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Abstract. As a follow-up to an earlier study demonstrating healthier cardiometabolic profiles among long-term multiple dietary supplement (LTMDS) users, we examined if cardiometabolic health benefits associated with LTMDS use persisted with aging. The study is based on LTMDS users from North America and 2007–2010 NHANES participants who were used for comparison to the LTMDS users. NHANES subjects were classified as non-dietary supplement (NS) users, single supplement/single purpose supplement (SS) users, multivitamin/mineral supplement (MVMS) users, and multiple dietary supplement (MDS) users. Supplement groups were compared for total, HDL and LDL cholesterol; triglycerides; glucose; insulin; CRP and HbA1c ≥ 6.5%, adjusting for age, sex, income, education, BMI, history of CVD, and medications for hypercholesterolemia and diabetes. Geometric mean (95% confidence interval) LDL cholesterol was significantly lower (P

Background Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. Methods We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Results Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. Conclusions CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

STUDY OBJECTIVES: First, to compare the upper airway's anatomic and aerodynamic characteristics of the edentulous older adults who experience mild, moderate, and severe obstructive sleep apnea (OSA). Second, to examine the correlation between the severity of OSA and the anatomic and aerodynamic characteristic(s) of the upper airway in these edentulous individuals. METHODS: NewTom5G cone beam computed tomography scans of 58 edentulous individuals with mild, moderate, and severe OSA were included in this analysis. 1) Computational models of the upper airway were reconstructed based on cone beam computed tomography images and the anatomical and aerodynamic characteristics of the upper airway were examined by an observer blind to OSA severity. 2) Pearson correlation analysis was used to determine the correlation between apnea-hypopnea index and the anatomic and aerodynamic characteristics of the upper airway. RESULTS: Compared with edentulous patients with mild and moderate OSA, those with severe OSA have a more hourglass-shaped upper airway. The severity of OSA, namely, apnea-hypopnea index, was significantly correlated with the length, shape, and minimum cross-sectional area of the upper airway. During inspiration, the mean velocity of the airflow within the upper airway of the edentulous patients with severe OSA was higher than that of patients with mild and moderate OSA. During both inspiration and expiration, apnea-hypopnea index was found to be significantly correlated with maximum velocity (P = .05) and airway resistance (P = .024, 0.038). CONCLUSIONS: The edentulous patients with severe OSA have a more hourglass-shaped upper airway. The findings also suggest that, during inspiration, the airflow travels faster in edentulous patients with severe OSA than in those with mild or moderate OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: The Effect of Nocturnal Wear of Dentures on Sleep and Oral Health Related Quality of Life; URL: https://clinicaltrials.gov/ct2/show/NCT01868295; Identifier: NCT01868295. CITATION: Chen H, Elham E, Li Y, et al. Comparison of anatomic and aerodynamic characteristics of the upper airway among edentulous mild, moderate, and severe obstructive sleep apnea in older adults. J Clin Sleep Med. 2022;18(3):759-768.

Incidental respiratory disease-related findings are frequently observed on low-dose CT (LDCT) lung cancer screenings. This study analyzed data from the National Lung Screening Trial (NLST) to assess the relationship between such findings and respiratory disease mortality (RDM), excluding lung cancer.Are incidental respiratory findings on LDCT scanning associated with increased RDM?Subjects in the NLST LDCT arm received three annual screens. Trial radiologists noted findings related to possible lung cancer, as well as respiratory-related incidental findings. Demographic characteristics, smoking history, and medical history were captured in a baseline questionnaire. Kaplan-Meier curves were used to assess cumulative RDM. Multivariate proportional hazards models were used to assess risk factors for RDM; in addition to incidental CT scan findings, variables included respiratory disease history (COPD/emphysema, and asthma), smoking history, and demographic factors (age, race, sex, and BMI).Of 26,722 subjects in the NLST LDCT arm, 25,002 received the baseline screen and a subsequent LDCT screen. Overall, 59% were male, 26.5% were aged ≥ 65 years at baseline, and 10.6% reported a history of COPD/emphysema. Emphysema on LDCT scanning was reported in 30.7% of subjects at baseline and in 44.2% at any screen. Of those with emphysema on baseline LDCT scanning, 18% reported a history of COPD/emphysema. Median mortality follow-up was 10.3 years. There were 3,639 deaths, and 708 were from respiratory diseases. Among subjects with no history of COPD/emphysema, 10-year cumulative RDM ranged from 3.9% for subjects with emphysema and reticular opacities to 1.1% for those with neither condition; the corresponding range among subjects with a COPD/emphysema history was 17.3% (both) to 3.7% (neither). Emphysema on LDCT imaging was associated with a significantly elevated RDM hazard ratio (2.27; 95% CI, 1.92-2.7) in the multivariate model. Reticular opacities (including honeycombing/fibrosis/scar) also had a significantly elevated hazard ratio (1.39; 95% CI, 1.19-1.62).Incidental respiratory disease-related findings observed on NLST LDCT screens were frequent and associated with increased mortality from respiratory diseases.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Background: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226

Vitamin B-12 is a water-soluble vitamin that plays important roles in intermediary metabolism. Vitamin B-12 deficiency has many identifiable causes, including autoimmune and other gastrointestinal malabsorption disorders, dietary deficiency, and congenital defects in genes that are involved in vitamin B-12 trafficking and functions. Another putative cause of vitamin B-12 deficiency is the high-folate-low vitamin B-12 interaction, first suspected as the cause for observed relapse and exacerbation of the neurological symptoms in patients with pernicious anemia who were prescribed high oral doses of folic acid. We propose that this interaction is real and represents a novel cause of vitamin B-12 depletion with specific etiology. We hypothesize that excessive intake of folic acid depletes serum holotranscobalamin (holoTC), thereby decreasing active vitamin B-12 in the circulation and limiting its availability for tissues. This effect is specific for holoTC and does not affect holohaptocorrin, the inert form of serum vitamin B-12. Depletion of holoTC by folic acid in individuals with already low vitamin B-12 status further compromises the availability of vitamin B-12 coenzymes to their respective enzymes, and consequently a more pronounced state of biochemical deficiency. This hypothesis is drawn from evidence of observational and intervention studies of vitamin B-12-deficient patients and epidemiological cohorts. The evidence also suggests that, in a depleted state, vitamin B-12 is diverted to the hematopoietic system or the kidney. This most likely reflects a selective response of tissues expressing folate receptors with high affinity for unmetabolized folic acid (UMFA; e.g., hematopoietic progenitors and renal tubules) compared with those tissues (e.g., liver) that only express the reduced folate carrier, which is universally expressed but has poor affinity for UMFA. The biochemical and physiological mechanisms underlying this interaction require elucidation to clarify its potential public health significance.

Background: Lateral epicondylitis (LE) is a highly prevalent musculoskeletal disorder in workers, often associated with physically demanding work. Knowledge of work-relatedness of LE is crucial to develop appropriate preventive measures. This study investigates the prospective association between work-related physical risk factors and LE. Methods: A systematic literature review was conducted in MedLine using PubMed from January 1, 2010 until February 16, 2021. Published reports were included if: (1) LE was clinically assessed, (2) exposure to work-related physical risk factors was assessed, and (3) associations between LE and work-related physical risk factors were reported in prospective studies. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation. Results: In total, 318 workers with LE from a population of 5036 workers in five studies were included. Meta-analyses revealed high-quality evidence for associations between LE and a Strain Index (SI) score >5.1 (odds ratio [OR]: 1.75, 95% confidence interval (CI): 1.11–2.78) and moderate-quality evidence for forearm rotation >4 h/day or forearm rotation ≥45° for ≥45% time (OR: 1.85, 95% CI: 1.10–3.10). Gripping, flexion and extension of the wrist, and repetitive movements showed no significant associations with LE. Conclusion: High-quality evidence was found indicating that a higher SI increased the risk of LE. Moderate-quality evidence was found for an association between forearm rotation and LE. No associations were found between other physical risk factors and LE. Primary preventive interventions should focus on a reduction of the SI and of high forearm rotation in work.

