis trachomateux, a été modifiée pour exclure du système de codage le trichiasis qui n'affecte que la paupière inférieure. Ce document expose le nouveau système, actualise sa présentation, formule des remarques sur son utilisation et identifie les domaines qui font encore l'objet de débats.En 1987, la Organización Mundial de la Salud (OMS) publicó un sistema de clasificación simplificado para el tracoma. Este sistema fue diseñado para que lo utilice el personal no especializado que trabaja a nivel comunitario e incluye cinco signos, cada uno de los cuales puede estar presente o ausente en los ojos: i) la triquiasis tracomatosa; ii) la opacidad corneal; iii) la inflamación tracomatosa-folicular; iv) la inflamación tracomatosa-intensa; y v) la cicatrización tracomatosa. Si bien no son perfectamente sensibles ni muy específicos del tracoma, estos signos han sido herramientas esenciales para identificar a las poblaciones que requieren intervenciones para eliminar el tracoma como problema de salud pública. En 2018, se modificó la definición de uno de los signos, la triquiasis tracomatosa, en la 4.ª Reunión Científica Mundial sobre el Tracoma de la OMS, para descartar la triquiasis que solo afecta al párpado inferior. En el presente documento se describe el sistema modificado, se actualiza su presentación, se ofrecen observaciones sobre su aplicación y se identifican los ámbitos de debate en curso.تم نشر نظام تصنيف مبسط للتراكوما من جانب منظمة الصحة العالمية (WHO) في عام 1987. وهو مخصص للاستخدام بواسطة الأشخاص غير المتخصصين الذين يعملون على مستوى المجتمع، ويشمل النظام خمس علامات يمكن أن يكون كل منها موجودًا أو غير موجود في أي عين: (1) داء الشعرة التراكومي؛ و(2) عتامة القرنية؛ و(3) الالتهاب الجريبي التراكومي؛ و(4) الالتهاب التراكومي الشديد؛ و(5) التندب التراكومي. وبالرغم من أن هذه العلامات لم تكن حساسة للغاية أو محددة للإصابة بالتراكوما، إلا أنها كانت مؤشرات أساسية لتحديد السكان الذين يحتاجون إلى تدخلات طبية للقضاء على التراكوما كمشكلة صحية عامة. في عام 2018، في الاجتماع العلمي العالمي الرابع لمنظمة الصحة العالمية حول التراكوما، تم تعديل تعريف إحدى العلامات، وهو داء الشعرة التراكومي، وذلك لاستبعاد داء الشعرة الذي يصيب الجفن السفلي فقط. تعرض هذه الورقة النظام المعدل، وتقوم بتحديث عرضه التقديمي، وتقدم ملاحظات حول استخدامه، وتحدد مجالات النقاش الدائر.1987 年,世界卫生组织 (WHO) 公布了沙眼简化分级系统。该系统旨在供社区非专业工作人员使用，具备五种体征，其中每个体征都可出现于任一眼睛中，也可能不出现：(I) 沙眼性倒睫；(ii) 角膜混浊； (iii) 沙眼性炎症-滤泡； (iv) 沙眼性剧烈-炎症；以及 (v) 沙眼性疤痕。尽管对沙眼而言，这些体征即非特别敏感，也非专属于沙眼，但其已是确定哪些民众需通过干预消除沙眼这个公共卫生问题的关键。2018 年世卫组织第四届全球沙眼科学会议对沙眼性倒睫的定义进行了修正，排除了仅影响下眼睑的倒睫。本文介绍了修正后的系统，并更新了其介绍，给出了使用说明，并确定了正在讨论中的领域。.В 1987 году Всемирная организация здравоохранения (ВОЗ) опубликовала упрощенную систему оценки трахомы. Предназначенная для использования неспециализированным персоналом, работающим на местном уровне, система включает пять признаков, каждый из которых может присутствовать или отсутствовать в любом глазу: (i) трахоматозный трихиаз; (ii) помутнение роговицы; (iii) трахоматозное воспаление фолликулярное; (iv) трахоматозное воспаление интенсивное; (v) трахоматозное рубцевание. Хотя эти признаки не являются ни абсолютно чувствительными, ни абсолютно специфичными для трахомы, они были важными инструментами для выявления групп населения, которым необходимы вмешательства для устранения трахомы как проблемы общественного здравоохранения. В 2018 году на 4-й Всемирной научной конференции ВОЗ по вопросам трахомы определение одного из признаков, трахоматозного трихиаза, было изменено, чтобы исключить трихиаз, поражающий только нижнее веко. В данном документе приведена измененная система, обновлено ее представление, даны примечания по ее использованию и определены сферы текущих дискуссий.

