DNA damage by genotoxic drugs such as gemcitabine and 5-fluorouracil (-FU) activates the ataxia telangiectasia, mutated (ATM)-Chk pathway and induces the expression of NKG2D ligands such as the MHC class I-related chain A and B (MICA/B). The mechanisms underlying this remain incompletely understood. Here we report that xanthine oxidoreductase (XOR), a rate-limiting enzyme that produces uric acid in the purine catabolism pathway, promotes DNA damage-induced MICA/B expression. Inhibition of the ATM-Chk pathway blocks genotoxic drug-induced uric acid production, TGF-β-activated kinase 1 (TAK1) activation, ERK phosphorylation, and MICA/B expression. Inhibition of uric acid production by the XOR inhibitor allopurinol blocks DNA damage-induced TAK1 activation and MICA/B expression in genotoxic drug-treated cells. Exogenous uric acid activates TAK1, NF-κB, and the MAP kinase pathway. TAK1 inhibition blocks gemcitabine- and uric acid-induced MAP kinase activation and MICA/B expression. Exogenous uric acid in its salt form, monosodium urate (MSU), induces MICA/B expression and sensitizes tumor cells to NK cell killing. MSU immunization with irradiated murine breast cancer cell line RCAS-Neu retards breast cancer growth in syngeneic breast cancer models and delays breast cancer development in a somatic breast cancer model. Our study suggests that uric acid accumulation plays an important role in activating TAK1, inducing DNA damage-induced MICA/B expression, and enhancing antitumor immunity.
Introduction To determine if treatment and clinical outcomes of adrenocortical carcinoma (ACC) vary by race and insurance status. Methods ACC patients from the National Cancer Database (2004-2017) were reviewed. Race was defined as White versus minority (Black and Hispanic). Insurance types were private (PI) versus other (Medicaid/uninsured/unknown). Metastatic ACC (M-ACC) was defined as distant metastases at the time of diagnosis; nonmetastatic ACC (NM-ACC) patient had no distant disease. Results Of 2351 NM-ACC patients, 83.6% were White and 16.4% minority. There were 1216 M-ACC patients, with 80.3% White and 19.8% minority. Both White NM-ACC and M-ACC patients had more PI (each P < 0.001). PI NM-ACC was associated with a shorter duration from diagnosis to first treatment (14 versus 18 d, P = 0.005). Both NM-ACC and M-ACC with PI were more likely to receive surgery (92.6% versus 86.9%, P = 0.001 and 35.4% versus 27%, P = 0.02) and to receive surgery sooner (13 versus 16 d, P = 0.03). M-ACC with PI were more likely to receive chemotherapy (63.6% versus 54.3%, P = 0.01) and to have lymph nodes examined (14.8% versus 8.6%, P = 0.02). Length of stay postoperatively was shorter for White NM-ACC (6 versus 7 d, P = 0.04) and M-ACC (8 versus 17 d, P = 0.02). For NM-ACC and M-ACC, the 30-d readmission, 90-d mortality, and overall survival were similar by race. A multivariable analysis showed minorities (OR 0.69, 95% confidence interval 0.54-0.88, P = 0.003) and patients without PI (OR 0.75, 95% confidence interval 0.58-0.97, P = 0.03) were less likely to have surgery. However, a multivariable analysis showed survival was similar for White versus minority patients and PI versus other. Conclusions White NM-ACC or M-ACC and PI were more likely to receive surgery and timely multimodality care. These disparities were not associated with differences in 90-d mortality or overall survival.
The current study investigates whether prepregnancy maternal posttraumatic stress disorder (PTSD) symptoms, depressive symptoms, and stress predict children's cortisol diurnal slopes and cortisol awakening responses (CARs) adjusting for relevant variables. Mothers were enrolled after delivering a baby and followed through their subsequent pregnancy with 5 years of longitudinal data on their subsequent child. This prospective design allowed assessment of PTSD symptoms, depressive symptoms, and perceived stress prior to pregnancy. Children provided three saliva samples per day on three consecutive days at two timepoints in early childhood (M age = 3.7 years, SD = 0.38; M age = 5.04 years, SD = 0.43). Mothers’ PTSD symptoms prior to pregnancy were significantly associated with flatter child diurnal cortisol slopes at 4 and 5 years, but not with child CAR. Findings at the age of 4 years, but not 5 years, remained statistically significant after adjustment for maternal socioeconomic status, race/ethnicity, child age, and other covariates. In contrast, maternal prepregnancy depressive symptoms and perceived stress did not significantly predict cortisol slopes or CAR. Results suggest that maternal prepregnancy PTSD symptoms may contribute to variation in early childhood physiology. This study extends earlier work demonstrating risk of adverse outcomes among children whose mothers experienced trauma but associations cannot be disentangled from effects of prenatal mental health of mothers on children's early childhood.