PURPOSE: Multiple studies demonstrate MRI-targeted biopsy detects more clinically significant cancer than systematic biopsy, however some clinically significant cancers are detected by systematic biopsy only. While these events are rare, we sought to perform a retrospective analysis of these cases to ascertain the reasons that MRI-targeted biopsy missed clinically significant cancer, which was subsequently detected on systematic prostate biopsy. METHODS: Patients were enrolled in a prospective study comparing cancer detection rates by transrectal MRI-targeted fusion biopsy and systematic 12-core biopsy. Patients with an elevated PSA, abnormal digital rectal exam, or imaging findings concerning for prostate cancer underwent prostate MRI and subsequent MRI-targeted and systematic biopsy in the same setting. The subset of patients with grade group (GG) ≥3 cancer found on systematic biopsy and GG≤2 cancer (or no cancer) on MRI-targeted biopsy were classified as MRI-targeted biopsy misses. A retrospective analysis of the MRI and MRI-targeted biopsy real-time screen captures determined the cause of MRI-targeted biopsy miss. Multivariable logistic regression analysis compared baseline characteristics of patients with MRI-targeted biopsy misses to GG-matched patients whose clinically significant cancer was detected by MRI-targeted biopsy. RESULTS: Over the study period of 2007 to 2019, 2103 patients met study inclusion criteria and underwent combined MRI-targeted and systematic prostate biopsies. 41 (1.9%) men were classified as MRI-targeted biopsy misses. Most MRI-targeted biopsy misses were due to errors in lesion targeting (n=21, 51.2%), followed by MRI-invisible lesions (n=17, 40.5%), and MRI lesions missed by the radiologist (n=3, 7.1%). On logistic regression analysis, lower PI-RADS score was associated with having clinically significant cancer missed on MRI-targeted biopsy. CONCLUSION: While uncommon, most MRI-targeted biopsy misses are due to errors in lesions targeting, which highlights the importance of accurate co-registration and targeting when using software-based fusion platforms. Additionally, some patients will harbor MRI-invisible lesions which are un-targetable by MRI-targeted platforms. The presence of a low PI-RADS score despite a high PSA is suggestive of harboring an MRI-invisible lesion.

BackgroundMany studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring.MethodsThis exploratory case–cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period).ResultsThe analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92–3.90), p = 2.43 × 10−8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38–2.57), p = 7.06 × 10−5] and psychiatric [depressive disorder; HR = 2.11 (1.32–3.35), p = 1.70 × 10−3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54–0.71), p = 1.80 × 10−11].ConclusionsSixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Active patients at The First Episode Mood and Anxiety Program (FEMAP) were asked to participate in a study monitoring their symptoms during early COVID-19 closures. Participants were asked to predict both possible positive and feared outcomes of the pandemic. Responses were analyzed with a descriptive qualitative approach using thematic analysis. Primary feared outcomes included death, prolonged pandemic impacts, and concerns about employment, mental health, and education. Prevalent positive predictions included a new perspective, improved relationships, personal growth, and environmental improvement. These findings suggest the complex relationship between fear and hope for young people in the early stages of the pandemic. [ FROM AUTHOR] Copyright of Social Work in Mental Health is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the “whole is greater than the sum of the parts.” Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, “real-world,” settings.

Background/Purpose To assess the use of “quick” MRI without contrast in the setting of percutaneous drain management in pediatric patients. Methods A retrospective medical record review was conducted to compare “quick” MRI without contrast to CT in the pediatric percutaneous drain placement setting. The study included 111 patients under 18-years-old having undergone percutaneous drain placement between January 2014 and January 2019. The “quick” MRI protocol consists of axial single-shot-fast-spin-echo (SSFSE) and fat-saturated SSFSE coronal sequences. Primary clinical outcomes included number of additional drain placement procedures, complications, length of hospitalization, and repeat drainage within 6 months following drain-free interval. The use of “quick” MRI post-procedurally was also investigated. Results Patients with pre-drain “quick” MRIs instead of CTs had no significant difference in the need for additional drain placement (p = 1), length of hospitalization (p = 0.275), or drainage complications (p = 0.728). Patients receiving “quick” MRI for follow-up imaging post-drain placement had no greater rate of repeat drainage within 6 months of initial drain discontinuation (p = 0.90) when compared to patients having CT. Conclusions Pre and post-drainage procedure “quick” MRIs were found to be equivalent to CT in regard to several key clinical outcomes.

Barium defecography can assess structural and functional abnormalities in patients with chronic constipation.The purpose of this study was to determine the prevalence of individual and overlapping defecographic findings in this setting.This was a cross-sectional study.The study was conducted at a university hospital tertiary GI physiology department.Consecutive examinations of 827 consecutive patients presenting over a 30-month period with well-defined symptom severity (≥12 points on the Cleveland Clinic Constipation score) were included. Systematic evaluation of images with results stratified by sex is described.Six individual functional or anatomic (intussusception, rectocele, enterocele, megarectum, excessive dynamic perineal descent) defecographic observations were defined a priori, thus permitting 26 possible combinations of findings (ie, 63 abnormal types + 1 normal).Patients with constipation (mean symptom score = 19) were predominantly female (88%), with median age of 49 years (range, 17-98 y) . All 6 individual radiologic findings were identified with a total of 43 combinations found in the cohort; the 14 most prevalent of these accounted for85% of patients. Only 136 patients (16.4%) had a normal defecography (34.3% males vs 13.9% females; p0.0001). Overall, 612 patients (74.0%) had structural (n = 508 (61.4%)) or functional (n=104 (12.6%)) abnormalities in isolation, with 79 (9.6%) others exhibiting combinations of both. Functional abnormalities in isolation were more common in males compared with females (22.5% vs11.2%; p = 0.025) as opposed to structural abnormalities (57.8% vs 85.7%; p0.0001). Expulsion time was longer in females compared with males (110 s (60-120 s) vs 90 s (60-120 s); p = 0.049).The study was limited by its lack of multiorgan opacification.These results provide a contemporary atlas of defecographic findings in constipation. Several individual structural and functional features have been systematically classified, with overlap greater than previously acknowledged and profound differences among sexes that carry implications for tailoring management. See Video Abstract at http://links.lww.com/DCR/B552.ANTECEDENTES:La defecografía con bario puede evaluar anomalías estructurales y funcionales en pacientes con estreñimiento crónico.OBJETIVO:Determinar la prevalencia de hallazgos defecográficos individuales y superpuestos en este entorno.DISEÑO:Transversal.ENTORNO CLINICO:Hospital Universitario de tercer nivel, departamento de fisiología gastrointestinal.PACIENTES:Exploraciones consecutivas de 827 pacientes consecutivos que se presentaron durante un período de 30 meses con una gravedad de los síntomas bien definida (≥12 puntos en la escala de estreñimiento de la Cleveland Clinic): evaluación sistemática de imágenes con resultados estratificados por sexo.PRINCIPALES MEDIDAS DE VALORACION:Se definieron a priori seis observaciones defecográficas individuales, funcionales o anatómicas (intususcepción, rectocele, enterocele, megarecto, descenso perineal dinámico excesivo), lo que permitió 26 combinaciones posibles de hallazgos (es decir, 63 tipos anormales + 1 normal).RESULTADOS:Los pacientes con estreñimiento (puntuación media de síntomas, 19) eran predominantemente mujeres (88%) con una edad mediana de 49 (17-98) años. Se identificaron 6 hallazgos radiológicos individuales con un total de 43 combinaciones encontradas en la cohorte; los 14 más predominantes de éstos representaron85% de los pacientes.Solo 136 (16,4%) pacientes tuvieron una defecografía normal (34,3% hombres vs. 13,9% mujeres; P0,0001). En general, 612 (74,0%) pacientes tenían anomalías estructurales (n = 508 [61,4%]) o funcionales (n = 104 [12,6%]) de forma aislada, y otros 79 (9,6%) presentaban combinaciones de ambas. Las anomalías funcionales aisladas fueron más comunes en los hombres en comparación con las mujeres (22,5% vs. 11,2%, P = 0,025) en comparación con las anomalías estructurales (57,8 vs. 85,7%, P0,0001). El tiempo de expulsión fue mayor en las mujeres en comparación con los hombres (110 [60-120] vs. 90 [60-120] segundos; P = 0,049).LIMITACIONES:Falta de opacificación multiorgánica.CONCLUSIONES:Estos resultados proporcionan un atlas contemporáneo de hallazgos defecográficos en estreñimiento. Varias características individuales, estructurales y funcionales; se han clasificado sistemáticamente, con una superposición mayor que la reconocida anteriormente y con grandes diferencias entre los sexos que tienen implicaciones para adaptar su tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/B552.

