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Elevated depressive symptoms are observed in a significant number of youth with inflammatory bowel disease (IBD) and have been linked to illness stigma and social isolation. Body image dissatisfaction is an understudied variable in the pediatric IBD literature that may be related to both stigma and social difficulties. It is suspected that, due to the stigmatizing nature of IBD, some youth may feel self-conscious about their body image, which contributes to decreased feelings of social belongingness and ultimately depressive symptoms. The current study tested an illness stigma→ body image dissatisfaction→ thwarted belongingness→ depressive symptoms serial mediation model, in which IBD stigma was hypothesized to indirectly influence youth depressive symptoms through the sequential effects of stigma on body image dissatisfaction and thwarted social belongingness.Youth with IBD (N = 75) between 10 and 18 years old were recruited from a pediatric gastroenterology clinic and completed psychosocial measures. Disease severity was assessed by a physician global assessment. Current medications and BMI data were collected.Analyses revealed significant direct effects among the modeled variables and a significant serial indirect path for illness stigma→ body image dissatisfaction→ thwarted belongingness→ depressive symptoms, controlling for sex, BMI and prednisone medication.Youth who perceive greater IBD stigma are more likely to experience increased body image dissatisfaction due to their IBD, which may engender feelings of social estrangement and ultimately elevated depressive symptoms. Depressive symptoms and the psychosocial challenges faced by youth should be routinely monitored as part of comprehensive IBD management.

OBJECTIVE: To describe the outcome of open thoracoabdominal aortic aneurysm (TAAA) repair following previous aortic arch repair including elephant trunk (ET) or frozen elephant trunk (FET) for acute and chronic pathologies.METHODS: This was a retrospective, observational, multicenter study including 32 patients treated between 2006 and 2019 in two aortic centers using identical surgical protocols. Assessment focused on perioperative and long-term outcome, namely in-hospital morbidity and mortality, as well as procedure-related reintervention rate and aortic-related mortality rate. Kaplan-Meier curves with 95% confidence intervals were used to analyze the overall survival after surgery within the cohort.RESULTS: Thirty-two patients (mean age, 45.0 ± 13.6 years; 20 males [62.5%]) were treated because of acute (34.38% [n = 11]) or chronic (65.62% [n = 21]) aortic pathologies, including residual dissection following acute, symptomatic type A dissection (n = 7) and symptomatic mega aortic syndrome (n = 4), as well as post-dissection TAAA (n = 18) and asymptomatic mega aortic syndrome (n = 3). Twenty-eight patients (87.5%) received type II repair, and 4 patients (12.5%) received type III repair after previous ascending aorta and arch repair including ET/FET. Concomitant infrarenal and iliac vessel repair was performed in 38.7% (n = 12) and 29.4% (n = 10), respectively. The in-hospital mortality rate was 18.75% (n = 6). Spinal cord ischemia occurred in two cases, both after one-stage emergency procedure with one case of permanent paraplegia. Temporary acute kidney injury occurred in 41.94% (n = 13). The estimated 1-year survival rate was 78.1% (95% confidence interval, 63.9%-95.6%), with a median follow-up time of 1.29 years (interquartile range, 0.26-3.88 years). No procedure-related reinterventions and one case of aortic-related mortality, namely sepsis because of graft infection, was observed.CONCLUSIONS: Open TAAA repair following aortic arch repair including ET or FET because of acute or chronic aortic pathologies is associated with a relevant perioperative morbidity and mortality rate. During follow-up, a low aortic-related mortality rate and procedure-related reintervention rate were observed.

OBJECTIVE: Treatment of extensive chronic venous obstruction (CVO) with post-thrombotic trabeculation involving the common femoral vein with extension into the femoral vein or deep femoral vein remains a challenge and the best treatment technique for such cases is not clear. In the present study, we compared the results of endovascular alone vs endovascular with additional endophlebectomy (hybrid) procedures for such patients.METHODS: The medical records of 102 consecutive patients (108 limbs) treated between 2015 and 2020 for iliofemoral CVO extending to the femoral confluence were retrospectively reviewed. The patients were divided into two groups: the hybrid procedure (HP) and endovascular treatment (EN) groups. The HP group consisted of those treated with stent implantation and endophlebectomy of the common femoral vein with creation of an arteriovenous fistula. The EN group included those who had undergone stent implantation alone. The patency rates, complications, and clinical outcomes were analyzed.RESULTS: Of the 102 patients, 47 (49 limbs) were in the EN group and 55 (59 limbs) were in the HP group. The demographics of the two groups were similar with no statistically significant differences in cumulative primary, assisted primary, or secondary patency rates at 36 months (33.7% vs 36.3%, P = .839; 59.8% vs 64%, P = .941; 69% vs 72.7%, P = .851; respectively). The patients in the EN group, however, had better clinical improvement with a lower postoperative complication rate (P = .012), shorter procedure duration (P < .001), and shorter hospital stay (P = .025).CONCLUSIONS: The EN and HP both provided similar patency rates for patients with CVO extending into the femoral confluence. The endovascular strategy has the benefit of fewer postoperative complications and a shorter procedure duration and hospital stay compared with the HP.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

PURPOSE Mild to moderate vision loss affects many children and can negatively impact a child's early literacy and academic achievement. Nevertheless, there is no consensus on which factors present in early childhood indicate the need for long-term ophthalmic follow up, particularly in children with a history of perinatal adversity. This study identified the relationship between visual, cognitive, motor and demographic factors at 2 years of age and visual acuity (VA) and stereoacuity at 4.5 years of age. METHODS Five hundred sixteen children identified as being at risk of neonatal hypoglycaemia were recruited soon after birth. At 2 years of age, binocular VA, stereoacuity and non-cycloplegic refraction were measured and a clinical neuro-developmental assessment with the Bayley Scales of Infant Development III (BSID-III) was conducted by a trained examiner. Monocular VA and stereoacuity were measured at 4.5 years of age. RESULTS Three hundred twenty-eight children completed both the 2 and 4.5 year vision and neurodevelopmental assessments. Multiple linear regression showed oblique astigmatism and motor function at 2 years were significantly associated with VA at 4.5 years of age, while spherical equivalent refraction, motor scores and stereoacuity at 2 years were significantly associated with stereoacuity at 4.5 years of age. BSID-III motor scores had the best sensitivity (81.8%) and specificity (51.5%) for identifying impaired stereoacuity at 4.5 years. However, all measures at 2 years were poorly associated with VA at 4.5 years old. CONCLUSION Vision and neurodevelopmental measures at 2 years were poorly associated with visual function at 4.5 years of age. However, lower scores on tests of motor function at 2 years may be associated with vision abnormalities, particularly reduced stereopsis, at 4.5 years of age and referral for comprehensive vision assessment for these children may be warranted.

