Dual treatment with kynurenine pathway inhibitors and NAD+ precursors synergistically extends life span in Drosophila.

Tryptophan catabolism is highly conserved and generates important bioactive metabolites, including kynurenines, and in some animals, NAD+. Aging and inflammation are associated with increased levels of kynurenine pathway (KP) metabolites and depleted NAD+, factors which are implicated as contributors to frailty and morbidity. Contrastingly, KP suppression and NAD+ supplementation are associated with increased life span in some animals. Here, we used DGRP_229 Drosophila to elucidate the effects of KP elevation, KP suppression, and NAD+ supplementation on physical performance and survivorship. Flies were chronically fed kynurenines, KP inhibitors, NAD+ precursors, or a combination of KP inhibitors with NAD+ precursors. Flies with elevated kynurenines had reduced climbing speed, endurance, and life span. Treatment with a combination of KP inhibitors and NAD+ precursors preserved physical function and synergistically increased maximum life span. We conclude that KP flux can regulate health span and life span in Drosophila and that targeting KP and NAD+ metabolism can synergistically increase life span.

Perception versus reality: analysis of time spent on bedside rounds in an academic ICU (Intensive Care Unit).

BACKGROUND: Despite its importance, teaching at the bedside is declining over time. This purported decline has not been quantified. Quantifying bedside teaching is challenging, and we found only one study quantifying bedside teaching on a hospitalist service. OBJECTIVE: We conducted a study to understand the prevalence of bedside teaching in our medical intensive care unit. METHODS: We conducted a single-center single-unit study in the medical intensive care unit of an academic tertiary care institution. We used a survey tool to assess perceived time spent on bedside teaching, quality of teaching, and total rounding time. In parallel, independent observers objectively measured time spent on rounds and on bedside teaching. Residents were asked to complete the survey once a week. Independent observers collected data daily and weekly averages were obtained. RESULTS: 43 responses were collected over a 4-month period. Most respondents (73%) reported a total rounding time of either 90-120 min or greater than 120 min. Median reported bedside teaching time was 16-20 min with 16 respondents (37%) reporting less than 15 min and 27 respondents (63%) reporting 16 min or more. The amount of time spent on bedside teaching was reported as adequate or more than adequate by 77% (33) of respondents with 58% (25) reporting that bedside teaching was very or extremely effective in helping them learn. Mean census reported by the independent observers was 12.75 patients per team. Bedside teaching represented an average of 12% of total rounding time, 16.85 min per day. While total rounding time increased with increasing census, there was no decline in bedside teaching time. CONCLUSION: It is reported that bedside teaching has decreased over time. Our study has demonstrated that bedside teaching occurs in our Medical ICU, and though it represents a minority of the time spent on rounds, residents still reported teaching in the ICU to be adequate.

High incidence of barotrauma in patients admitted with COVID-19 to ICU and associated mortality in rural Appalachia: An observational study.

OBJECTIVES: To assess the incidence of barotrauma and its impact on mortality in COVID-19 patients admitted to ICU. DESIGN: Single-center retrospective study of consecutive COVID-19 patients admitted to a rural tertiary-care ICU. The primary outcomes were incidence of barotrauma in COVID-19 patients and all-cause 30-day mortality. Secondary outcomes were the length of stay (LOS) in the hospital and ICU. Kaplan-Meier method and log-rank test were used in the survival data analysis. SETTING: Medical ICU, West Virginia University Hospital (WVUH), USA. PATIENTS: All adult patients were admitted to the ICU for acute hypoxic respiratory failure due to coronavirus disease 2019 between September 1, 2020, and December 31, 2020. Historical controls were ARDS patients admitted pre-COVID. INTERVENTION: Not applicable. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty-five consecutive patients with COVID-19 were admitted to the ICU during the defined period, compared to 39 historical non-COVID controls. The overall incidence of barotrauma in COVID-19 patients was 37/165 (22.4%) compared to 4/39 (10.3%) in the control group. Patients with COVID-19 and barotrauma had a significantly worse survival (HR = 1.56, p = 0.047) compared to controls. In those requiring invasive mechanical ventilation, the COVID group also had significantly higher rates of barotrauma (OR 3.1, p = 0.03) and worse all-cause mortality (OR 2.21, p = 0.018). COVID-19 with barotrauma had significantly higher LOS in the ICU and the hospital. CONCLUSIONS: Our data on critically ill COVID-19 patients admitted to the ICU shows a high incidence of barotrauma and mortality compared to the controls. Additionally, we report a high incidence of barotrauma even in non-ventilated ICU patients.

Polygenic risk score improves the accuracy of a clinical risk score for coronary artery disease.