Background Greater whole grain (WG) consumption is associated with reduced risk of cardiovascular disease (CVD); however, few prospective studies have examined WG or refined grain (RG) intake and intermediate cardiometabolic risk factors. Objectives We examined the longitudinal association between WG and RG intake on changes in waist circumference (WC); fasting HDL cholesterol, triglyceride, and glucose concentrations; and blood pressure. Methods Subjects were participants in the Framingham Offspring cohort study [n = 3121; mean ± SD baseline age: 54.9 ± 0.2 y; BMI (kg/m2) 27.2 ± 0.1]. FFQ, health, and lifestyle data were collected approximately every 4 y over a median 18-y follow-up. Repeated measure mixed models were used to estimate adjusted mean changes per 4-y interval in risk factors across increasing categories of WG or RG intake. Results Greater WG intake was associated with smaller increases in WC (1.4 ± 0.2 compared with 3.0 ± 0.1 cm in the highest compared with the lowest category, respectively; P-trend

Objectives To characterize high-risk HPV types associated with cervical precancerous lesions in women living in Yaounde, Cameroon, and to determine their distribution with HIV status. Methods Women with abnormal pap smears recorded from February 2015 to May 2019 at Saint Martin de Porres' Health Centre, Yaounde, Cameroon, were recruited in this study after obtaining informed consent. Pap smears were collected and re-examined. Human immunodeficiency virus (HIV) serology was determined. HPV16, 18, 33, and 45 were assessed using standard PCR. Results All included participants (370) were HPV-positive and had either low grade squamous intraepithelial lesions (67.03%) or high grade squamous intraepithelial lesions (31.35%). They were subdivided into HIV-positive (N =102) and HIV-negative (N =268). In the HIV-negative subgroup, we observed 66.04% HPV16-positve, 41.79% HPV18-positve, 21.27% HPV33-positve and 8.21% HPV45-positve. In the HIV-positive subgroup, we observed 22.55% HPV16-positve, 5.88% HPV18-positve, 75.49% HPV33-positve, and 49.02% HPV45-positve. Married HIV-positive participants (47.14 ± 1.19) were older than both their single counterparts (34.94±1.22, P = 0.0008) and HIV-negative participants (41.43 ± 0.79, P = 0.0001). Single HIV-positive women reported higher numbers of miscarriages (P = 0.0023), and had later first sexual intercourse than HIV-negative (P = 0.0079) women. Conclusion Our study suggested differential expressions in high-risk HPV types with HIV status and cervical precancerous lesions and warrants more extensive studies.

Studies finding lower incidence rates of prostate cancer among men with diabetes have been primarily conducted in White non-Hispanic (WNH) populations. The purpose of this analysis is to compare the relationship between diabetes and prostate cancer among Black (BNH) and White non-Hispanic men. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2011 to 2015 to compare incidence rates and tumor characteristics between BNH and WNH men by diabetes status. Age-adjusted incidence rates and corresponding rate ratios (RR) by diabetes status were calculated overall and by tumor grade, stage, and PSA level separately for BNH and WNH men. We used multivariable logistic regression to compare tumor characteristics among men with prostate cancer in the numerator, both within and across race/ethnic groups. Overall age-adjusted incidence rates were significantly lower in men with diabetes compared to those without among WNH men [RR = 0.88 95% Confidence Interval (CI) 0.86–0.90] but there was no difference in rates by diabetes status among BNH men (RR = 1.01 95% CI 0.96–1.07). Men with diabetes were less likely to be diagnosed with distant-staged tumors compared to those without diabetes in both race/ethnic groups but the magnitude of difference by diabetes status was greater in BNH [Odds Ratio (OR) = 0.52 95% CI 0.42–0.64] than WNH (OR = 0.88 95% CI 0.81–0.95) men (p-value for interaction

The act of defaecation, although a ubiquitous human experience, requires the coordinated actions of the anorectum and colon, pelvic floor musculature, and the enteric, peripheral and central nervous systems. Defaecation is best appreciated through the description of four phases, which are, temporally and physiologically, reasonably discrete. However, given the complexity of this process, it is unsurprising that disorders of defaecation are both common and problematic; almost everyone will experience constipation at some time in their life and many will develop faecal incontinence. A detailed understanding of the normal physiology of defaecation and continence is critical to inform management of disorders of defaecation. During the past decade, there have been major advances in the investigative tools used to assess colonic and anorectal function. This Review details the current understanding of defaecation and continence. This includes an overview of the relevant anatomy and physiology, a description of the four phases of defaecation, and factors influencing defaecation (demographics, stool frequency/consistency, psychobehavioural factors, posture, circadian rhythm, dietary intake and medications). A summary of the known pathophysiology of defaecation disorders including constipation, faecal incontinence and irritable bowel syndrome is also included, as well as considerations for further research in this field.

OBJECTIVE. The purpose of this study was to evaluate the safety and efficacy of percutaneous drainage of peripancreatic fluid collections after pancreas transplant and to determine factors predicting a successful clinical outcome. MATERIALS AND METHODS. This single-center retrospective study included 28 patients who underwent percutaneous drainage for peripancreatic collections after transplant between January 2008 and December 2018. Clinical success was defined as drainage resulting in resolution of symptoms. Primary clinical success was defined as symptom resolution after the initial drainage procedure, and secondary success was defined as symptom resolution after additional drainage procedures. Operative intervention or death was considered clinical failure. Patient, collection, and procedural factors were assessed for their potential impact on the clinical outcome. RESULTS. Clinical success was achieved in 23 of 28 drainage procedures (82.1%), with primary success in 15 procedures. Of the five patients with failed drainage procedures, three required pancreatectomies, one required surgical washout, and one died from a disseminated infection. The median duration of drainage in the clinical success group was 25 days (range, 3-136 days), and patients with longer drainage periods had more successful outcomes (p = .04). Graft pancreatitis was diagnosed in five patients (17.9%) and was not associated with drainage outcome (p = .21). Collections were positive for bacterial growth in 13 patients (46.4%) and were high in amylase in 12 (42.9%). We observed drainage failure in collections with polymicrobial growth and in the presence of fistulas (p = .05 and p = .07, respectively). Patients with successful outcomes had smaller collection volumes (p = .045). No complications attributed to drainage were encountered. CONCLUSION. Percutaneous drainage is safe and effective for management of peripancreatic fluid collections after pancreas transplant.