Study objective Despite the popularity of vaping and electronic vapor delivery systems (EVDS), the healthcare community remains largely unfamiliar with their potential to induce harm. The purpose of this systematic review is to identify how EVDS use affects the pulmonary system in order to support future anesthetic guidelines for patients who vape. Design Systematic Review. An electronic search of databases CINAHL and PubMed was performed in October 2020. Study eligibility criteria Studies were included if they were deemed original research published in English, if they were performed exclusively in humans or on human tissue, if they examined the effects of EVDS on pulmonary function or tissue, and/or if they produced quantitative data. Studies were excluded if they utilized animal samples, studied subjects under the age of 18, presented expert opinions or reviews, offered qualitative data, reported case studies, or only evaluated EVDS' efficacy as a smoking cessation tool. Main results This review identified six EVDS-induced pulmonary implications warranting anesthetic consideration: alterations in pulmonary function tests, disrupted ventilation, impaired mucociliary clearance, tissue destruction, a disrupted immune response, and oxidative stress with DNA fragmentation. Conclusion A total of 38 studies described the effects of EVDS on pulmonary function, airway epithelial tissue, and inflammatory mechanisms that may lead to chronic pulmonary disease. Anesthesia providers are encouraged to assess patients for EVDS use during the preoperative period and use the information generated by this systematic review to drive subsequent care.
Background Reliability of prostate cancer (PCa) genetic risk score (GRS), that is, the concordance between its estimated risk and observed risk, is required for genetic testing at the individual level. Reliability data are lacking for non-European racial/ethnic populations, which hinders its clinical use and exacerbates racial disparity. Objective To calibrate PCa ancestry-specific GRS in four racial/ethnic populations. Design, setting, and participants PCa ancestry-specific GRSs, calculated from published risk-associated single-nucleotide polymorphisms in corresponding racial/ethnic populations, were evaluated in men who participated in 23andMe, Inc. genetic testing and consented for research, including 888 086 of European (EUR), 81 109 of Hispanic (HIS), 30 472 of African (AFR), and 13 985 of East Asian (EAS) ancestry, as classified by 23andMe's ancestry composition algorithm. Outcome measurements and statistical analysis The concordance between the observed and estimated PCa risks at ten ancestry-specific GRS deciles was measured primarily by using the calibration slope (β), where 1 represents a perfect calibration. Platt scaling was used to correct the systematic bias of GRS. Results and limitations A linear trend of an increased observed PCa prevalence in men with higher ancestry-specific GRS deciles was found in each racial population (all p-trend < 0.001). A calibration analysis revealed a systematic bias of GRS; β was considerably lower than 1 (0.73, 0.64, 0.66, and 0.75 in EUR, HIS, AFR, and EAS ancestries, respectively). This bias was reduced after the Platt scaling correction: β for scaled GRS in the testing dataset (40% of individuals) approximated 1 for all groups (0.95, 1.05, 1.02, and 1.01 in EUR, HIS, AFR, and EAS populations, respectively). The generalizability of the Platt correction needs to be validated in independent cohorts. Conclusions A systematic bias of ancestry-specific GRS in the direction of an overestimated risk for men in the highest decile was found in EUR and non-EUR populations. GRS is well calibrated after correction and is appropriate for genetic testing at the individual level for personalized PCa screening. Patient summary A corrected genetic risk score is more reliable (supported by the observed prostate cancer [PCa] risk) and appropriate for genetic testing for personalized PCa screening.
Introduction and hypothesis: Same-day discharge (SDD) is increasing in popularity following surgical repair of pelvic organ prolapse. The aim of this study was to evaluate factors associated with unplanned admission (UA) in women undergoing apical prolapse repair. Methods: This retrospective, observational cohort study included patients who underwent apical prolapse repair and planned same-day discharge (SDD) between March 2019 and December 2021. The cohort was divided into two groups: patients who were discharged on the same day as surgery (SDD group) and patients who had an unplanned admission (UA group). Demographic, pre-, intra-, and post-operative data were collected. Risk factors associated with unplanned admission were evaluated using univariate and multivariate analyses. Results: One-hundred and eighty-four cases of apical prolapse repair met the criteria for inclusion in the final analysis; this included 142 in the SDD group and 42 in the UA group. Patients in the UA group had significantly increased estimated blood loss, longer total operative time, later time arriving to the Post-Anesthesia Care unit (PACU) and longer overall stay in the PACU. No differences were observed in the 30-day complication rate, or 30-day unanticipated healthcare encounters, between groups. Multivariate analysis revealed that receiving ketorolac post-operatively was associated with a higher likelihood of SDD (OR=2.6, 95% CI 1.032-6.580, p=0.043). Conclusions: Among women undergoing apical prolapse repair, same-day discharge was associated with comparable immediate and 30-day complication rates. Within our cohort, post-operative treatment with ketorolac was associated with greater likelihood of SDD.