Summary: Background: Ruptured juxtarenal aortic aneurysms (RJAAA) represent a special challenge in clinical practice, but the evidence to guide therapeutic decision-making is scarce. The aim of this study was to present two different approaches, open surgical (OAR) and chimney endovascular repair (CHEVAR), for treating patients with RJAAA. Patients and methods: This retrospective two-center study included all patients per center undergoing OAR or CHEVAR for RJAAA between February 2008 and January 2020. Juxtarenal aortic aneurysms were defined as having an infrarenal neck of 2–5 mm, measured after three-dimensional reconstruction of the computed tomography angiography scan. Results: 12 OAR patients (10 male, median age 73 years [58–90 years]) and 6 CHEVAR patients (all male, median age 74 years [59–83 years]) were included. In the OAR group, the proximal aortic clamping was suprarenal in 7 and interrenal in 5 patients. Cold renal perfusion was used in 4 patients, in 2 with suprarenal aortic clamping and in 2 with interrenal aortic clamping. 3 CHEVAR patients received a single renal chimney, the other 3 received double renal chimneys. Technical success was 12/12 in the OAR group 5/6 in the CHEVAR group. In-hospital mortality and 30-day mortality were 3/12 after OAR and 0/6 after CHEVAR. 2 OAR patients required transient dialysis. Median in-hospital stay was 14 (10–63) and 8 (6–21) days and median follow-up (FU) was 20 (3–37) and 30 (7–101) months, respectively. No further deaths occurred during FU. One OAR patient and 4 CHEVAR patients required aortic reinterventions. Conclusions: RJAAAs are rare. Both OAR and CHEVAR can represent adequate treatments for RJAAAs. OAR is the traditional approach, but CHEVAR has - in a high-volume center - promising early results with nonetheless a need for continuous FU to prevent reinterventions. Defining the studied aortic pathology precisely is essential for future research in order to draw valid conclusions.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

Background: Cannabis use is increasing, including among smokers, an at-risk population for cancer. Research is equivocal on whether using cannabis inhibits quitting cigarettes. The current longitudinal study investigated associations between smoking cannabis and subsequently quitting cigarettes. Methods: Participants were 4,535 adult cigarette smokers from a cohort enrolled in the American Cancer Society's Cancer Prevention Study-3 in 2009–2013. Cigarette quitting was assessed on a follow-up survey in 2015–2017, an average of 3.1 years later. Rates of quitting cigarettes at follow-up were examined by retrospectively assessed baseline cannabis smoking status (never, former, recent), and by frequency of cannabis smoking among recent cannabis smokers (low: ≤3 days/month; medium: 4–19 days/month; high: ≥20 days/month). Logistic regression models adjusted for sociodemographic factors, smoking- and health-related behaviors, and time between baseline and follow-up. Results: Adjusted cigarette quitting rates at follow-up did not differ significantly by baseline cannabis smoking status [never 36.2%, 95% confidence interval (CI), 34.5–37.8; former 34.1%, CI, 31.4–37.0; recent 33.6%, CI, 30.1–37.3], nor by frequency of cannabis smoking (low 31.4%, CI, 25.6–37.3; moderate 36.7%, CI, 30.7–42.3; high 34.4%, CI, 28.3–40.2) among recent baseline cannabis smokers. In cross-sectional analyses conducted at follow-up, the proportion of cigarette smokers intending to quit smoking cigarettes in the next 30 days did not differ by cannabis smoking status (P = 0.83). Conclusions: Results do not support the hypothesis that cannabis smoking inhibits quitting cigarette smoking among adults. Impact: Future longitudinal research should include follow-ups of >1 year, and assess effects of intensity/frequency of cannabis use and motivation to quit on smoking cessation.

Aims Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms. Methods and results We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P Conclusion In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.

Background: To share the results of a web-based expert panel discussion focusing on the management of acute and chronic aortic disease during the coronavirus (COVID-19) pandemic. Methods: A web-based expert panel discussion on April 18, 2020, where eight experts were invited to share their experience with COVID-19 disease touching several aspects of aortic medicine. After each talk, specific questions were asked by the online audience, and results were immediately evaluated and shared with faculty and participants. Results: As of April 18, 73.3% answered that more than 200 patients have been treated at their respective settings. Sixty-four percent were reported that their hospital was well prepared for the pandemic. In 57.7%, the percentage of infected healthcare professionals was below 5% whereas 19.2% reported the percentage to be between 10% and 20%. Sixty-seven percent reported the application of extracorporeal membrane oxygenationin less than 2% of COVID-19 patients whereas 11.8% reported application in 5%–10% of COVID-19 patients. Thirty percent of participants reported the occurrence of pulmonary embolism in COVID-19 patients. Three percent reported to have seen aortic ruptures in primarily elective patients having been postponed because of the anticipated need to provide sufficient ICU capacity because of the pandemic. Nearly70% reported a decrease in acute aortic syndrome referrals since the start of the pandemic. Conclusion: The current COVID-19 pandemic has—besides the stoppage of elective referrals—also led to a decrease of referrals of acute aortic syndromes in many settings. The reluctance of patients seeking medical help seems to be a major driver. The number of patients, who have been postponed due to the provisioning of ICU resources but having experienced aortic rupture in the waiting period, is still low. Further, studies are needed to learn more about the influence that the COVID-19 pandemic has on the treatment of patients with acute and chronic aortic disease.

Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of

Background Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. Methods CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. Results Kinome analysis can distinguish between non-specific, toxic effects caused by 10 mu M of Lovastatin and specific effects on cell signalling caused by 2 mu M Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. Conclusions Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC.

Context In March 2020, the World Health Organization declared the novel coronavirus disease 2019 (COVID-19) outbreak a pandemic. Due to the rapid spread, strong contagion, high incidence of lethality in severe cases, and the lack of a pharmaceutical prevention or cure, COVID-19 has posed a serious threat to human life and health. It has also had a tremendous impact on mental health, including fear and worry, difficulty sleeping or concentrating, and increased use of poor coping mechanisms. Osteopathic medical students have had additional concerns regarding the interruption of their studies, closing of clinical rotations, and postponed licensing exams. To date, few reports have focused on osteopathic medical students and their reactions to the outbreak. Objectives To assess resilience, coping, health behaviors, and emotional wellbeing of osteopathic medical students during the onset of the COVID-19 pandemic. Methods In this cross-sectional study, we distributed an anonymous online survey to all medical students enrolled at Nova Southeastern University in May 2020 (n=1,310) via an e-mail invitation using the institution’s student listservs. Our major study variables were based on published reports and anecdotal evidence; we subsequently developed the Emotional Wellbeing in Healthcare Professions Students Questionnaire (EWB-Q). This EWB-Q contained validated scales to assess the contribution of levels of coping strategies used, personal resilience, and health behaviors on the emotional wellbeing of osteopathic medical students. Multiple linear regression and other statistical analyses were conducted using SPSS v0.26. Results Of the 1,310 students invited to participate, 335 (25.5%) surveys were returned. Of those, 133 had more than 33% of the necessary data missing and were removed, resulting in 202 (15.4%) completed questionnaires. The mean age of the participants was 26.7 years. About half (n=92; 45.5%) were in the clinical phase (years 3 and 4) of their medical school training (in rotations). A significant regression equation was found (F[4,171]=17.481, pR 2 =0.290, R 2adjusted=0.274), indicating that levels of coping, personal resilience, and health behaviors (i.e., not sleeping more than usual, not exercising less than usual) accounted for a significant amount of the variance in emotional wellbeing scores in osteopathic medical students. Higher levels of resilience, greater use of coping strategies, not sleeping more than usual, and not exercising less than usual were predictors of emotional wellbeing. Conclusions Cultivating positive mental health should be a high priority for medical educators as they develop and implement curriculum-based initiatives to help medical students bolster their personal resilience and to encourage healthy coping behaviors during times of crisis and beyond. A proactive position that assists with building personal resilience and developing stress management habits is paramount in assisting students who are grappling not only with the challenges of rigorous medical training, but also with the uncertainty and stress that exists during any major global health or socioeconomic crisis.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)

Little is known about the underlying molecular mechanisms of prostate cancer, especially advanced and fatal prostate cancer.To examine associations of prediagnostic plasma metabolomic profiles with advanced and fatal prostate cancer.In a case-cohort study of the Cancer Prevention Study-II Nutrition Cohort, of 14 210 cancer-free men with a blood sample in 1998-2001, 129 were diagnosed with advanced prostate cancer (T3-T4 or N1 or M1) through June 2013 and 112 died from prostate cancer through December 2014. Plasma samples from advanced and fatal cases, and a randomly selected subcohort of 347 men were metabolically profiled using untargeted mass spectroscopy-based platforms.Prentice-weighted Cox proportional hazards regression models were used to assess associations of 699 known metabolites with advanced and fatal prostate cancer.Two metabolites derived from fatty acid metabolism (ethylmalonate and butyrylcarnitine), aspartate, sphingomyelin (d18:1/18:0), and two γ-glutamyl amino acids (γ-glutamylmethionine and γ-glutamylglutamine) were statistically significantly associated (false discovery rate0.2) with fatal prostate cancer. One standard deviation (SD) increase in each γ-glutamyl amino acid was associated with 34-38% decreased risk, whereas one SD increase in each of the other metabolites was associated with 45-53% increased risk. A metabolic risk score based on four of these metabolites (excluding butyrylcarnitine and γ-glutamylglutamine, which were not independent predictors) was strongly associated with fatal prostate cancer (relative risk per SD: 2.72, 95% confidence interval: 2.05-3.60). No metabolites were statistically significantly associated with advanced prostate cancer. These results were observational and may not be causal.These findings identified metabolic pathways that are altered in the development of fatal prostate cancer. Further research into these pathways may provide insights into the etiology of fatal prostate cancer.In a large follow-up study of cancer-free men, those with a certain metabolomic profile had a higher risk of dying from prostate cancer.

PurposeTo investigate the dosimetric impact of breathing motion on robustly optimized proton therapy treatment plans for left-sided breast cancer patients with an indication for locoregional irradiation.Materials and methodsClinical Target Volumes (CTVs) (left-sided breast, level 1 to 4 axillary lymph nodes, interpectoral and internal mammary lymph node regions) and organs at risk were delineated on 4 D-CTs of ten female patients. After treatment planning to a prescribed dose of 40.05 Gy(RBE) in 15 fractions on the time-averaged CT, the dose was calculated on all ten phases of the breathing cycle. Robustness to setup (5 mm) and range errors (3%) was evaluated for those ten phases. Correlations were evaluated between the phases of the breathing cycle and the D98% of the CTV and the D-mean of the heart.ResultsCorrelations coefficients were between -0.12 and 0.29. At the most extreme values of the 28 robustness scenarios, the clinical goals were met for all but two patients. The mean heart dose was 0.41 Gy(RBE) with a standard deviation of 0.31 Gy(RBE) of proton therapy plans.ConclusionThe effect of breathing motion on the robustness of proton therapy treatment plans for this patient group is minor and not of clinical significance. Based on this patient group, a deep-inspiration breath hold seems to be unnecessary to improve robustness for these patients.