BACKGROUND: The purpose of this study is to evaluate the safety and intermediate-term efficacy of percutaneous microwave (MW) ablation for the treatment of colorectal liver metastases (CRLM) at a single institution. METHODS: A retrospective review was performed of all CRLM treated with MW ablation from 3/2011 to 7/2020 (102 tumors; 72 procedures; 57 patients). Mean age was 60 years (range, 36–88) and mean tumor size was 1.8 cm (range, 0.5–5.0 cm). The patient population included 19 patients with extra-hepatic disease. Chemotherapy (pre- and/or post-ablation) was given in 98% of patients. Forty-five sessions were preceded by other focal CRLM treatments including resection, ablation, radiation, and radioembolization. Kaplan-Meier curves were used to estimate local tumor progression-free survival (LTPFS), disease-free survival (DFS), and overall survival (OS) and multivariate analysis (Cox Proportional Hazards model) was used to test predictors of OS. RESULTS: Technical success (complete ablation) was 100% and median follow-up was 42 months (range, 1–112). There was a 4% major complication rate and an overall complication rate of 8%. Local tumor progression (LTP) rate during the entire study period was 4/98 (4%), in which 2 were retreated with MW ablation for a secondary LTP-rate of 2%. LTP-free survival at 1, 3, and 5 years was 93%, 58%, and 39% and median LTP-free survival was 48 months. OS at 1, 3, and 5 years was 96%, 66%, 47% and median OS was 52 months. There were no statistically significant predictors of OS. CONCLUSIONS: MW ablation of hepatic colorectal liver metastases appears safe with excellent local tumor control and prolonged survival compared to historical controls in selected patients. Further comparative studies with other local treatment strategies appear indicated.

Background: Due to the late diagnosis, resulting partly from the absence of national screening programs, Cervical cancer is a public health concern for women in Sub-Saharan Africa, where 34 over 100,000 are diagnosed with cervical cancer and 23 over 100,000 die yearly. We evaluated the knowledge and practices of the female population towards the prevention of cervical cancer in the city of Bafoussam, West Cameroon, considering that poor awareness about the disease and its prevention drives its progression in Africa.Methods: 228 women were recruited during a cross-sectional study with simple random selection of participants in two District Health Centres in Bafoussam from February to August 2017. They were administered a questionnaire aimed at asserting their knowledge about cervical cancer, risk factors and prevention. Subsequently, cervicovaginal smears were screened and gynaecological signs were assessed. Data analysis was done using Epi info version 7.2.2.6. with Chi 2 test application.Statistical significance was set at p < 0.05.Results: The most represented age group was [25-35] (50.88%). Only 89 participants (39.04%) had heard about cervical cancer, 63 (27.63%) had heard about risk factors with only 13 (5.70%) able to name at least one risk factor. Moreover, 72 participants (31.58%) had heard about cervical screening test, 48 (21.05%) were aware about the existence of means of prevention, and only 6 (2.63%) had heard about human papillomavirus (HPV) relationship to cervical cancer or HPV vaccine. An incidence of 07.63% was obtained. The most common reason reported for not attending cervical cancer screening was ignorance (68.92%). Conclusions: Our data suggest that there is a real need for raising the awareness about cervical cancer and its prevention in the western region of Cameroon.

Objectives This study sought to determine the level of understanding and opinion among rheumatologist and pulmonologists regarding risk factors, diagnostic approach and treatment of RA-associated interstitial lung disease (RA-ILD). Methods We conducted an international electronic survey of rheumatologists and pulmonologists utilizing two separate Redcap-based surveys with questions on the epidemiology, workup and management of RA-ILD as well as ILD screening questions using case-based scenarios directed at rheumatologists. The survey also collected demographic data on participants including their practice setting, years in practice and country of practice. Results We received a total of 616 responses (354 rheumatologists and 262 pulmonologists) from six continents. There were significant differences in responses between pulmonologists and rheumatologists in estimated prevalence and mortality, risk factors for the development of ILD in RA and medications that are effective or should be avoided. Rheumatologists were much less likely to consider assessment for ILD in high risk, asymptomatic patients compared with high-risk patients with either symptoms or exam findings suggestive of ILD. Conclusion Our study brought to light the variability in disease assessment and clinical practice among providers caring for patients with RA-ILD and indicate that greater education is needed to optimize clinical decision making in the risk assessment, screening and treatment of RA-ILD. Research questions that address appropriate screening and treatment strategies for RA-ILD will be valuable for rheumatologists given their central role in the overall health and lung health of patients with RA.

Aims Cognitive impairment in patients with alcohol use disorder (AUD) is highly prevalent, and it negatively impacts treatment outcome. However, this condition is neither systematically assessed nor treated. Thus, we aimed to explore the usability of a virtual reality-based protocol (‘Rehabilitation Gaming System’, RGS) for patients with AUD. Methods Twenty AUD patients (50% also cognitive impairment) underwent a single session of the RGS protocol (four cognitive training tasks, 10 minutes each). System Usability Scale (SUS) and Post-Study System Usability Questionnaire (PSSUQ) were applied to assess the RGS usability and patients’ satisfaction with it. Also, the Perceived Competence Scale was administered to assess the patients’ feelings of competence when using the training protocol. Comparisons of the responses to these questionnaires were performed between AUD patients with cognitive impairment and those without cognitive impairment. Results RGS usability was very positively rated (median SUS score = 80, Interquartile Range, IQR = 68.13–86-88). No significant differences were found in the median SUS scores for any of the sociodemographic or clinical variables, excepting for gender (women median score = 85; IQR = 80–94.38 vs. men median score = 71.25; IQR = 61.25–89.25; P-value = 0.035). The quality of the information provided by the RGS training scenarios and the usability were positively rated (PSSUQ), and patients experienced high feelings of competence. Conclusions The RGS has been found to be usable in the short term and patients with AUD stated to be satisfied with it. Future larger, randomized trials are needed to explore the effectiveness of this tool to help overcome the cognitive deficits in AUD patients.

To compare the outcomes of Aurolab aqueous drainage implant (AADI; Aurolab) placement and trabeculectomy with mitomycin C (MMC) in patients with glaucoma secondary to aniridia.Retrospective comparative interventional case series.This study included patients with congenital aniridia who underwent AADI implantation or trabeculectomy with MMC. Surgical failure was defined as IOP21 mm Hg or reduced20% from baseline, IOP ≤ 5 mm Hg, reoperation for glaucoma or a complication, or loss of light perception vision.A total of 30 eyes of 30 patients underwent surgical treatment, including 18 eyes that received an AADI and 12 eyes that had a trabeculectomy with MMC. The cumulative probability of failure at 2 years was 11.1% (95% CI = 2.9%-37.6%) in the AADI group and 58.3% (95% CI = 33.5%-84.8%) in the trabeculectomy group (P = .05, log-rank). At 2 years, IOP (mean ± SD) was 14.1 ± 2.8 mm Hg in the AADI group and 19.6 ± 6.6 mm Hg in the trabeculectomy group (P = .02), and the number of glaucoma medications was 1.7 ± 0.9 in the AADI group and 2.2 ± 0.8 in the trabeculectomy group (P = .25). Surgical complications developed in 1 patient in each treatment group (P = .65). Cataract surgery was performed in 5 (42%) patients in the trabeculectomy group and no patients in the AADI group (P = .01).Placement of an AADI resulted in lower IOP and a higher rate of surgical success compared to trabeculectomy with MMC in eyes with glaucoma associated with aniridia. Cataract extraction was more frequently required after trabeculectomy with MMC than AADI implantation.