BackgroundFor the prehospital diagnosis of raised intracranial pressure (ICP), clinicians are reliant on clinical signs such as the Glasgow Coma Score (GCS), pupillary response and/or Cushing’s triad (hypertension, bradycardia and an irregular breathing pattern). This study aimed to explore the diagnostic accuracy of these signs as indicators of a raised ICP.MethodsWe performed a retrospective cohort study of adult patients attended by a Helicopter Emergency Medical Service (Air Ambulance Kent, Surrey Sussex), who had sustained a traumatic brain injury (TBI), requiring prehospital anaesthesia between 1 January 2016 and 1 January 2018. We established optimal cut-off values for clinical signs to identify patients with a raised ICP and investigated diagnostic accuracy for combinations of these values.ResultsOutcome data for 249 patients with TBI were available, of which 87 (35%) had a raised ICP. Optimal cut-off points for systolic blood pressure (SBP), heart rate (HR) and pupil diameter to discriminate patients with a raised ICP were, respectively, >160 mm Hg,5 mm. Cushing criteria (SBP >160 mm Hg and HR ConclusionTraditional clinical signs of raised ICP may under triage patients to prehospital treatment with hyperosmolar drugs. Further research should identify more accurate clinical signs or alternative non-invasive diagnostic aids in the prehospital environment.

Background: Recent data suggest that acidosis alone is not a good predictor of mortality in trauma patients. Little data are currently available regarding factors associated with survival in trauma patients presenting with acidosis. Aims: The aims were to characterize the outcomes of trauma patients presenting with acidosis and to identify modifiable risk factors associated with mortality in these patients. Settings and Design: This is a retrospective observational study of University of Arkansas for Medical Sciences (UAMS) trauma patients between November 23, 2013, and May 21, 2017. Methods: Data were collected from the UAMS trauma registry. The primary outcome was hospital mortality. Analyses were performed using t-test and Pearson's Chi-squared test. Simple and multiple logistic regressions were performed to determine crude and adjusted odds ratios. Results: There were 532 patients identified and 64.7% were acidotic (pH < 7.35) on presentation: 75.9% pH 7.2–7.35; 18.5% pH 7.0–7.2; and 5.6% pH ≤ 7.0. The total hospital mortality was 23.7%. Nonsurvivors were older and more acidotic, with a base deficit >−8, Glasgow Coma Scale (GCS) ≤ 8, systolic blood pressure ≤ 90, International Normalized Ratio (INR) >1.6, and Injury Severity Score (ISS) >15. Mortality was significantly higher with a pH ≤ 7.2 but mortality with a pH 7.2–7.35 was comparable to pH > 7.35. In the adjusted model, pH ≤ 7.0, pH 7.0–7.2, INR > 1.6, GCS ≤ 8, and ISS > 15 were associated with increased mortality. For patients with a pH ≤ 7.2, only INR was associated with increase in mortality. Conclusions: A pH ≤ 7.2 is associated with increased mortality. For patients in this range, only the presence of coagulopathy is associated with increased mortality. A pH > 7.2 may be an appropriate treatment goal for acidosis. Further work is needed to identify and target potentially modifiable factors in patients with acidosis such as coagulopathy.

BackgroundThe coronavirus disease 2019 pandemic has necessitated almost exclusive National Health Service focus on emergency work and cancer care. There are concerns that increased hospital and community pressures will lead to decreased referrals and worse outcomes for head and neck cancer patients.MethodThis is a retrospective review of all cases referred for suspected head and neck cancer to our institution in January and April 2020.ResultsThere was a 55 per cent decrease in referrals but diagnostic yield rose from 2.9 per cent in January to 8.06 per cent in April. In both months, 100 per cent of patients met the 31- and 62-day targets, with similar 14-day wait time success (97.83 per cent for January vs 98.33 per cent for April). Referrals for laryngopharyngeal reflux rose from 27.5 per cent to 41.9 per cent. Referrals for those aged over 60 years fell from 42 per cent to 26 per cent.ConclusionIt is suggested that further research be conducted into the reasons why fewer patients were referred, particularly elderly patients, and why laryngopharyngeal reflux is so prevalent in fast-track referrals.