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case–Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98–1.02; arachidonic acid OR = 1.00, 95% CI = 0.99–1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87–1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Significance Time cells are neurons in the hippocampus and entorhinal cortex that fire at specific moments within a cognitive task or experience. While many prominent theories of memory encoding offer time cells as the source of the temporal component to memory, they have never been observed in human recordings. We identify time cell populations in the medial temporal lobe of humans during memory encoding and retrieval. Further, we demonstrate that the stability of the time signal provided by time cells during encoding influences the ability to temporally order memories at time of retrieval., The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of “time cells” in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of retrieved memory items. We also uncover evidence of ramping cell activity in humans, which represents a complementary type of temporal information. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Background Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. Objective The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain. Methods To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. Results Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. Conclusion By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

Background: Despite all efforts, spinal cord ischemia (SCI) is a relevant and feared complication after open and endovascular thoracoabdominal aortic aneurysm (TAAA) repair. Besides the established correlation of motor evoked potentials (MEPs) and SCI, the usage of biomarkers for early detection of SCI intraoperatively and postoperatively after TAAA surgery is scarcely described in literature.Methods: The methods include retrospective assessment of 33 patients (48.48% male) undergoing open and endovascular TAAA repair between January 2017 and January 2018. Levels of the biomarkers neurone-specific enolase (NSE), glial fibrillary acidic protein (GFAP), and S100 B were correlated with a decrease of the amplitude of the MEPs of more than 50%, indicating SCI. Linear mixed models were applied to test for differences in the biomarker levels between open and endovascular surgery and between different times of measurement. Post hoc analyses were performed using Tukey's multiple comparisons test. Logistic regression models were used to investigate the association between GFAP, NSE, and S100 B levels at different times and a significant decrease in MEP or in-hospital mortality.Results: Altogether, 19 patients were treated by endovascular repair; 14 patients were treated by open repair; 5 patients were treated because of a type I TAAA; 7 received treatment because of a type II TAAA; 7, 10, and 4 patients received type III, IV, or V TAAA repair, respectively. In-hospital mortality was 18.18% (n = 6); 5 of these patients were treated because of symptomatic TAAA. MEP decrease could be observed in 18 cases (54.5%), with 16 (48.4%) recovering during the intervention. SCI could be observed in 9.09% (n = 3), 2 endovascular repairs leading to paraplegia and one open repair leading to paraparesis. All biomarkers showed increasing levels over time, with no statistically significant difference between open and endovascular repair. The difference in NSE and S100 B levels between the different times of measurements was statistically significant (P < 0.0001, P = 0.0017, respectively). In a univariable logistic regression analysis, no correlation with the end points "significant decrease in MEP'' or "in-hospital mortality'' was observed for any of the assessed biomarkers.Conclusions: SCI-related biomarkers, namely NSE and S100 B, show a relevant increase directly after open and endovascular TAAA surgery, while no clear association between these biomarker levels and an intraoperatively measurable indicator for SCI could be observed.

Background The New Zealand Ministry of Health provides funding for the delivery of health care across regions via 20 District Health Boards. Funding includes the subsidisation of therapeutic pharmaceutical agents/drugs. The distribution of optometrists and ophthalmologists across the regions was investigated to understand the accessibility of eye care in New Zealand. Changes made to the optometrists' scope of practice in 2005 and in 2014 increased the range of drugs that suitably qualified optometrists could prescribe. Therefore, the distribution of optometrists authorised to prescribe drugs and those not authorised to prescribe drugs was also investigated. Methods Information from the New Zealand Optometrists and Dispensing Opticians Board register and information from the Medical Council's website were used to create a database of ophthalmic practitioners and their locations. The χ2 goodness-of-fit test was carried out to determine whether the distribution of the number of practitioners across the regions was in proportion to the population of the regions. Results Ophthalmologists were distributed across the regions in proportion to the regional population size. However, optometrists were concentrated in Auckland and other regions with high populations. Optometrists authorised to prescribe drugs comprised over 74 per cent of optometrists and were the majority of optometrists in most regions. Many of the regions with populations less than 200,000 had high population-to-practitioner ratios, indicating that they may not have sufficient numbers of ophthalmic practitioners in order to provide for the ocular needs of the community. Conclusion Better distribution of the optometric workforce could make eye care more accessible in many regions of New Zealand.

Plasma proteins are covalently modified in vivo by the high-glucose conditions in the bloodstreams of people with diabetes, resulting in changes to both structure and function. Human Serum Albumin (HSA) functions as a carrier-protein in the bloodstream, binding various ligands and tightly regulating their bioavailability. HSA is known to react with glucose via the Maillard reaction, causing adverse effects on its ability to bind and deliver certain ligands, such as metals. Here, the binding between in vivo glycated HSA and zinc (Zn2+) was determined using a novel centrifugal ultrafiltration method that was developed using a 3D-printed device. This method is rapid (90 minutes), capable of high-throughput measurements (24 samples), low-cost (