A deterministic mathematical model of cholera infection incorporating health education campaign, vaccination of susceptible humans, treatment of infected human and water sanitation is developed. It is shown that the solution of the model uniquely exist, it is positive and bounded in a certain region. The disease-free equilibrium (DFE) state of the model was determined and used to compute the basic reproduction number as a threshold for effective disease management. The result from stability analysis for the disease-free equilibrium state (DFEs) shows that it is locally as well as globally asymptotically stable whenever the basic reproduction number is less than unity (). The results obtained from the sensitivity index of show that the control parameters of public health education campaign, vaccination of susceptible individuals, treatment of infected humans and water sanitation are crucial parameters to cholera management. Numerical simulations show that, expanded and improved vaccination among other interventions is crucial in decreasing cholera burden. Furthermore, from the numerical simulations and results it is recommended that a combination of mass and consistent public health education campaigns, expanded vaccination coverage, prompt treatment of infected individuals, with water sanitation, is vital to public health strategies in eradicating cholera infection and deaths in the shortest possible time

Background Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. Methods We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. Results Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. Conclusions Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

BackgroundEpidemiological studies have shown increased comorbidity between depression and autoimmune diseases. The mechanisms driving the comorbidity are poorly understood, and a highly powered investigation is needed to understand the relative importance of shared genetic influences. We investigated the evidence for pleiotropy from shared genetic risk alleles between these traits in the UK Biobank (UKB).MethodsWe defined autoimmune and depression cases using information from hospital episode statistics, self-reported conditions and medications, and mental health questionnaires. Pairwise comparisons of depression prevalence between autoimmune cases and controls, and vice-versa, were performed. Cross-trait polygenic risk score (PRS) analyses were performed to test for pleiotropy, i.e. testing whether PRS for depression could predict autoimmune disease status, and vice-versa.ResultsWe identified 28k cases of autoimmune diseases (pooling across 14 traits) and 324k autoimmune controls, and 65k cases of depression and 232k depression controls. The prevalence of depression was significantly higher in autoimmune cases compared to controls, and vice-versa. PRS for myasthenia gravis and psoriasis were significantly higher in depression cases compared to controls (p < 5.2×10−5, R2 −5, R2 range 0.06% to 0.27%), and lower in coeliac disease cases compared to controls (p < 5.4×10−7, R2 range 0.11% to 0.15%).ConclusionsConsistent with the literature, depression was more common in individuals with autoimmune diseases compared to controls, and vice-versa, in the UKB. PRS showed some evidence for involvement of shared genetic factors, but the modest R2 values suggest that shared genetic architecture accounts for only a small proportion of the increased risk across traits.

The purpose of this study was to describe the mechanism of injury (MOI) and examine factors associated with greater risk for specific MOIs involving concussions in collegiate soccer players.Participants included 3,288 collegiate soccer players from 28 institutions across four competitive seasons, 2014-17. MOIs were documented for 262 soccer-related concussions during the study and placed into one of four categories: collisions, unintentional contact, aerial challenges, and others.70% of the concussions occurred in DI soccer players. Collisions and unintentional contact were the MOIs that resulted in 66.5% of all concussions. DI and DIII soccer players sustained more concussions by unintentional contact versus collisions and aerial challenges when compared to their DII counterparts. Defenders were more likely than midfielders to sustain concussions by aerial challenges than collisions. As expected, the field players experienced more concussions as a result of collisions, unintentional contact, and aerial challenges when compared to goalkeepers.Future research should explore preventive strategies for decreasing collisions, especially during aerial challenges while heading the soccer ball, and unintentional contacts from errant balls in soccer in order to decrease concussion risk.

Aims This study aims to explore cardiovascular magnetic resonance (CMR)-derived left ventricular (LV) function, strain, and infarct size characteristics in patients with transient ST-segment elevation myocardial infarction (TSTEMI) compared to patients with ST-segment and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI, respectively). Methods and results In total, 407 patients were enrolled in this multicentre observational prospective cohort study. All patients underwent CMR examination 2–8 days after the index event. CMR cine imaging was performed for functional assessment and late gadolinium enhancement to determine infarct size and identify microvascular obstruction (MVO). TSTEMI patients demonstrated the highest LV ejection fraction and the most preserved global LV strain (longitudinal, circumferential, and radial) across the three groups (overall P ≤ 0.001). The CMR-defined infarction was less frequently observed in TSTEMI than in STEMI patients [77 (65%) vs. 124 (98%), P Conclusion TSTEMI yielded favourable cardiac LV function, strain, and infarct-related scar mass compared to STEMI and NSTEMI. LV function and infarct characteristics of TSTEMI tend to be more similar to NSTEMI than STEMI.

Aim Injection of Permacol collagen paste can be used as a sphincter‐sparing treatment for perianal fistulas. In a tertiary referral population we aimed to evaluate the efficacy of Permacol injection and the clinical and fistula‐related factors associated with recurrence. Method This was a retrospective analysis of consecutive patients with perianal fistulas treated with Permacol injection at a specialist centre between June 2015 and April 2019. Endoanal ultrasonography was systematically reanalysed, blinded to treatment outcome. Rectovaginal, anovaginal and Crohn's disease fistulas were excluded. Healed fistulas were defined as absent anal symptoms and a closed external opening on physical examination at a minimum follow‐up of 6 months. Regression analyses were performed to identify factors associated with unhealed fistulas. Results A total of 90 patients (51 men; median age 45 years) were analysed. Seventy‐two (80.0%) patients had complex perianal fistulas (greater than one‐third sphincter involvement or multiple tracts). After a single Permacol injection, fistulas were healed in 20 (22.2%) patients at 3 months follow‐up and in 18 (20.0%) patients at a median follow‐up of 30 months (interquartile range 17–37). Eight (11.1%) patients with unhealed fistulas had significant improvement in their symptoms. Complex fistulas were significantly associated with unhealed status [OR 3.53 (95% CI 1.12–11.09); p = 0.031]. Twenty patients underwent subsequent Permacol injections, which were successful in six (30.0%) patients after one (n = 3) or two (n = 3) additional injections. Conclusion This largest study to date in patients with mainly complex perianal fistulas, demonstrated that the efficacy of a single Permacol injection was only 20%. Complex fistulas were associated with a poor outcome.

Chlamydia trachomatis is the causative agent of a highly prevalent sexually transmitted bacterial disease and is associated with a number of severe disease complications. Current therapy options are successful at treating disease, but patients are left without protective immunity and do not benefit the majority asymptomatic patients who do not seek treatment. As such, there is a clear need for a broad acting, protective vaccine that can prevent transmission and protect against symptomatic disease presentation. There are three key elements that underlie successful vaccine development: 1) Chlamydia biology and immune-evasion adaptations, 2) the correlates of protection that prevent disease in natural and experimental infection, 3) reflection upon the evidence provided by previous vaccine attempts. In this review, we give an overview of the unique intra-cellular biology of C. trachomatis and give insight into the dynamic combination of adaptations that allow Chlamydia to subvert host immunity and survive within the cell. We explore the current understanding of chlamydial immunity in animal models and in humans and characterise the key immune correlates of protection against infection. We discuss in detail the specific immune interactions involved in protection, with relevance placed on the CD4+ T lymphocyte and B lymphocyte responses that are key to pathogen clearance. Finally, we provide a timeline of C. trachomatis vaccine research to date and evaluate the successes and failures in development so far. With insight from these three key elements of research, we suggest potential solutions for chlamydial vaccine development and promising avenues for further exploration.