Purpose We aimed to investigate the possible effect of SARS-CoV-2 vaccination on sperm quality by evaluating semen analyses of men prior to vaccination and 6–14 months after vaccination.Methods This was a retrospective cohort study, conducted in a university-affiliated in vitro fertilization center between October 2021 and March 2022, including men not previously infected with the SARS-CoV-2 virus who received at least 2 doses of the Pfizer-BioNTech (BNT162b2) SARS-CoV-2 vaccine. Semen analyses of samples given pre-vaccination and 6–14 months post-vaccination were analyzed for the parameters of volume, concentration, motility, morphology, and total motile count (TMC) and compared. These parameters were also compared separately for men who received a third (booster) dose and for men with pre-vaccination normal and abnormal sperm. Correlations between time from vaccination and post-vaccination sperm parameters were also assessed.ResultsFifty-eight men were included in the final analysis. Semen volume (2.9 ± 1.4 vs. 2.9 ± 1.6 ml), sperm concentration (42.9 ± 37.9 vs. 51.5 ± 46.2 million/ml), motility (42.5 ± 23.1 vs. 44.3 ± 23.4 percent), morphology (8.8 ± .16.6 vs. 6.6 ± 8.8 percent), and TMC (55.7 ± 57.9 vs. 71.1 ± 77.1 million) were comparable between the pre- and post-vaccination samples. This was true for the entire study cohort, for the subgroup of men who received a third dose and for the subgroups of men with a pre-vaccination normal and abnormal semen samples. No correlation was found between time from vaccination and post-vaccination sperm parameters.Conclusions The Pfizer-BioNTech (BNT162b2) SARS-CoV-2 vaccine does not impair any of the sperm parameters over a relatively long-time interval of 6 to 14 months from vaccination.
Natural hazards (NHs) associated with climate change have been increasing in frequency and intensity. These acute events impact humans both directly and through their effects on social and environmental determinants of health. Rather than relying on a fully reactive incident response disposition, it is crucial to ramp up preparedness initiatives for worsening case scenarios. In this perspective, we review the landscape of NH effects for human health and explore the potential of health informatics to address associated challenges, specifically from a preparedness angle. We outline important components in a health informatics agenda for hazard preparedness involving hazard-disease associations, social determinants of health, and hazard forecasting models, and call for novel methods to integrate them toward projecting healthcare needs in the wake of a hazard. We describe potential gaps and barriers in implementing these components and propose some high-level ideas to address them.
Introduction Genetic contributions to hernia development are incompletely understood. This study performed the first comprehensive genome-wide association study (GWAS) for diaphragmatic hernia using a large population-based cohort in the UK Biobank (UKB). Methods and procedures Two-stage GWAS (discovery and confirmation) was performed for diaphragmatic hernia in the UKB. Briefly, 275,549 and 91,850 subjects were randomly selected for association tests in Stages 1 and 2, respectively. Association tests between 8,568,156 SNPs (genotyped or imputed with MAF > 0.01) in the autosomal genome and diaphragmatic hernia were performed in Stage 1. SNPs with P < 1 × 10–5 were selected for confirmation in Stage 2, and those with P < 0.05 and the same direction of association as Stage 1 were selected for combined association testing; SNPs with combined P < 5 × 10–8 were considered GWAS-significant. LD clumping analysis identified genetically independent chromosomal regions (loci). A genetic risk score (GRS) measured the cumulative risk of independent SNPs in 91,849 additional subjects using odds ratios (ORs) from Stages 1 and 2. Results 36,351 patients were identified with diaphragmatic hernia (ICD-10 K44). In Stage 1 analysis, 2654 SNPs were associated (P < 1 × 10–5) with diaphragmatic hernia. Stage 2 analysis confirmed 338 SNPs (P < 0.05). In combined analysis, 245 SNPs reached GWAS significance (P < 5 × 10–8). LD clumping analysis revealed 14 independent loci associated with diaphragmatic hernia. Two loci have been previously associated with inguinal hernia at 2p16 (rs181661155) and 11p13 (rs5030123). eQTL analysis suggested genes CRLF1, UBA52, and CALD1 are also significantly associated with these loci. GRS showed significant increase in cases compared to controls (P < 1 × 10–16) and is associated with increased risk of diaphragmatic hernia (P < 1 × 10–7). Conclusions We identified 245 SNPs at 14 susceptibility loci associated with diaphragmatic hernia in a large population-based cohort. These results offer insight into pathogenetic mechanisms of diaphragmatic hernia development and may be used in genetic risk scores for pre-operative risk-stratification and clinical prediction models. Graphical abstract