PURPOSE To investigate the association of postdiagnosis body mass index (BMI) and weight change with prostate cancer–specific mortality (PCSM), cardiovascular disease–related mortality (CVDM), and all-cause mortality among survivors of nonmetastatic prostate cancer. METHODS Men in the Cancer Prevention Study II Nutrition Cohort diagnosed with nonmetastatic prostate cancer between 1992 and 2013 were followed for mortality through December 2016. Current weight was self-reported on follow-up questionnaires approximately every 2 years. Postdiagnosis BMI was obtained from the first survey completed 1 to < 6 years after diagnosis. Weight change was the difference in weight between the first and second postdiagnosis surveys. Deaths occurring within 4 years of the follow-up were excluded to reduce bias from reverse causation. Analyses of BMI and weight change included 8,330 and 6,942 participants, respectively. RESULTS Postdiagnosis BMI analyses included 3,855 deaths from all causes (PCSM, n = 500; CVDM, n = 1,155). Using Cox proportional hazards models, hazard ratios (HRs) associated with postdiagnosis obesity (BMI ≥ 30 kg/m2) compared with healthy weight (BMI 18.5 to < 25.0 kg/m2) were 1.28 for PCSM (95% CI, 0.96 to 1.67), 1.24 for CVDM (95% CI, 1.03 to 1.49), and 1.23 for all-cause mortality (95% CI, 1.11 to 1.35). Weight gain analyses included 2,973 deaths (PCSM, n = 375; CVDM, n = 881). Postdiagnosis weight gain (> 5% of body weight), compared with stable weight (± < 3%), was associated with a higher risk of PCSM (HR, 1.65; 95% CI, 1.21 to 2.25) and all-cause mortality (HR, 1.27; 95% CI, 1.12 to 1.45) but not CVDM. CONCLUSION Results suggest that among survivors of nonmetastatic prostate cancer with largely localized disease, postdiagnosis obesity is associated with higher CVDM and all-cause mortality, and possibly higher PCSM, and that postdiagnosis weight gain may be associated with a higher mortality as a result of all causes and prostate cancer.

The COVID-19 pandemic has disrupted every aspect of society in a way never previously experienced by our nation's orthopaedic surgeons. In response to the challenges the American Board of Orthopaedic Surgery has taken steps to adapt our Board Certification and Continuous Certification processes. These changes were made to provide flexibility for as many Candidates and Diplomates as possible to participate while maintaining our high standards. The American Board of Orthopaedic Surgery is first and foremost committed to the safety and well-being of our patients, physicians, and families while striving to remain responsive to the changing circumstances affecting our Candidates and Diplomates.

The purpose of this retrieval study was to determine the effect of implant positioning on wear, taking patient-related factors into account. Therefore, the volumetric material loss of 59 retrieved tibial liners was quantitatively determined using a coordinate measuring-machine. All retrievals were made of the same polyethylene and design by a single manufacturer. Using time in-situ and linear regression, a wear rate for each liner was determined and corrected for bedding-in. Backside damage was qualitatively scored. The following implant positioning parameters were obtained from radiographs: anatomical lateral-distal femoral angle, anatomical medial-proximal tibial angle, femoral tilt angle and posterior tibial slope. The patella position was assessed by the Blackburne-Peel Index and the Insall-Salvati Ratio. Unlike the Insall-Salvati Ratio, the Blackburne-Peel Index is known to detect surgical joint line elevation. Using general linear modeling the most impactful factors on wear rate and backside damage was determined, thereby taking patient demographic factors into account. The mean volumetric wear rate was 11.6 mm(3)/yr. Wear decreased with older age (p=0.021) and female sex (p=0.001). The wear rate increased with joint line elevation as indicated from a decreased Blackburne-Peel Index (p=0.019), and increased with increased posterior tibial slope (p = 0.026). The backside damage score also increased with joint line elevation (p=0.036). A Blackburne-Peel Index decrease of 0.1, signifying joint line elevation, was found to increase the wear rate by 1.8 mm(3)/yr and increase back-sided wear. A high tibial slope (>7°) led to a 9.3 mm(3)/yr increase in wear rate compared with a low tibial slope (

The aim of this study was to determine the effect of two in-vivo-determined gait patterns, one with low and one with high anteroposterior (AP) motion, on total and backside polyethylene insert wear in comparison with the ISO (International Organization for Standardization) standard 14243-3. In order to differentiate and accurately quantify topside and backside wear, a novel technique was employed where different lanthanide tracers were incorporated into the polyethylene during manufacture. Wear particle analysis was conducted following established protocols. For all tested liners and motion protocols, the chemically calculated wear rates correlated closely with gravimetrically determined wear. Both in vivo motion groups displayed higher wear rates than the ISO group following the order of the AP motion amplitudes. Backside wear for ISO constituted 2.76% ± 0.90% (mean ± SE) of the total wear, increasing significantly to 15.8% ± 3.2% for the low AP and further increasing to 19.3% ± 0.95% for the high AP motion protocol. The mean wear particle sizes were under 200 nm for all three motion patterns, being largest for the protocol with high AP motion. Particle release from the low and high AP gait patterns was 1.9 to 2.8 times that from the ISO protocol. Testing for the proportion of backside wear across various activities of daily living should be an important consideration in evaluating knee prostheses wear.

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4–10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta’s function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior–posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes., We show that the human hippocampus exhibits two distinct theta oscillations during spatial navigation with the faster oscillation in posterior regions showing movement modulation. This result suggests a distinct feature of the human hippocampus compared to rodents, which generally show a single 8 Hz rhythm.

Purpose: To analyze the changes in target vessel (TV) anatomy after fenestrated endovascular aneurysm repair (fEVAR) during midterm follow-up. Materials and Methods: A retrospective single-center study analyzed 56 patients (mean age 71±7 years; 49 men) who underwent fEVAR using custom-made stent-grafts (22 Zenith and 34 Anaconda) between June 2010 and July 2016. Advanta V12 (V12; 74, 53%) and BeGraft (BeG; 66, 47%) stent-grafts were used to bridge to the 140 TVs. Measurements of the TV deviation at the aortic origin, the vessel shift distal to the bridging stent-graft (BSG), and the outer and inner BSG curve lengths were performed after 3-dimensional reconstruction of the serial computed tomography angiography scans. The results of the measurements for the main devices, the TVs, and the bridging stent-grafts were compared using univariable and multivariable analysis. Results: Of the 140 BSGs examined (74 V12s and 66 BeGs), 393 measurements (38 celiac trunks, 102 superior mesenteric arteries, 121 left renal arteries, and 132 right renal arteries) were analyzed. The outer/inner BSG curve length ratio was larger after implantation of Zenith devices compared with Anaconda (p