Primary repair of hypospadias is associated with risk of complications, specifically urethrocutaneous fistula and glanular dehiscence. Caudal block may potentially increase the risk of these complications. Therefore, we studied the incidence of hypospadias complications in children who underwent correction at our institution having received either penile or caudal block.We analyzed all primary hypospadias repair cases from December 2011 through December 2018 at Texas Children's Hospital with a minimum of 1-year followup for the presence of complications: urethrocutaneous fistula and glanular dehiscence. Surgical (surgeon, operative time, block type, local anesthetic, meatal position) and patient (age at correction, prematurity) factors were additionally analyzed.For the primary aim, 983 patients underwent primary hypospadias correction with a minimum of 1 year of postoperative followup data. There were 897 patients (91.3%) in which no complications were identified and 86 (8.7%) with either urethrocutaneous fistula (81) or glanular dehiscence (5). Of the 86 identified complications, 45/812 (5.5%) were distal, 41/171 (24%) were proximal (p0.001) with a complication. Rate of complications was not associated with caudal block (OR 0.67, 95% CI 0.41-1.09; p=0.11). On univariable analysis, age (OR 1.12, 95% CI 1.04-1.20; p=0.04), surgical duration (OR 1.02; 95% CI 1.01-1.02; p0.001), prematurity32 weeks (OR 4.38, 95% CI 1.54-4.11 p0.001) and position of meatus as proximal (OR 5.38 95% CI 3.39-8.53; p0.001) were associated with an increased rate of complications. However, on multivariable analysis, associations of age (OR 1.13, 95% CI 1.05-1.22; p=0.001), surgery duration (OR 1.01, 95% CI 1.01-1.02; p0.001) and meatal position (OR 3.85, 95% CI 2.32-6.39; p0.001) were associated with increased rate of complications.Our data suggest that meatal location, older age, extreme prematurity and surgical duration are associated with increased incidence of complications (urethrocutaneous fistula and glanular dehiscence) following hypospadias correction. Analgesic block was not associated with increased hypospadias complication risk.

Purpose We sought to describe the outcomes of the Aurolab aqueous drainage implant (AADI) placed in the superotemporal (ST) versus the inferonasal (IN) quadrant in pediatric eyes with refractory glaucoma. Design Retrospective comparative interventional case series. Methods This was a retrospective study of patients ≤18 years of age who underwent AADI implantation and completed a minimum of 2-year follow-up. The choice of the quadrant depended upon the amount of scarring and conjunctival mobility. Cumulative success at 2 years was defined as intraocular pressure (IOP) ≤21 mm Hg or reduced by ≥20% below baseline on 2 consecutive follow-up visits after 3 months, IOP ≤5 mm Hg on 2 consecutive follow-up visits after 3 months, reoperation for glaucoma or a complication, or loss of light perception vision. Results A total of 144 patients (144 eyes) underwent AADI placement, including 48 eyes (33%) in the IN and 96 eyes (67%) in the ST quadrants. The IOP was significantly higher in the IN group (17.5 ± 7.4 mm Hg vs 13.7 ± 6.2 mm Hg, P = .005) with a greater number of medications (1.5 ± 1.0 vs 0.8 ± 0.9, P = .001) after 2 years of follow-up. Cumulative success rates at 2 years were 50.7% (95% confidence interval 35.4%-63.9%) in the IN group and 65.6% (95% confidence interval 56.5%-75.7%) in the ST group (P = .15). Complications occurred more frequently in the IN group, with significantly more tube exposure (12% vs 0%, P = .05). Conclusions Placement of the AADI in the ST quadrant has better IOP-related outcomes and is a safer surgical option in pediatric eyes compared with the IN quadrant. It may be prudent to avoid AADI in the IN quadrant in children unless the ST location is not a viable option.

Microcirculatory dysfunction occurs early in cardiovascular disease (CVD) development. Acute myocardial infarction (MI) is a late consequence of CVD. The conjunctival microcirculation is readily-accessible for quantitative assessment and has not previously been studied in MI patients. We compared the conjunctival microcirculation of acute MI patients and age/sex-matched healthy controls to determine if there were differences in microcirculatory parameters. We acquired images using an iPhone 6s and slit-lamp biomicroscope. Parameters measured included diameter, axial velocity, wall shear rate and blood volume flow. Results are for all vessels as they were not sub-classified into arterioles or venules. The conjunctival microcirculation was assessed in 56 controls and 59 inpatients with a presenting diagnosis of MI. Mean vessel diameter for the controls was 21.41 ± 7.57 μm compared to 22.32 ± 7.66 μm for the MI patients (p −1 vs 145 ± 88 s−1, p

This study sought to determine prognostic markers for disease recurrence and survival in a cohort of neoadjuvant-treated, node-negative gastric cancer patients (ypT0-4N0M0). Clinicopathologic data from patients treated with neoadjuvant therapy followed by curative-intent gastrectomy at the University of Texas MD Anderson Cancer Center from 1995 to 2017 were evaluated. Patients with AJCC TNM stage ypT0-4N0M0 were considered for analysis. The inclusion criteria were met by 212 patients with a mean age of 58.3 years. Of these patients, 60 % were male, 53 % were Caucasian, 87 % received chemoradiation, and 13 % received chemotherapy. The findings showed a median overall survival (OS) rate of 11.3 years, a 5-year survival rate of 72 %, and a 10-year survival rate of 57 %. During a median follow-up period of 5.5 years, 38.2 % of the patients died. In the multivariable analysis, ypT4-stage and nodal yield fewer than 16 were significantly associated with reduced OS. Cancer classified as ypT4 had more aggressive biologic traits, including lymphovascular and perineural invasion, and was treated more aggressively with total gastrectomy and additional organ resection despite frequent positive margins. Depth of invasion remained significantly associated with worse outcome after the analysis controlled for nodal yield and possible stage migration. Compared with ypT0-3 tumors, ypT4 cancers were associated with significantly more recurrences (13 % vs. 45 %; p < 0.05), and the primary modes of failure for ypT4 lesions were local recurrence and peritoneal metastases (88 % of recurrences). Depth of primary tumor invasion and nodal yield were significantly associated with OS among the patients with ypT0-4N0M0 gastric cancer. Serosal invasion (ypT4) was associated with a high rate of peritoneal recurrence, and trials of intraperitoneal therapy targeting these patients should be considered.

Background Lutein and zeaxanthin are carotenoids associated with better cognition at older age. To our knowledge, no previous study has evaluated their cognitive implications in the prenatal period, when the brain undergoes its most rapid development. Objective The objective of this study was to examine associations of maternal lutein and zeaxanthin (L/Z) intake during pregnancy with child cognition. Design Among 1580 mother-child pairs in Project Viva, a prospective cohort, we assessed maternal intake of L/Z during pregnancy using food frequency questionnaires and offspring cognition by the Visual Recognition Memory paradigm in infancy, the Peabody Picture Vocabulary Test and the Wide Range Assessment of Visual Motor Abilities (WRAVMA) in early childhood, and the Kaufman Brief Intelligence Test (KBIT-II), the WRAVMA drawing subtest, and the Wide Range Assessment of Memory and Learning in mid-childhood. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and Strengths and Difficulties Questionnaire. Results Mothers consumed a daily mean (SD) of 2.6 (2.0) mg L/Z in the first and second trimesters of pregnancy. Mean mid-childhood KBIT-II verbal scores were higher with greater maternal L/Z intake [difference of Q4–Q1 means for first trimester: 2.67 (95% CI: 0.13, 5.20) and for second trimester: 3.55 (95% CI: 0.81, 6.28)], indicating better verbal intelligence. Secondary analyses on cognitive subtests showed that mean mid-childhood BRIEF Behavioral Regulation Index scores were lower with greater maternal L/Z intake [difference of Q4–Q1 means for first trimester: –1.63 (95% CI: –3.22, –0.04) and for second trimester: –1.89 (95% CI: –3.58, –0.21)], indicating better behavior regulation ability. Conclusions Higher maternal L/Z intake during pregnancy was associated with better offspring verbal intelligence and behavior regulation ability in mid-childhood, suggesting a potential benefit during prenatal development. We did not find a benefit of higher maternal L/Z intake on other child cognitive or behavioral outcomes. Project Viva is registered at clinicaltrials.gov as NCT02820402.