The interconnectivity between brain development and the immune system has become an area of interest for many neuroscientists. However, to date, a limited number of known immune mediators of the peripheral nervous system (PNS) have been found to influence the development of the central nervous system (CNS). FOXP3 is a well-established mediator of regulatory T-cells in the PNS. However, the expression pattern of FOXP3 in the CNS and the PNS throughout development is unknown. To fill this void, we have characterized, in several brain regions, the developmental profile of Foxp3 for both sexes using rats. We found different patterns of Foxp3 in the CNS and PNS. In the CNS, we found Foxp3 was ubiquitously expressed, with the levels of Foxp3 varying by brain region. We also found both Foxp3 mRNA and protein levels peak during embryonic development and then steadily decrease with a peak increase during adulthood. In adulthood, the protein but not mRNA increases to the equivalent levels found at the embryonic stage of life. In the PNS, Foxp3 protein levels were low embryonically and increased steadily over the life of the animal with maximal levels reached in adulthood. Patterns observed for both the PNS and CNS were similar in males and females across all developmental timepoints. Our novel findings have implications for understanding how the neural immune system impacts neurodevelopmental disorders such as autism and schizophrenia.

Background The objective of this study was to explore the association between fresh fruit consumption and long-term risk of upper gastrointestinal cancer (UGI) in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort. Methods A cohort of 3318 subjects with esophageal squamous dysplasia participated in the Linxian Dysplasia NIT in May 1985 and were followed up until 30 September 2015. Demographic characteristics, lifestyle, and history of diseases were collected at the baseline. The primary endpoint was death from esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric noncardia carcinoma (GNCC). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model. Results In the 30-year follow-up, a total of 541 ESCC, 284 GCC, and 77 GNCC deaths occurred. Relative to those who never or rarely consumed fresh fruit, the risk of ESCC mortality in participants who consumed fresh fruit more than 12 times/year were significantly decreased by 37.3% (HR = 0.63, 95% CI: 0.49-0.81). In the subgroup analyses, significantly protective effects on ESCC mortality were observed especially in females (HR = 0.59, 95% CI: 0.40-0.89), non-smokers (HR = 0.67, 95% CI: 0.48-0.94), and nondrinkers (HR = 0.69, 95% CI: 0.51-0.93). Conclusions Consuming fresh fruit more than 12 times/year may reduce the long-term risk of ESCC mortality in this dysplasia population, particularly in females, non-smokers, and nondrinkers. Future studies are needed to confirm these findings.

Polytrauma and traumatic brain injury (TBI) frequently co-occur and outcomes are routinely measured by the Glasgow Outcome Scale-Extended (GOSE). Polytrauma may confound GOSE measurement of TBI-specific outcomes. Adult patients with TBI from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study had presented to a Level 1 trauma center after injury, received head computed tomography (CT) within 24 h, and completed the GOSE at 3 months and 6 months post-injury. Polytrauma was defined as an Abbreviated Injury Score (AIS) ≥3 in any extracranial region. Univariate regressions were performed using known GOSE clinical cutoffs. Multi-variable regressions were performed for the 3- and 6-month GOSE, controlling for known demographic and injury predictors. Of 361 subjects (age 44.9 ± 18.9 years, 69.8% male), 69 (19.1%) suffered polytrauma. By Glasgow Coma Scale (GCS) assessment, 80.1% had mild, 5.8% moderate, and 14.1% severe TBI. On univariate logistic regression, polytrauma was associated with increased odds of moderate disability or worse (GOSE ≤6; 3 month odds ratio [OR] = 2.57 [95% confidence interval (CI): 1.50-4.41; 6 month OR = 1.70 [95% CI: 1.01-2.88]) and death/severe disability (GOSE ≤4; 3 month OR = 3.80 [95% CI: 2.03-7.11]; 6 month OR = 3.33 [95% CI: 1.71-6.46]). Compared with patients with isolated TBI, more polytrauma patients experienced a decline in GOSE from 3 to 6 months (37.7 vs. 24.7%), and fewer improved (11.6 vs. 22.6%). Polytrauma was associated with greater univariate ordinal odds for poorer GOSE (3 month OR = 2.79 [95% CI: 1.73-4.49]; 6 month OR = 1.73 [95% CI: 1.07-2.79]), which was conserved on multi-variable ordinal regression (3 month OR = 3.05 [95% CI: 1.76-5.26]; 6 month OR = 2.04 [95% CI: 1.18-3.42]). Patients with TBI with polytrauma are at greater risk for 3- and 6-month disability compared with those with isolated TBI. Methodological improvements in assessing TBI-specific disability, versus disability attributable to all systemic injuries, will generate better TBI outcomes assessment tools.