OBJECTIVE: The aim of this pilot study was to evaluate intraoperative contrast-enhanced ultrasound (iCEUS) examination for endoleak (EL) detection after complex endovascular aortic repairs (EVAR) in comparison with the standard angiographic completion control.METHODS: Twenty-one patients (16 male; median age, 73 years [range, 54-81 years]) who underwent single-stage EVARs at our center between October 2016 and October 2018 were included prospectively. The procedures comprised fenestrated and/or branched EVAR (n = 14; 66%), infrarenal EVAR (n = 5; 24%), infrarenal EVAR with bilateral iliac side branch implantation (n = 1; 5%), and infrarenal EVAR with occluder implantation into the internal iliac artery (n = 1; 5%). The used endografts included 14 custom made devices (Cook, Australia Pty Ltd, Brisbane, Australia, n = 6; Vascutek Terumo, Glasgow, Scotland, n = 8) and seven standard infrarenal endografts (Medtronic Inc, Santa Rosa, Calif, n = 5; Vascutek Terumo, Glasgow, Scotland, n = 1; Cook, n = 1). All patients underwent an angiographic completion control for EL detection followed by iCEUS examination. The iCEUS examination was performed by the same examiner who was blinded to the angiography result. In addition to the comparison of the angiographic results to iCEUS examination, iCEUS examination was also compared with the computed tomography angiography (CTA) before discharge (median time to CTA, 5 days [range, 1-7 days]).RESULTS: Angiography detected eight type II EL, defining the EL origin in four cases. In addition to detecting all of those eight EL, iCEUS examination revealed eight more type II EL not seen on angiography (P = .002) and allowed a definition of the EL origin in all cases. CTA before discharge showed a persistence of only 5 of the 16 type II EL detected by iCEUS examination (31%, P = .002).CONCLUSIONS: An iCEUS examination can be used as another adjunct to decrease exposure to contrast agent and radiation during EVAR, including complex procedures. A replacement of the completion angiography by iCEUS examination is conceivable for infrarenal EVAR, but also for endovascular type IV or type V repairs. Future studies with larger patient numbers will help to further validate iCEUS examination during complex EVAR.

Thoraco-abdominal aneurysm (TAA) repair carries a significant risk of spinal cord infarction. The latter results from irreversible changes in the spinal cord arterial network, e.g., sacrifice of the segmental arteries. Intra-operative neurophysiology with somatosensory and especially motor evoked potential (SEP and MEP respectively) monitoring, has emerged as an effective tool to assess the efficiency of the collateral blood flow, detect reversible spinal cord ischemia and guide the peri-operative multidisciplinary management to prevent postoperative paraplegia. The main roles of such monitoring include diagnosis of spinal cord vs peripheral limb ischemia, titration of mean arterial pressure during aortic clamping, the guidance of selective re-implantation of critical segmental arteries, and management of hemodynamics in the immediate postoperative period. In addition, manipulation of the aortic arch and proximal descending aorta, adds the risk of cerebral infarction from both low flow state and/or thromboembolic events. As such, EEG monitoring may be a useful add-on for either assessment of the efficiency of cerebral cooling as a neuroprotective method and/or for detection and treatment of reversible cerebral ischemia. This chapter presents the multimodality approach to open TAA monitoring as a versatile tool for the prevention of devastating postoperative neurologic deficits.

An earlier trial of a school-based, preventative intervention, HealthWise South Africa, demonstrated some efficacy in preventing adolescent drinking and smoking in the Western Cape, South Africa. This was followed by the current implementation trial, which examined how implementation support conditions influenced adolescent drinking and smoking behavior change in the HealthWise intervention. The hybridized implementation-effectiveness trial included 34 schools (n = 2,175 students) that provided student data at four waves through grades 8 to 10. Implementation support conditions included a combination of two components (enhanced school environment and teacher consultation), resulting in four conditions: enhanced school environment, teacher consultation, both components, and standard delivery. Using configural frequency analysis, we examined how drinking and smoking behavior change differed across four configurations of intervention support longitudinally and by gender. For baseline non-smokers, results indicated sustained differences in abstention from smoking and smoking initiation between schools that received both support components and schools in the standard delivery condition. These results were primarily driven by girls. For baseline drinkers and smokers in the both components condition, changes in drinking were delayed until grade 9 and smoking decayed by grade 10. Results suggest that providing both school and teacher implementation support synergistically facilitates improved intervention outcomes both immediately following intervention and two years later across schools with diverse resource levels. Future iterations of HealthWise, and other interventions, may benefit from a multilevel implementation support strategy to improve student outcomes. More research is needed to understand how to improve HealthWise effectiveness among boys.

BACKGROUND & AIMS: We aimed to perform geriatric assessment in older patients with inflammatory bowel disease (IBD) to evaluate which IBD characteristics associate with deficits in geriatric assessment and the impact of deficits on disease burden (health-related quality of life).METHODS: A prospective multicenter cohort study including 405 consecutive outpatient patients with IBD aged ≥65 years. Somatic domain (comorbidity, polypharmacy, malnutrition), impairments in (instrumental) activities of daily living, physical capacity (handgrip strength, gait speed), and mental (depressive symptoms, cognitive impairment) and social domain (life-partner) were assessed. Deficits in geriatric assessment were defined as ≥2 abnormal domains; 2-3 moderate deficits and 4-5 severe deficits. Clinical (Harvey Bradshaw Index >4/partial Mayo Score >2) and biochemical (C-reactive protein ≥10 mg/L and/or fecal calprotectin ≥250 μg/g) disease activity and disease burden (short Inflammatory Bowel Disease Questionnaire) were assessed.RESULTS: Somatic domain (51.6%) and activities of daily living (43.0%) were most frequently impaired. A total of 160 (39.5%) patients had moderate deficits in their geriatric assessment; 32 (7.9%) severe. Clinical and biochemical disease activity associated with deficits (clinical: adjusted odds ratio, 2.191; 95% confidence interval, 1.284-3.743; P = .004; biochemical: adjusted odds ratio, 3.358; 95% confidence interval, 1.936-5.825; P < .001). Deficits in geriatric assessment independently associate with lower health-related quality of life.CONCLUSION: Deficits in geriatric assessment are highly prevalent in older patients with IBD. Patients with active disease are more prone to deficits, and deficits associate with lower health-related quality of life, indicating higher disease burden. Prospective data validating impact of frailty and geriatric assessment on outcomes are warranted to further improve treatment strategies.