Background: The optimal number of examined lymph nodes (ELNs) and the positive lymph node ratio (LNR) for potentially curable gastric cancer are not established. We sought to determine clinical benchmarks for these values using a large national database. Methods: Demographic, clinicopathologic, and treatment-related data from patients treated using an R0, curative-intent gastrectomy registered in the National Cancer Database during 2004 to 2016 were evaluated. Patients with node-positive (pTxN+M0) disease were considered for analysis. Results: A total of 22,018 patients met the inclusion criteria, with a median follow-up of 2.2 years. Mean age at diagnosis was 65.6 years, 66% were male, 68% were White, 33% of tumors were located near the gastroesophageal junction, and 29% of patients had undergone preoperative therapy. Most primary tumors (62%) were category pT3–4, 67% had a poor or anaplastic grade, and 19% had signet features. Clinical nodal staging was inaccurate compared with staging at final pathology. The mean [SD] number of nodes examined was 19 [11]. On multivariable analysis, the pN category, ELNs, and LNR were independently associated with survival (all PConclusions: Using a large national cancer registry, we determined that an ELN threshold of ≥30 allowed for prognostically advantageous LNRs to be achieved in 96% of patients. Therefore, ≥30 examined nodes should be considered a clinical benchmark for practice in the United States.

Background Dosing limits in opioid clinical practice guidelines in the United States are likely misapplied to cancer patients, however, opioid use may be difficult to ascertain as they are largely excluded from opioid use studies. Methods The primary objective was to determine whether cancer patients were more likely to be chronic opioid users after diagnosis. We described prescription opioid use among U.S. older adult cancer patients during two time periods, within 2 years of diagnosis (short‐term) and at least 2 years beyond diagnosis (long‐term), compared to those without cancer (controls). Among participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial with linkages to Medicare Part D data during 2011–2015, we used multivariable logistic regression to estimate the association between cancer diagnosis and opioid use outcomes controlling for demographics. The primary outcome of opioid use was measured with the following metrics: Any opioid use, chronic use (90 consecutive days supply of opioid use while allowing for a 7‐day gap between refills), high use (average daily morphine equivalent (MME) ≥120 mg for any 90‐day period), and total MME dose above 2,000 mg (MME2000). Results The short‐term cohort included 1,491 cancer patients and 24,930 controls. Any use in the 2‐year post‐diagnosis period was higher among cancer patients OR 3.3 (95% CI: 3.0–3.7). Chronic use rates were similar by cancer status (4.6% vs. 3.8% for cases and controls, respectively). The long‐term cohort included 4,377 cancer patients and 27,545 controls. Rates of any use were similar among cancer patients and controls (63% vs. 59%). Conclusions Any opioid use was similar among long‐term cancer survivors compared to controls, but differed among short‐term survivors for any opioid use and marginally for chronic opioid use., Use of any opioid was similar among long‐term cancer survivors compared to controls, but differed among short‐term survivors for any opioid use and marginally for chronic opioid use. Continued monitoring of opioid use among subgroups of cancer patients is important. This should include concomitant use of opioids and non‐opioid medications commonly used to manage pain among cancer patients.

Objectives: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. Methods: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. Results: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. Conclusions: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Objective This study identifies trajectories of parent depressive symptoms after having a child born with genital atypia due to a disorder/difference of sex development (DSD) or congenital adrenal hyperplasia (CAH) and across the first year postgenitoplasty (for parents who opted for surgery) or postbaseline (for parents who elected against surgery for their child). Hypotheses for four trajectory classes were guided by parent distress patterns previously identified among other medical conditions. Methods Participants included 70 mothers and 50 fathers of 71 children diagnosed with a DSD or CAH with reported moderate to high genital atypia. Parents were recruited from 11 US DSD specialty clinics within 2 years of the child’s birth and prior to genitoplasty. A growth mixture model (GMM) was conducted to identify classes of parent depressive symptoms over time. Results The best fitting model was a five-class linear GMM with freely estimated intercept variance. The classes identified were termed “Resilient,” “Recovery,” “Chronic,” “Escalating,” and “Elevated Partial Recovery.” Four classes have previously been identified for other pediatric illnesses; however, a fifth class was also identified. The majority of parents were classified in the “Resilient” class (67.6%). Conclusions This study provides new knowledge about the trajectories of depressive symptoms for parents of children with DSD. Future studies are needed to identify developmental, medical, or familial predictors of these trajectories.

INTRODUCTION: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high gamma activity as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment. METHODS: Ictal high gamma activity (80–150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high gamma signature were identified, and seizure hubs defined as stereotypically recruited non-overlapping clusters. Clusters were correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared. RESULTS: Ictal high gamma activity was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (Odds ratio=19.7, p=0.029). Interictal ripples demonstrated greater spatial overlap with ictal high gamma activity in cases with single seizure hubs compared to those with multiple hubs (100% vs 66% per patient, p=0.03). CONCLUSIONS: Ictal high gamma activity may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

Background Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management. Methods We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS‐MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted. Objectives To describe the clinical presentation and outcomes of different therapeutic approaches. Results Seventy‐five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity

To synthesize the evidence from randomized controlled trials of prostatic urethral lift (PUL) and convective water vapor thermal energy therapy (WAVE) for minimally invasive treatment of men with benign prostatic hyperplasia. A systematic search of databases was performed to identify trials comparing WAVE or PUL to either an active or sham surgery control in subjects with symptomatic benign prostatic obstruction. A controlled indirect treatment comparison based on the approach of Bucher was performed for outcomes including International Prostate Symptom Score and maximum urinary flow rate (Qmax). The durability of treatment response was assessed by life-table analysis of freedom from retreatment through 4 years. Two multicenter sham-controlled trials (Rezum II Study, NCT01912339: LIFT Study, NCT01294150) were identified. The trials employed a common sham procedure and were similar with respect to their designs and subjects’ baseline characteristics. Comparisons on the treatment effect in excess of sham response found non-significant differences between WAVE and PUL for symptom score [mean difference (MD): − 1.7 points; 95% confidence interval (CI): − 4.8, 1.4] but Qmax improvements favored WAVE [MD: 3.4 ml/sec; CI: 1.2, 5.6]. The proportion free of retreatment through 4 years was 89.1% for WAVE versus 75.4% for PUL [log-rank P = 0.004]. PUL and WAVE provide similar subjective improvements but flow-rate improvement and durability of response seem greater for WAVE. The confirmation of these findings in a randomized trial is warranted.

Symptom resolution is a key marker in determining fitness for return to activity following concussion, but in some cases, distinguishing persistent symptoms due to concussion versus symptoms related to other factors can be challenging. To determine base rates of postconcussional syndrome (PCS) diagnostic categorization in healthy cadets and student athletes with no recent concussion. 13,009 cadets and 21,006 student athletes completed baseline preseason testing. After inclusion/exclusion criteria were applied, the final sample included 12,039 cadets [9123 men (75.8%); 2916 women (24.2%)] and 18,548 student athletes [10,192 men (54.9%); 8356 women (45.1%)]. Participants completed the Sport Concussion Assessment Tool–3rd Edition (SCAT3) symptom evaluation as part of baseline preseason testing. The PCS diagnostic categorization was classified by the International Classification of Diseases, 10th Revision (ICD-10) symptom criteria for PCS. In the absence of recent concussion, subgroups of cadets (17.8% of men; 27.6% of women) and student athletes (11.4% of men; 20.0% of women) reported a cluster of symptoms that would meet the ICD-10 symptom criteria for PCS. Participants with insufficient sleep and/or preexisting conditions (e.g., mental health problems), freshmen cadets, and cadets at the U.S. Coast Guard Academy and at the U.S. Air Force Academy (freshmen were tested during basic cadet training) were more likely to report a cluster of symptoms that would meet the ICD-10 symptom criteria for PCS. The ICD-10 symptom criteria for PCS can be mimicked by preexisting conditions, insufficient sleep, and/or stress. Findings support person-specific assessment and management of symptoms following concussion.