Maternal obesity is a major risk factor for adverse health outcomes for both the mother and the child, including the serious public health problem of childhood obesity which is globally on the rise. Given the relatively intensive contact with health/care professionals following birth, the interpregnancy period provides a golden opportunity to focus on preconception and family health, and to introduce interventions that support mothers to achieve or maintain a healthy weight in preparation for their next pregnancy. In this review, we summarise the evidence on the association between interpregnancy weight gain with birth and obesity outcomes in the offspring. Gaining weight between pregnancies is associated with an increased risk of large-for-gestational age (LGA) birth, a predictor of childhood obesity, and weight loss between pregnancies in women with overweight or obesity seems protective against recurrent LGA. Interpregnancy weight loss seems to be negatively associated with birthweight. There is some suggestion that interpregnancy weight change may be associated with preterm birth, but the mechanisms are unclear and the direction depends if it is spontaneous or indicated. There is limited evidence on the direct positive link between maternal interpregnancy weight gain with gestational diabetes, pre-eclampsia, gestational hypertension and obesity or overweight in childhood, with no studies using adult offspring adiposity outcomes. Improving preconception health and optimising weight before pregnancy could contribute to tackling the rise in childhood obesity. Research testing the feasibility, acceptability and effectiveness of interventions to optimise maternal weight and health during this period is needed, particularly in high-risk and disadvantaged groups.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

Introduction Data on the associations between esophageal histological lesions and risk of esophageal squamous cell carcinoma (ESCC) in general populations are limited. We aimed to investigate these associations in a large Chinese general population to inform future Chinese ESCC screening guidelines. Methods We performed endoscopic screening of 21,111 participants aged 40-69 years from 3 high-risk areas of China in 2005-2009, and followed the cohort through 2016. Cumulative incidence and mortality rates of ESCC were calculated by baseline histological diagnosis, and hazard ratios of ESCC, overall and by age and sex, were assessed using the Cox proportional hazards models. Results We identified 143 new ESCC cases (0.68%) and 62 ESCC deaths (0.29%) during a median follow-up of 8.5 years. Increasing grades of squamous dysplasia were associated with the increasing risk of ESCC incidence and mortality. The cumulative ESCC incidence rates for severe dysplasia/carcinoma in situ, moderate dysplasia (MD), and mild dysplasia were 15.5%, 4.5%, and 1.4%, respectively. Older individuals (50-69 years) had 3.1 times higher ESCC incidence than younger individuals (40-49 years), and men had 2.4 times higher ESCC incidence than women. Conclusions This study confirmed that increasing grades of squamous dysplasia are associated with increasing risk of ESCC and that severe dysplasia and carcinoma in situ require clinical treatment. This study suggests that in high-risk areas of China, patients with endoscopically worrisome MD should also receive therapy, the first screening can be postponed to 50 years, and endoscopic surveillance intervals for unremarkable MD and mild dysplasia can be lengthened to 3 and 5 years, respectively.

IMPORTANCE: Projections of Australia's future burden of vision loss will inform eye health service delivery. BACKGROUND: This study aimed to forecast bilateral vision loss in Australia from 2020 to 2050. DESIGN: Population-based survey. PARTICIPANTS: Indigenous and non-indigenous Australians (n = 4253) aged ≥50 years from the National Eye Health Survey (NEHS, 2015-2016). METHODS: Using the age-and-sex-stratified prevalence of vision loss (better eye visual acuity

Neurofibromatosis 1 (NF1) is a single gene disorder associated with working Memory (WM) impairments. The aim of this study was to investigate P300 event-related potential (ERP) associated with WM in NF1. Sixteen adolescents with NF1 were compared with controls on measures of WM and EEG was recorded during a WM nback task. The NF1 group showed poorer performance on measures of WM as compared to the control group. No group differences were observed in P300 amplitude at Pz, but P300 latency was shorter in the NF1 group. Topographic analyses of P300 amplitude showed group differences indicating neural processing differences in the NF1 group relative to controls, which possibly contribute to the cognitive deficits seen in this population.

Received 12th May 2021. Accepted 17th May 2021. Published online 28th May 2021. Issue published 1st August 2021.