While the primary goal of focal therapy for prostate cancer (PCa) is conserving patient quality of life by reducing oncological burden, available modalities use thermal energy or whole-gland radiation which can damage critical neurovascular structures within the prostate and increase risk of genitourinary dysfunction. High-frequency irreversible electroporation (H-FIRE) is a promising alternative ablation modality that utilizes bursts of pulsed electric fields (PEFs) to destroy aberrant cells via targeted membrane damage. Due to its nonthermal mechanism, H-FIRE offers several advantages over state-of-the-art treatments, but waveforms have not been optimized for treatment of PCa. In this study, we characterize lethal electric field thresholds (EFTs) for H-FIRE waveforms with three different pulse widths as well as three interpulse delays in vitro and compare them to conventional irreversible electroporation (IRE). Experiments were performed in non-neoplastic and malignant prostate cells to determine the effect of waveforms on both targeted (malignant) and adjacent (non-neoplastic) tissue. A numerical modeling approach was developed to estimate the clinical effects of each waveform including extent of nonthermal ablation, undesired thermal damage, and nerve excitation. Our findings indicate that H-FIRE waveforms with pulse durations of 5 and 10 μs provide large ablations comparable to IRE with tolerable levels of thermal damage and minimized muscle contractions. Lower duration (2 μs) H-FIRE waveforms exhibit the least amount of muscle contractions but require increased voltages which may be accompanied by unwanted thermal damage.

Summary: Background: We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. Methods: Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. Findings: Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. Interpretation: This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenges. Funding: The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research Moorfields Biomedical Research Centre, Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The Seva Foundation, British Council for the Prevention of Blindness, and Christian Blind Mission. Translations: For the French, Spanish, Chinese, Portuguese, Arabic and Persian translations of the abstract see Supplementary Materials section.

Medicina 58(11), 1594 (2022). doi:10.3390/medicina58111594 special issue: "Special Issue "Modern Endovascular Therapy for Peripheral Arterial Disease" / Special Issue Editors: Dr. Florian Enzmann, Guest Editor; Prof. Dr. Sabine Helena Wipper, Guest Editor", Published by Kaunas Univ. of Medicine, Kaunas

Purpose The coronavirus disease 2019 (COVID-19) pandemic resulted in accelerated market access to remdesivir worldwide. Therefore, data about complications experienced during use of the drug are limited. This is the first published case series (1 case report exists) to describe remdesivir infiltration in 3 patients with COVID-19. Summary In the first case, a 91-year-old woman experienced remdesivir infiltration resulting in edema, hematoma at the area of infiltration; on palpation, the affected area felt cooler than the surrounding areas. Swelling was still present after 6 weeks. In the second case, remdesivir infiltration occurred in a 72-year-old male, resulting in edema, hematoma, and pain at the area of infiltration. The hematoma lasted for 7 days. The third case concerned a 67-year-old woman, in whom remdesivir infiltration led to edema and a small hematoma. The hematoma regressed to a negligible size within 3 days. However, a week after infiltration, redness had reappeared. In 2 cases, the patient was immediately treated with hyaluronidase injections, but no specific treatments were provided in the other case. Conclusion Based on the product information provided by remdesivir’s manufacturer, we believe symptoms and signs observed in the 3 cases may have resulted from the low pH (~4) of the nonbuffered remdesivir solution, although the patients were not formally assessed for caustic injury. Previous experience with other noncytotoxic medications suggests that infusion-specific factors (eg, volume of leaked fluid) and patient-specific factors (eg, advanced age) may have a role in the outcome of remdesivir infiltration. The possibility of symptoms caused by cyclodextrins in the formulation or by intrinsic toxicity of remdesivir warrants exploration.

The extracellular matrix (ECM) has pleiotropic effects, ranging from cell adhesion to cell survival. In tissue engineering, the use of ECM and ECM-like scaffolds has separated the field into two distinct areas—scaffold-based and scaffold-free. Scaffold-free techniques are used in creating reproducible cell aggregates which have massive potential for high-throughput, reproducible drug screening and disease modeling. Though, the lack of ECM prevents certain cells from surviving and proliferating. Thus, tissue engineers use scaffolds to mimic the native ECM and produce organotypic models which show more reliability in disease modeling. However, scaffold-based techniques come at a trade-off of reproducibility and throughput. To bridge the tissue engineering dichotomy, we posit that finding novel ways to incorporate the ECM in scaffold-free cultures can synergize these two disparate techniques.

Currently, preclinical mechanical wear testing of total knee replacements (TKRs) is done using ideally aligned components using standardized TKR level walking under either force or displacement-control regimes. To understand the influence of implant alignment and testing control regime, we studied the effect of nine component alignment parameters on TKR volumetric wear in silico. We used a computational framework combining Latin Hypercube sampling design of experiments, finite element analysis, and a numerical model of polyethylene wear, to create a predictive model of how component alignment affects wear rate for each control regime. Nine component alignment parameters were investigated, five femoral variables and four tibial variables. To investigate perturbations of the nine implant alignment variables, two separate 300-point designs were executed, one for each control regime. The results were then used to generate surrogate statistical models using stepwise multiple linear regression. Wear at the neutral position was 4.5mm(3)/million cycle and 8.6mm(3)/million cycle for displacement and force-control, respectively. Stepwise multiple linear regression surrogate models were highly significant for each control regime, but force-control generated a stronger predictive model, with a higher R(2), more included terms, and a lower RMSE. Both models predicted transverse plane rotational mismatch can lead to large changes in predicted wear; a transverse plane alignment mismatch of 15° can elicit a change in wear of up to 5mm(3)/million cycle, almost double that of neutral alignment. Therefore, transverse plane alignment is particularly important when considering failure of the implant due to wear.