BACKGROUND AND OBJECTIVES We sought to evaluate the impact of lymphovascular invasion (LVI) and perineural invasion (PNI) on survival outcomes in gastric cancer patients treated with preoperative therapy. METHODS Patients with gastric cancer treated with preoperative therapy and potentially curative resection were stratified according to the presence of LVI, PNI, or both. Kaplan-Meier and Cox regression analyses were used to evaluate the impact on overall survival (OS) and disease-free survival (DFS). RESULTS The study included 281 patients, of whom 93 (33%) had LVI, 69 (25%) had PNI, 51 (18%) had both LVI and PNI, and 170 (61%) had neither. LVI and PNI were each associated with higher ypT and ypN categories and more positive lymph nodes (all p

High grade neuroendocrine neoplasms (G3 NENs) are rare aggressive tumors with limited treatment options. Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. Baseline tumor samples were assessed for PD-L1 and tumor infiltrating lymphocytes (TIL). Peripheral blood samples drawn pre-treatment, prior to cycle three, and at disease progression were analyzed by flow cytometry. One patient achieved partial response, two had stable disease, and 18 exhibited progressive disease. The partially responding patient did not progress after 392 days, and the median progression-free survival (PFS) was 59 days. Longer PFS correlated independently with higher pre-treatment peripheral blood T-cell counts and lower pre-treatment activation state (CD69 expression) of naive T cells and NK cells. Peripheral T-cell viability was reduced in patients with greater TILs. Post-treatment, T cells had reduced numbers of CD4+ cells, reduced PD-1 expression, increased activation of effector (CD62L−) cells, and increased expression of TIGIT. Baseline TIGIT expression on peripheral T cells also correlated positively with Ki67 in tumor. Patients with higher baseline T-cell expression of TIM-3 had shorter PFS. Despite limited activity of pembrolizumab, this study highlights the immune phenotype in this rare tumor type before and after treatment. High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.

Aim: Conventional parameters (anal resting and squeeze pressures) measured with anorectal manometry (ARM) fail to identify anal sphincter dysfunction in many patients with low anterior resection syndrome (LARS). We aimed to assess whether there are differences in anal canal slow-wave pressure activity in LARS patients and healthy individuals. Method: High-resolution ARM (HR-ARM) traces of 21 consecutive male LARS patients referred to the Royal London Hospital, UK (n = 12) and Aarhus University Hospital, Denmark (n = 9) were compared with HR-ARM data from 37 healthy men. Results: Qualitatively (by visual inspection of HR-ARM recordings), the frequency of slow-wave pressure activity was strikingly different in 11/21 (52.4%) LARS patients from that observed in all the healthy individuals. Quantitative analysis showed that peaks of the mean spectrum in these 11 LARS patients occurred at approximately 6–7 cycles per minute (cpm), without activity at higher frequencies. An equivalent pattern was found in only 2/37 (5.4%) healthy individuals (P

In the last 5 years, there has been a surge in evidence that hearing loss (HL) may be a risk factor for cognitive dysfunction, including dementia. At the same time, there has been an increase in the number of studies implicating vestibular loss in cognitive dysfunction. Due to the fact that vestibular disorders often present with HL and other auditory disorders such as tinnitus, it has been suggested that, in many cases, what appears to be vestibular-related cognitive dysfunction may be due to HL (e.g., Dobbels et al. Front Neurol 11:710, 2020). This review analyses the studies of vestibular-related cognitive dysfunction which have controlled HL. It is suggested that despite the fact that many studies in the area have not controlled HL, many other studies have (~ 19/44 studies or 43%). Therefore, although there is certainly a need for further studies controlling HL, there is evidence to suggest that vestibular loss is associated with cognitive dysfunction, especially related to spatial memory. This is consistent with the overwhelming evidence from animal studies that the vestibular system transmits specific types of information about self-motion to structures such as the hippocampus.

Purpose To report the incidence and outcomes of hypertensive phase (HP) following Aurolab Aqueous Drainage Implant (AADI) (Aurolab) surgery in adults with refractory glaucoma. Design Retrospective, noncomparative, interventional case series. Methods All eyes that received the AADI and had a minimum of 2-year follow-up were identified, and data of patients who had intraocular pressure (IOP) ≤21 mm Hg at 6 weeks (ie, the time at which the tube-ligature suture dissolves) were used for statistical analysis. HP was defined as IOP >21 mm Hg during the first 3 months after the release of the tube ligating suture (with or without medications) in the absence of tube obstruction. Results A total of 200 eyes were included in the study, and HP was seen in 64 eyes (32%) with a peak IOP (mean ± SD) of 29.6 ± 7.8 mm Hg and peak incidence at 2-3 months after surgery. HP resolved within 3 months of its onset in 60 of the 64 eyes (94%) with additional IOP-lowering medications. The cumulative success rates were 71.8% (95% CI = 59.3%-81.2%) in HP eyes and 76.4% (95% CI = 68.7%-82.7%) in non-HP eyes (P = .23). Unadjusted Cox proportional hazards analysis showed that eyes experiencing HP had a marginally higher risk of failure (HR = 1.16, 95% CI = 0.6-2.1), but this relationship was not statistically significant (P = .61). Conclusions A third of eyes that underwent AADI placement experienced HP. HP was successfully managed with additional IOP-lowering medications in a majority of cases and did not have a significant influence on long-term success rate.

Understanding the health effects of protein intake is bedeviled by a number of factors, including protein quality and source. In addition, different units, including grams, grams per kilogram body weight (g/kg BW), and percent energy, may contribute to confusion about protein's effects on health, especially BW-based units in increasingly obese populations. We aimed to review the literature and to conduct a modeling demonstration of various units of protein intake in relation to markers of cardiometabolic health. Data from the Framingham Heart Study Offspring (n = 1847; 60.3 y; 62.5% women) and Third Generation (n = 2548; 46.2 y; 55.3% women) cohorts and the NHANES 2003–04 (n = 1625; 46.2 y; 49.7% women) and 2005–06 (n = 1347; 43.7 y; 49.5% women) cycles were used to model cross-sectional associations between 7 protein units (grams, percent energy, g/kg ideal BW, g/kg actual BW, BW-adjusted g/kg actual BW, g/kg lean BW, and g/kg fat-free BW) and 9 cardiometabolic outcomes (fasting glucose, systolic and diastolic blood pressure, total and HDL cholesterol, triglycerides, BMI, waist circumference, and estimated glomerular filtration rate). The literature review indicated the use of myriad units of protein intake, with differential results on cardiometabolic outcomes. The modeling demonstration showed units expressed in BW were confounded by BW, irrespective of outcome. Units expressed in grams, percent energy, and ideal BW showed similar results, with or without adjustment for body size. After adjusting for BW, results of units expressed in BW aligned with results of grams, percent energy, and ideal BW. In conclusion, protein intake in cardiometabolic health appears to depend on protein's unit of expression. Authors should be specific about the use of WHO (g/kg ideal BW) compared with US (g/kg actual BW) units, and ideally use gram or percent energy in observational studies. In populations where overweight/obesity are prevalent, intake based on actual BW should be reevaluated., Protein units vary across the literature, likely obscuring true relationships between protein intake and cardiometabolic outcomes. A narrative review and modeling demonstration illustrate these problems, followed by recommendations for best practices.