PURPOSE The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies. PATIENTS AND METHODS A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. RESULTS Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1/ 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1/ 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. CONCLUSION ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.

Hip fractures associated with a high economic burden, loss of independence, and a high rate of post-fracture mortality, are a major health concern for modern societies. Areal bone mineral density is the current clinical metric of choice when assessing an individual's future risk of fracture. However, this metric has been shown to lack sensitivity and specificity in the targeted selection of individuals for preventive interventions. Although femoral strength derived from computed tomography based finite element models has been proposed as an alternative based on its superior femoral strength prediction ex vivo, such predictions have only shown marginal or no improvement for assessing hip fracture risk. This study compares finite element derived femoral strength to aBMD as a metric for hip fracture risk assessment in subjects (N = 601) from the AGES Reykjavik Study cohort and analyses the dependence of femoral strength predictions and classification accuracy on the material model and femoral loading alignment. We found hip fracture classification based on finite element derived femoral strength to be significantly improved compared to aBMD. Finite element models with non-linear material models performed better at classifying hip fractures compared to finite element models with linear material models and loading alignments with low internal rotation and adduction, which do not correspond to weak femur alignments, were found to be most suitable for hip fracture classification., Bone, 154, ISSN:8756-3282

BACKGROUND: Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation has been implicated in chronic widespread pain (CWP); the hallmark of fibromyalgia (FM). This is the first study to compare HPA axis changes in individuals with CWP and those at high risk of symptom development.METHODS: We sought to determine differences in morning and evening salivary cortisol levels in FM (n = 19), those at-risk (n = 20) and pain-free controls (n = 17). Risk factors included non-CWP pain, somatic symptoms, illness behaviour and sleep disturbance. We conducted the study in the absence of centrally acting medication, to address limitations of previous research.RESULTS: Repeated measures ANOVA revealed significant main effects of group (p = 0.003), and time of day (p = 0.002), with no significant interaction. Cortisol levels were higher in FM (p = 0.027) and at-risk (p = 0.003) groups, compared to controls, but there was no significant difference between FM and at-risk groups. The main effect of group remained significant with sleep problems (p = 0.021) and life events (p = 0.007), but was not significant with anxiety (p = 0.076) or depression (p = 0.098) scores as covariates. With sleep problems as a covariate, cortisol levels remained significantly higher only in the at-risk group (p = 0.017).CONCLUSIONS: This study indicates elevated salivary cortisol in FM and those at high risk, and identifies anxiety, depression and sleep problems as potential contributing factors. The results shed light on the dynamic relationship between stress, mood and sleep disorders and the brain's resilience to pain.SIGNIFICANCE: This study examines neurobiological changes in chronic widespread pain and high risk individuals. One strength of the study is the absence of centrally acting medication. We found high salivary cortisol common to Fibromyalgia and those at risk and identified contributing factors. Our results offer insight into the early mechanistic changes underlying Fibromyalgia development and open up possibilities for early diagnosis and prevention.

In nearly all clinical and research contexts, the initial severity of a traumatic brain injury (TBI) is measured using the Glasgow Coma Scale (GCS) total score. However, the GCS total score may not accurately reflect level of consciousness, a critical indicator of injury severity. We investigated the relationship between GCS total scores and level of consciousness in a consecutive sample of 2,455 adult subjects assessed with the GCS 69,487 times as part of the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We assigned each GCS subscale score combination a level of consciousness rating based upon published criteria for the following disorders of consciousness (DoC) diagnoses: coma, vegetative state/unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state, and present our findings using summary statistics and four illustrative cases. Participants had the following characteristics: mean (standard deviation) age 41.9 (17.6) years, 69% male, initial GCS 3-8=13%; 9-12=5%; 13-15=82%. All GCS total scores between 4-14 were associated with more than one DoC diagnosis; the greatest variability was observed for scores of 7-11. Furthermore, a wide range of total scores were associated with identical DoC diagnoses. Importantly, a diagnosis of coma was only possible with GCS total scores of 3-6. The GCS total score does not accurately reflect level of consciousness based on published DoC diagnostic criteria. To improve the classification of patients with TBI and to inform the design of future clinical trials, clinicians and investigators should consider individual subscale behaviors and more comprehensive assessments when evaluating TBI severity.