BACKGROUND: Long-term use of statins is associated with a small reduced risk of colorectal cancer but their mechanism of action is not well understood. While they are generally believed to act on KRAS, we have previously proposed that they act via influencing the BMP pathway. The objective of this study was to look for associations between statin use and the risk of developing colorectal cancer of a particular molecular subtype.METHODS: By linking two registries unique to the Netherlands, 69,272 statin users and 94,753 controls were identified and, if they developed colorectal cancer, their specimens traced. Colorectal cancers were molecularly subtyped according to the expression of SMAD4 and the mutation status of KRAS and BRAF.RESULTS: Statin use was associated with a reduction in the risk of developing colorectal cancer regardless of molecular subtype (HR 0.77; 95% CI 0.66-0.89) and a larger reduction in the risk of developing SMAD4-positive colorectal cancer (OR 0.64; 95% CI 0.42-0.82). There was no relationship between statin use and the risk of developing colorectal cancer with a mutation in KRAS and/or BRAF.CONCLUSIONS: Statin use is associated with a reduced risk of developing colorectal cancer with intact SMAD4 expression.

Childhood visual impairment has a life-long impact that, with early access to eyecare, is largely avoidable. We aimed to understand visual impairment and its correction among Pacific youth in Aotearoa New Zealand.The Pacific Islands Families Study is a birth cohort study that tracks an original sample of 1,398 Pacific children born at Middlemore Hospital (Auckland). This analysis focuses on assessed visual acuity (at 9- and 18-years, using 0.3logMAR or 6/12 as the cut-off for visual impairment) and participants' self-reports about accessing eyecare services.Less than a fifth of children (111/729, 15.2%) and teens (86/457, 18.8%) reported having sought eyecare. The percentage of participants with refractive correction was 3.6% (32/887) at 9-years and 14.3% (66/463) at 18-years. At 9-years, 1.9% of children (16/853) had visual impairment in one eye only, and 0.9% (8/853) had visual impairment impacting both eyes. By 18-years these values increased to 7.9% (36/456) and 4.2% (19/456), respectively. Among those with visual impairment, most children (15/24, 62.5%) and teens (32/55, 58.2%) reported they did not have refractive correction.Although prevalence of visual impairment is relatively low compared to non-Pacific youth, much of the reported impairment appears to be avoidable with improved eyecare.

In 2017 the AtellicaWe evaluated the performance characteristics of the AtellicaErythrocyte and leukocyte analyses indicated high intra- and inter-run precisions and good correlations with the iQ200. We found that the AtellicaThe Atellica

PURPOSE Inflammatory bowel disease (IBD) management creates significant caregiver demands that can interfere with parents' ability to engage in a number of role functions (i.e., illness intrusiveness) well into their child's adolescence, potentially resulting in excessive or misdirected parenting (i.e., overparenting). Disruptions and limited access to routine and valued activities (e.g., family, work, and leisure) due to IBD and excessive parenting may result in parents neglecting their own personal and emotional self-care needs, increasing their risk for depressive symptoms. To explore these associations, the present study examined parents' experience of illness intrusiveness and subsequent overparenting as serial mediators in the association between disease severity and parent depressive symptoms. DESIGN AND METHODS Participants were 146 caregivers of adolescents with IBD from an outpatient pediatric gastroenterology clinic. During a scheduled outpatient visit, parents completed measures of illness intrusiveness, overparenting, and depressive symptoms. Pediatric gastroenterologists provided ratings of disease severity. RESULTS Several direct and indirect associations were observed among the modeled variables. Notably, mediation analysis revealed a significant disease severity → illness intrusiveness → overparenting → depressive symptoms serial indirect effect. CONCLUSIONS Parents' experience of greater IBD-induced lifestyle disruptions is associated with increased overparenting and a heightened risk for depressive symptoms. PRACTICE IMPLICATIONS Parents should be encouraged to establish and maintain a healthy balance between parenting and self-care/role function activities, especially during adolescence when greater youth autonomy and independence are crucial. These types of clinical efforts may reduce the likelihood of parents experiencing depressive symptoms, and have the added benefit of improving adolescent IBD self-management.

Perceived illness stigma is associated with increased depressive symptoms in youth with inflammatory bowel disease (IBD), but the mechanisms by which stigma influences emotional adjustment remain unclear. It is possible that youth with IBD who are more present-focused and better able to come to terms with aspects of their disease that are less controllable (i.e. are mindful) may develop more adaptive strategies when facing illness uncertainty, resulting in more positive emotional adjustment. The present study examined the indirect association between illness stigma, illness uncertainty, depressive symptoms, and the potential moderating effect of mindfulness on this process. One hundred and seven youth (56 female, 51 male; M

IntroductionZinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested.Methods64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well.ResultsInjecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail.ConclusionZinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

The medial temporal lobe is critical for both spatial navigation and memory. Although single neurons in the medial temporal lobe activate to represent locations in the environment during navigation, how this spatial tuning relates to memory for events involving those locations remains unclear. We examined memory-related changes in spatial tuning by recording single-neuron activity from neurosurgical patients performing a virtual-reality object-location memory task. We identified 'memory-trace cells' with activity that was spatially tuned to the retrieved location of the specific object that participants were cued to remember. Memory-trace cells in the entorhinal cortex, in particular, encoded discriminable representations of different memories through a memory-specific rate code. These findings indicate that single neurons in the human entorhinal cortex change their spatial tuning to target relevant memories for retrieval.