BACKGROUND: The value of polygenic risk scores (PRSs) towards improving guideline-recommended clinical risk models for coronary artery disease (CAD) prediction is controversial. Here we examine whether an integrated polygenic risk score improves the prediction of CAD beyond pooled cohort equations.  METHODS: An observation study of 291,305 unrelated White British UK Biobank participants enrolled from 2006 to 2010 was conducted. A case-control sample of 9499 prevalent CAD cases and an equal number of randomly selected controls was used for tuning and integrating of the polygenic risk scores. A separate cohort of 272,307 individuals (with follow-up to 2020) was used to examine the risk prediction performance of pooled cohort equations, integrated polygenic risk score, and PRS-enhanced pooled cohort equation for incident CAD cases. The performance of each model was analyzed by discrimination and risk reclassification using a 7.5% threshold. RESULTS: In the cohort of 272,307 individuals (mean age, 56.7 years) used to analyze predictive accuracy, there were 7036 incident CAD cases over a 12-year follow-up period. Model discrimination was tested for integrated polygenic risk score, pooled cohort equation, and PRS-enhanced pooled cohort equation with reported C-statistics of 0.640 (95% CI, 0.634-0.646), 0.718 (95% CI, 0.713-0.723), and 0.753 (95% CI, 0.748-0.758), respectively. Risk reclassification for the addition of the integrated polygenic risk score to the pooled cohort equation at a 7.5% risk threshold resulted in a net reclassification improvement of 0.117 (95% CI, 0.102 to 0.129) for cases and - 0.023 (95% CI, - 0.025 to - 0.022) for noncases [overall: 0.093 (95% CI, 0.08 to 0.104)]. For incident CAD cases, this represented 14.2% correctly reclassified to the higher-risk category and 2.6% incorrectly reclassified to the lower-risk category. CONCLUSIONS: Addition of the integrated polygenic risk score for CAD to the pooled cohort questions improves the predictive accuracy for incident CAD and clinical risk classification in the White British from the UK Biobank. These findings suggest that an integrated polygenic risk score may enhance CAD risk prediction and screening in the White British population.

Interstitial lung abnormalities and interstitial lung diseases associated with cigarette smoking in a rural cohort undergoing surgical resection.

BACKGROUND: Cigarette smoking is a risk factor for interstitial lung abnormalities (ILAs) and interstitial lung diseases (ILDs). Investigation defining the relationships between ILAs/ILDs and clinical, radiographic, and pathologic findings in smokers have been incomplete. Employing a cohort undergoing surgical resection for lung nodules/masses, we (1) define the prevalence of ILAs/ILDs, (2) delineate their clinical, radiographic and pathologic predictors, and (3) determine their associations with mortality. METHODS: Patients undergoing resection of lung nodules/masses between 2017 and 2020 at a rural Appalachian, tertiary medical center were retrospectively investigated. Predictors for ILAs/ILDs and mortality were assessed using multivariate logistic regression analysis. RESULTS: In the total study cohort of 352 patients, radiographic ILAs and ILDs were observed in 35.2% and 17.6%, respectively. Among ILA patterns, subpleural reticular changes (14.8%), non-emphysematous cysts, centrilobular (CL) ground glass opacities (GGOs) (8% each), and mixed CL-GGO and subpleural reticular changes (7.4%) were common. ILD patterns included combined pulmonary fibrosis emphysema (CPFE) (3.1%), respiratory bronchiolitis (RB)-ILD (3.1%), organizing pneumonitis (2.8%) and unclassifiable (4.8%). The group with radiographic ILAs/ILDs had a significantly higher proportion of ever smokers (49% vs. 39.9%), pack years of smoking (44.57 ± 36.21 vs. 34.96 ± 26.22), clinical comorbidities of COPD (35% vs. 26.5%) and mildly reduced diffusion capacity (% predicated 66.29 ± 20.55 vs. 71.84 ± 23). Radiographic centrilobular and paraseptal emphysema (40% vs. 22.2% and 17.6% vs. 9.6%, respectively) and isolated traction bronchiectasis (10.2% vs. 4.2%) were associated with ILAs/ILDs. Pathological variables of emphysema (34.9% vs. 18.5%), any fibrosis (15.9% vs. 4.6%), peribronchiolar metaplasia (PBM, 8% vs. 1.1%), RB (10.3% vs. 2.5%), and anthracosis (21.6% vs. 14.5%) were associated with ILAs/ILDs. Histologic emphysema showed positive correlations with any fibrosis, RB, anthracosis and ≥ 30 pack year of smoking. The group with ILAs/ILDs had significantly higher mortality (9.1% vs. 2.2%, OR 4.13, [95% CI of 1.84-9.25]). CONCLUSIONS: In a rural cohort undergoing surgical resection, radiographic subclinical ILAs/ILDs patterns were highly prevalent and associated with ever smoking and intensity of smoking. The presence of radiographic ILA/ILD patterns and isolated honeycomb changes were associated with increased mortality. Subclinical ILAs/ILDs and histologic fibrosis correlated with clinical COPD as well as radiographic and pathologic emphysema emphasizing the co-existence of these pulmonary injuries in a heavily smoking population.

Pre-existing cardiovascular disease increases risk of atrial arrhythmia and mortality in cancer patients treated with Ibrutinib.