Diabetic retinopathy is a diabetes-mediated retinal microvascular disease that is the leading cause of blindness in the working-age population worldwide. Interleukin (IL)-17A is an inflammatory cytokine that has been previously shown to play a pivotal role in the promotion and progression of diabetic retinopathy. Retinoic acid-related orphan receptor gammaT (ROR&gamma, t) is a ligand-dependent transcription factor that mediates IL-17A production. However, the role of ROR&gamma, t in diabetes-mediated retinal inflammation and capillary degeneration, as well as its potential therapeutic attributes for diabetic retinopathy has not yet been determined. In the current study, we examined retinal inflammation and vascular pathology in streptozotocin-induced diabetic mice. We found ROR&gamma, t expressing cells in the retinal vasculature of diabetic mice. Further, diabetes-mediated retinal inflammation, oxidative stress, and retinal endothelial cell death were all significantly lower in ROR&gamma, t&minus, /&minus, mice. Finally, when a ROR&gamma, t small molecule inhibitor (SR1001) was subcutaneously injected into diabetic mice, retinal inflammation and capillary degeneration were ameliorated. These findings establish a pathologic role for ROR&gamma, t in the onset of diabetic retinopathy and identify a potentially novel therapeutic for this blinding disease.

Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.

Key Points Question What is the prevalence of financial hardship, including unmet health care need due to cost, health care unaffordability, and general financial stress, among peripartum women in the United States? Findings This cross-sectional study of 3509 peripartum women, weighted to represent more than 1 million women, found that financial hardship was common: from 2013 to 2018, 24% reported unmet health care needs; 60%, health care unaffordability; and 54%, general financial stress. Private insurance was associated with lower odds of unmet health care need but higher odds of health care unaffordability, and lower household income was associated with higher odds of both unmet health care need and health care unaffordability. Meaning These findings suggest that financial hardship is highly prevalent among peripartum women, which should prompt policy interventions to promote the economic well-being of families., This cross-sectional study evaluates the prevalence of financial hardship, including as unmet health care need due to cost, health care unaffordability, and general financial stress, among peripartum women over time and by insurance type and income., Importance Financial hardship affects health care access and health outcomes among peripartum women. Objective To evaluate the prevalence of financial hardship among peripartum women over time and by insurance type and income. Design, Setting, and Participants This cross-sectional study included peripartum women, defined as women aged 18 to 45 years who reported being currently pregnant or pregnant in the past 12 months, who participated in the National Health Interview Survey from 2013 to 2018. Data were analyzed from January to May 2021. Exposures Current pregnancy or recent pregnancy as well as insurance type and income. Main Outcomes and Measures Three measures of financial hardship within the last year were evaluated: (1) unmet health care need due to cost (unmet need for medical care or delayed or deferred medical care due to cost); (2) health care unaffordability (worry about paying for potential medical bills or existing medical debt); and (3) general financial stress (worry about subsistence spending [eg, monthly bills, housing]). Results The study cohort included 3509 peripartum women, weighted to represent 1 050 789 women (2018: an estimated 36 045 of 184 018 [19.6%] Hispanic, 39 017 [21.2%] Black, and 97 366 [52.9%] White), with a mean (SD) age of 29 (6) years. Overall, from 2013 to 2018, 24.2% (95% CI, 22.6%-26.0%) of peripartum women reported unmet health care need, 60.0% (95% CI, 58.0%-61.9%) reported health care unaffordability, and 54.0% (95% CI, 51.5%-56.5%) reported general financial stress. The prevalence of financial hardship outcomes did not substantially change between 2013 and 2018 (unmet health care need in 2013: 27.9% [95% CI, 24.4%-31.7%]; in 2018: 23.7% [95% CI, 19.5%-28.6%]; health care unaffordability in 2013: 65.7% [95% CI, 61.1%-70.0%]; in 2018: 58.8% [95% CI, 53.4%-64.0%]; general financial stress in 2013: 60.6% [95% CI, 55.2%-65.8%]; in 2018: 53.8% [95% CI, 47.8%-59.8%]). Women with private insurance had lower odds of unmet need (adjusted odds ratio [aOR], 0.67; 95% CI, 0.52-0.87) but higher odds of health care unaffordability (aOR, 1.88; 95% CI, 1.49-2.36) compared with women with public insurance. Peripartum women with household incomes less than 400% of the federal poverty level had higher odds of unmet need (aOR, 1.50; 95% CI, 1.08-2.08) and unaffordable care (aOR, 1.98; 95% CI, 1.54-2.55) compared with those with household incomes 400% or more of federal poverty level. Conclusions and Relevance These findings suggest that financial hardship among peripartum women in the United States was common from 2013 to 2018, including 24% of pregnant and postpartum women reporting unmet health care need and 60% reporting health care unaffordability. Women with private insurance and those living on lower incomes were more likely to experience unaffordable health care than women with pubic insurance and those with higher incomes, respectively. Targeted policy interventions are needed to improve health care affordability and promote overall economic security among peripartum women.