Purpose: To characterize patients with urinary urgency (UU) with and without urgency urinary incontinence (UUI) who presented to clinics actively seeking treatment for their symptoms. Materials and methods: Participants who enrolled in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN-I) were categorized into UU with versus without UUI. Participants were followed for 1 year; their urinary symptoms, urologic pain, psychosocial factors, bowel function, sleep disturbance, physical activity levels, physical function, and quality of life (QOL) were compared. Mixed effects linear regression models were used to examine the relationships between UUI and these factors. Results: Among 683 participants with UU at baseline, two-thirds (n=453) also had UUI; one-third (n=230) had UU-only without UUI. No differences were detected in urologic pain between UU-only and UUI. Those with UUI had more severe urgency and frequency symptoms, higher depression, anxiety, perceived stress scores, more severe bowel dysfunction and sleep disturbance, lower physical activity levels, lower physical function, and worse QOL than those with UU-only. Among those with UU-only at baseline, 40% continued to have UU-only, 15% progressed to UUI, and 45% had no urgency at 12-months. 58% with UUI at baseline continued to report UUI at 12-months, while 15% improved to UU-only, and 27% had no urgency. Conclusions: Patients with UUI have severe storage symptoms, more psychosocial symptoms, poorer physical functioning, and worse QOL. Our data suggested UUI may be a more severe manifestation of UU, rather than UU and UUI being distinct entities.
Systemic lupus erythematosus (SLE) is a systemic autoimmune condition with many clinical presentations. It is classically seen in young to middle-aged females and can present with cutaneous, renal, serosal, hematological, joint, and/or neurological manifestations at the time of diagnosis or may develop over the course of the disease. Late-onset SLE or SLE in the elderly is a subtype that differs from the classic SLE in age group, clinical presentation, involvement of organs, and severity. Here, we present the case of a geriatric Hispanic male noted to have worsening renal function. The patient was diagnosed with lupus nephritis (LN) upon obtaining serological markers and renal biopsy. LN, a renal sequela of SLE, presents with a full-house immunofluorescence pattern. LN, along with high titers of the antinuclear antibody (ANA) and/or anti-double-stranded DNA (anti-dsDNA) antibody, is an effective tool to diagnose SLE in patients without extrarenal manifestations of the disease. The patient was managed with glucocorticoids and mycophenolate mofetil therapy, which led to a rapid downtrend of creatinine, resulting in stabilization of renal function and deferring the need for a hemodialysis. This case highlights the topic of late-onset SLE presenting with LN in geriatric patients.
The diagnosis of concussion requires a focused clinical examination and history, paired with an awareness of multiple symptoms that may be present with concussive injury. On-site assessment tools may aid the provider in the diagnosis of concussion. Adjuncts to the clinical assessment, such as advanced neuropsychological testing, neuroimaging techniques, and blood-based biomarkers of injury can also be used to aid in identifying injury and secure the diagnosis of concussion. Although these new technologies are not required or recommended for routine clinical care, they show promise as investigative tools to advance our understanding of the pathophysiology of concussion and recovery. Differentiating among etiologies can prove to be difficult. The differential diagnosis also can include vestibular dysfunction, visual dysfunction, cervical injury, somatization, chronic fatigue and pain, or combination of these in some form. Thus, it is crucial to correlate the patient’s history, mechanism of injury, new symptoms, and neurological exam when making a diagnosis of concussion. Most concussive symptoms resolve over the course of the first several days following injury, allowing the patient to return gradually to social and academic activities. A stepwise program for return to athletic play is generally accepted. There are no clinically validated treatments that have demonstrated benefit with regard to expedited recovery or amelioration of deficits attributed to concussion. However, patients with post-concussive syndrome or prolonged post-concussive syndrome may experience some benefit from symptomatic medical treatment during the recovery phase.KeywordsPost-concussion syndromeDifferential diagnosisBrain concussionNeurologic examinationClinical decision-making
Breathing is a process that is tightly controlled by a system of feedback loops that produce a relatively constant output of minute ventilation. Response of the medullary respiratory center to stimuli of peripheral and central chemoreceptors, several types of lung receptors, and respiratory muscle afferents assure that serum PAO2 and PACO2 stay within a narrow physiological range. Like any other system controlled by feedback loops, breathing has the potential to become unstable. Cheyne–Stokes breathing pattern (CSBP), a form of central sleep apnea (CSA) characterized by cyclic episodes of hypopnea/apnea alternating with periods of hyperpnea that is frequently found in patients with congestive heart failure (CHF) and stroke, is a reflection of such an instability of the respiratory system. Under other circumstances, erratic behavior of the medullary control center may lead to intermittent centrally mediated apneas. A range of therapies, including oxygen supplementation, carbon dioxide supplementation, continuous positive airway pressure (CPAP), and various forms of noninvasive positive pressure ventilation, have been employed in the treatment of the various CSA syndromes. Here, we describe adaptive servoventilation (ASV) and its applications (Figure 1).