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase inhibitor used in the treatment of hematological malignancies. The most common cardiotoxicity associated with ibrutinib is atrial arrhythmia (atrial fibrillation and flutter). It is known that patients with cardiovascular disease (CVD) are at an increased risk for developing atrial arrhythmia. However, the rate of atrial arrhythmia in patients with pre-existing CVD treated with ibrutinib is unknown. OBJECTIVE: This study examined whether patients with pre-existing CVD are at a higher risk for developing atrial arrhythmias compared to those without prior CVD. METHODS: A single-institution retrospective chart review of patients with no prior history of atrial arrhythmia treated with ibrutinib from 2012 to 2020 was performed. Patients were grouped into two cohorts: those with CVD (known history of coronary artery disease, heart failure, pulmonary hypertension, at least moderate valvular heart disease, or device implantation) and those without CVD. The primary outcome was incidence of atrial arrhythmia, and the secondary outcomes were all-cause mortality, risk of bleeding, and discontinuation of ibrutinib. The predictors of atrial arrhythmia (namely atrial fibrillation) were assessed using logistic regression. A Cox-Proportional Hazard model was created for mortality. RESULTS: Patients were followed for a median of 1.1 years. Among 217 patients treated with ibrutinib, the rate of new-onset atrial arrhythmia was nearly threefold higher in the cohort with CVD compared to the cohort without CVD (17% vs 7%, p = 0.02). Patients with CVD also demonstrated increased adjusted all-cause mortality (OR 1.9, 95% CI 1.06-3.41, p = 0.01) and decreased survival probability (43% vs 54%, p = 0.04) compared to those without CVD over the follow-up period. There were no differences in risk of bleeding or discontinuation between the two cohorts. CONCLUSIONS: Pre-existing cardiovascular disease was associated with significantly higher rates of atrial arrhythmia and mortality in patients with hematological malignancies managed with ibrutinib.

Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data: a multi-phased study of prostate cancer.

BACKGROUND: DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. METHODS: Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. RESULTS: Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. CONCLUSIONS: We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

A general diversity oriented synthesis of asymmetric double-decker shaped silsesquioxanes.

A strategically novel synthesis of nano-sized, asymmetrically functionalized double-decker shaped silsesquioxanes (DDSQ) is reported. Selective protection with a boronic acid affords the crucial mono-protected intermediate en route to the asymmetric products. Generation of symmetric by-products is minimized by judicious choice of base, and high recovery of recyclable starting DDSQ tetraol is achieved.

Prediction of symptom improvement in children with biliary dyskinesia.

BACKGROUND: Rates of cholecystectomy for biliary dyskinesia are rising. Our objective was to identify clinical determinants of symptom improvement in children undergoing cholecystectomy for biliary dyskinesia. METHODS: This retrospective cohort study included patients undergoing cholecystectomy for biliary dyskinesia from 2006-2013 who had their gallbladder ejection fraction (EF) measured by either cholecystokinin-stimulated hepatobiliary iminodiacetic acid scan and/or fatty meal ultrasound. Patients presenting from 2010-2013 were interviewed >1 y after cholecystectomy to determine symptom improvement, complete symptom resolution, and any postoperative clinical interventions related to biliary dyskinesia. Sensitivity and positive predictive values for the diagnostic tests for symptom improvement were calculated. Multivariable logistic regression models were used to identify preoperative characteristics associated with symptom improvement. RESULTS: Of the 153 included patients, 76% were female, 89% were Caucasian, and 39% were obese. At postoperative evaluation, symptom improvement was reported by 82% of the patients and complete symptom resolution in 56%. For both the hepatobiliary iminodiacetic acid and fatty meal ultrasound, the sensitivity of the test to predict symptom improvement increased with higher EF, whereas the positive predictive values remained around 80%. Of the 41 patients who participated in phone interview for long-term follow-up, 85% reported symptom improvement and 44% reported complete symptom resolution. Factors associated with symptom improvement included a shorter duration of pain, a history of vomiting, and a history of epigastric pain. CONCLUSIONS: Despite not identifying an EF level that predicted symptom improvement, over 80% of patients undergoing cholecystectomy for biliary dyskinesia reported symptom improvement. These results support continuing to offer cholecystectomy to treat biliary dyskinesia in children.

The Stout prosthesis: an alternate means of restoring speech in selected laryngectomy patients.

We discuss the effectiveness of the Stout prosthesis, a device that was developed more than 30 years ago to restore speech in postlaryngectomy patients. This prosthesis has not been previously described in the literature. The placement of this device entails the creation of a pharyngeal cutaneous fistula that extends to the musculature at the base of the tongue. The prosthesis is then used to connect the fistula and the stoma. Central to this discussion was our evaluation of a patient who had used the Stout prosthesis for 30 years. In this patient, the prosthesis produced excellent long-term voice production with minimal leakage of saliva or other liquids. We conclude that in light of the device's simplicity, low cost, and minimal maintenance requirements with regard to the fistula site, the Stout prosthesis should be considered as an alternative to the standard tracheosophageal puncture method for patients who are unable to comply with the latter's maintenance requirements and for those in poorly developed countries where costs and hygiene are paramount considerations. Moreover, because the Stout technique does not involve the esophagus and does not require invasive procedures around the stoma, it is also practical for patients who have esophageal rigidity or stomal problems.