Background Proximal tubular cells (PTCs) are the most abundant cell type in the kidney. PTCs are central to normal kidney function and to regeneration versus organ fibrosis following injury. This study used single-nucleus RNA sequencing (snRNAseq) to describe the phenotype of PTCs in renal fibrosis.\ud\udMethods Kidneys were harvested from naïve mice and from mice with renal fibrosis induced by chronic aristolochic acid administration. Nuclei were isolated using Nuclei EZ Lysis buffer. Libraries were prepared on the 10× platform, and snRNAseq was completed using the Illumina NextSeq 550 System. Genome mapping was carried out with high-performance computing.\ud\udResults A total of 23,885 nuclei were analyzed. PTCs were found in five abundant clusters, mapping to S1, S1–S2, S2, S2-cortical S3, and medullary S3 segments. Additional cell clusters (“new PTC clusters”) were at low abundance in normal kidney and in increased number in kidneys undergoing regeneration/fibrosis following injury. These clusters exhibited clear molecular phenotypes, permitting labeling as proliferating, New-PT1, New-PT2, and (present only following injury) New-PT3. Each cluster exhibited a unique gene expression signature, including multiple genes previously associated with renal injury response and fibrosis progression. Comprehensive pathway analyses revealed metabolic reprogramming, enrichment of cellular communication and cell motility, and various immune activations in new PTC clusters. In ligand-receptor analysis, new PTC clusters promoted fibrotic signaling to fibroblasts and inflammatory activation to macrophages.\ud\udConclusions These data identify unrecognized PTC phenotype heterogeneity and reveal novel PTCs associated with kidney fibrosis.

Fatigue is a dominant feature of both acute and convalescent coronavirus disease 2019 (COVID-19) (sometimes termed “long-COVID”), with up to 46% of patients reporting fatigue that lasts from weeks to months. The investigators of the international Collaborative on Fatigue Following Infection (COFFI) conducted a systematic review of post-COVID fatigue and a narrative review on fatigue after other infections, and made recommendations for clinical and research approaches to assessing fatigue after COVID-19. In the majority of COVID-19 cohort studies, persistent fatigue was reported by a significant minority of patients, ranging from 13% to 33% at 16–20 weeks post-symptom onset. Data from the prospective cohort studies in COFFI and others indicate that fatigue is also a prevalent outcome from many acute systemic infections, notably infectious mononucleosis, with a case rate for clinically significant Post-infective fatigue after exclusion of recognized medical and psychiatric causes, ranging from 10%–35% at 6 months. To better characterize post-COVID fatigue, the COFFI investigators recommend the following: application of validated screening questionnaires for case detection; standardized interviews encompassing fatigue, mood, and other symptoms; and investigative approaches to identify end-organ damage and mental health conditions., Fatigue after COVID-19 is common but generally resolves over months, like other postinfective fatigue states. Post-COVID fatigue results from end-organ injury, mental health conditions, or idiopathic post-COVID fatigue. Post-COVID fatigue should be assessed with validated questionnaires, interviews, and protocolized investigations.

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 genomic epidemiology of infectious disease. AmpSeq data for infectious microbes can inform disease control in multiple ways, including 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 measuring relatedness, and a locus to detect Plasmodium vivax co-infections. We explore the performance of each panel in various public health use cases with in silico simulations as well as empirical experiments. We find that the smaller 4CAST panel performs reliably across a wide range of parasitemia levels without DNA pre-amplification, and could be highly informative for evaluating the number of distinct parasite strains within samples (complexity of infection), and distinguishing recrudescent infections from new infections in therapeutic efficacy studies. The AMPLseq panel performs similarly to two existing panels of comparable size for relatedness measurement, despite differences in the data and approach used for designing each panel. Finally, we describe an R package (paneljudge) that facilitates design and comparative evaluation of AmpSeq panels for relatedness estimation, and we provide general guidance on the design and implementation of AmpSeq panels for genomic epidemiology of infectious disease.