Introduction Compliance is the ability of a hollow organ to dilate and increase volume with an increase in pressure, an accurate representation of food bolus transit through the gastroesophageal junction (GEJ). Impedance planimetry system can calculate compliance (change in volume over pressure) and distensibility (cross-sectional area over pressure) of the GEJ. We aim to describe the changes in compliance during anti-reflux surgery and hypothesize that compliance is a better predictor of patient outcomes than distensibility (DI). Methods and procedures A review of a prospectively maintained quality database was performed. Patients with FLIP measurements during laparoscopic fundoplication between August 2018 and June 2021 were included. GEJ compliance and DI were measured after hernia reduction, cruroplasty, and fundoplication. Patient-reported outcomes were collected through standardized surveys up to 2 years after surgery. A scatter plot was used to identify a correlation between compliance and DI. Comparisons of measurements between time points were made using paired t-tests. Spearman’s correlation coefficients (ρ), Wilcoxon rank-sum, and chi-square tests were used to evaluate associations between measurements and outcomes. Results One hundred and forty-four patients underwent laparoscopic fundoplication. Compliance is strongly associated with DI (r = 0.96), and a comparison of measurements showed similar trends at specific time points during the operation. After hernia reduction, compliance at the GEJ was 168 ± 74 mm³/mmHg, cruroplasty 79 ± 39 mm³/mmHg, and fundoplication 90 ± 33 mm³/mmHg (all comparisons p < 0.05). GEJ compliance of 80–92 mm³/mmHg after fundoplication was associated with the best patient-reported outcome scores. A compliance of ≤ 79 mm³/mmHg had the highest percentage of patients who reported dysphagia. Conclusions Compliance and DI are strongly associated displaying the same directional change during anti-reflux surgery. GEJ compliance of 80–92 mm³/mmHg revealed the best patient-reported outcome scores, and avoiding a compliance ≤ 79 mm³/mmHg may prevent postoperative dysphagia. Therefore, GEJ compliance is an underutilized FLIP measurement warranting further investigation.
Background Flexible endoscopy is a valuable tool for the gastrointestinal (GI) surgeon, creating a need for effective and efficient training curricula in therapeutic endoscopic techniques for trainees and practicing providers. Here, we present a simulation-based modular curriculum using an “into the fire” approach with hands-on pre- and post-testing to teach endoscopic stenting to practicing surgeons. Methods Three advanced flexible endoscopy courses were taught by expert surgical endoscopists from 2018 to 2019. The stenting module involved using self-expandable metal stents to manage simulated esophageal and gastroduodenal strictures on a non-tissue GI model. Based on the educational theories of inquiry-based learning, the simulation curriculum was designed with a series of pre-tests, didactics, mentored hands-on instructions, and post-tests. Assessments included a confidence survey, knowledge-based written test, and evaluation form specific to the hands-on performance of endoscopic stenting. Results Twenty-eight practicing surgeons with varying endoscopic experiences participated in the course. Most of the participants (67.9%) had completed over 100 upper endoscopic procedures and 57.1% were certified in Fundamentals of Endoscopic Surgery. After completing the modular curriculum, participant confidence survey scores improved from 11.4 ± 4.2 to 20.7 ± 4.0 (p < 0.001). Knowledge-based written test scores also improved from 7.1 ± 1.2 to 8.4 ± 0.9 (p < 0.001). In terms of technical performance, overall hands-on performance scores improved from 21.3 ± 2.7 to 28.9 ± 1.2 (p < 0.001) with significant improvement in each individual component of the assessment (all p values < 0.01) and the greatest improvement seen in equipment handling (88%) and flow of procedure (54%). Conclusion Our modular simulation curriculum using an “into the fire” approach to teach endoscopic stenting is effective in improving learner knowledge, confidence, and hands-on performance of endoscopic stenting. This approach to simulation is effective, efficient, and adaptable to teaching practicing surgeons with varying levels of experience.
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