Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial.

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown. METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes. RESULTS: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001). CONCLUSIONS: Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.).

High-Throughput Screening and Proteomic Characterization of Compounds Targeting Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population of incompletely differentiated immune cells. They are known to suppress T cell activity and are implicated in multiple chronic diseases, which make them an attractive cell population for drug discovery. Here, we characterized the baseline proteomes and phospho-proteomes of mouse MDSC differentiated from a progenitor cell line to a depth of 7000 proteins and phosphorylation sites. We also validated the cellular system for drug discovery by recapitulating and identifying known and novel molecular responses to the well-studied MDSC drugs entinostat and mocetinostat. We established a high-throughput drug screening platform using a MDSC/T cell coculture system and assessed the effects of ∼21,000 small molecule compounds on T cell proliferation and IFN-γ secretion to identify novel MDSC modulator. The most promising candidates were validated in a human MDSC system, and subsequent proteomic experiments showed significant upregulation of several proteins associated with the reduction of reactive oxygen species (ROS). Proteome-wide solvent-induced protein stability assays identified Acyp1 and Cd74 as potential targets, and the ROS-reducing drug phenotype was validated by measuring ROS levels in cells in response to compound, suggesting a potential mode of action. We anticipate that the data and chemical tools developed in this study will be valuable for further research on MDSC and related drug discovery.

Reimagining Ambulatory Care in Urology: Conversion of the Urology Clinic into a Procedure Center Improves Patient's Experience.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic made it necessary to practice social distancing and limited in-person encounters in health care. These restrictions created alternative opportunities to enhance patient access to care in the ambulatory setting. We hypothesized that by transforming clinics into centers that prioritize procedures and transitioning ambulatory appointments to telehealth, we could establish a secure, streamlined, and productive method for providing patient care. Methods: Clinic templates were restructured to allow the use of the physical space to perform procedure-based clinics exclusively, while switching to virtual telemedicine for all nonprocedural encounters. Staff members were given specific roles to support one of the patient care modalities for a given day (Procedures vs. Telehealth). Performance and patient satisfaction metrics were collected between two periods of time defined as P1 (February-June 2019) and P2 Post-COVID (February-June 2020) and compared. These served as proxies of periods when the clinic workflow and templates were structured in the traditional versus the emerging way. Statistical analysis was performed using bivariate analyses. Results: The percentage of procedures performed among all in-person visits were higher in P2 compared to P1 (45% vs. 29%, p < 0.001). Although total charges and relative value units were lower in P2, the overall revenue generated was higher compared to P1 ($4,597,846 vs. $4,517,427$, respectively). This increase in revenue was mainly driven by the higher relative income generated by procedures. Patient experience, reflected through patient-reported outcomes, was more favorable in P2 where patients seemed more likely to "Recommend this provider office" (90% vs. 85.7%, p = 0.01), report improved "Access overall" (56% vs. 49%, p = 0.02), and felt they were "Moving through your visit overall" (59% vs. 51%, p = 0.007). Conclusions: Our data suggest that reorganizing urology clinics into a space that is centered around outpatient procedures can represent a model that improves the patient's access to care and clinical experience, while simultaneously improving operational financial strength. This efficient care model could be considered for many practice settings and drive high-value outpatient care.

Specific human leucocyte antigen-DQ risk epitope mismatches are associated with chronic lung allograft dysfunction after lung transplantation.

A high-risk epitope mismatch (REM) (found in DQA1∗05 + DQB1∗02/DQB1∗03:01) is associated with de novo donor specific antibodies after lung transplantation (LTx). Chronic lung allograft dysfunction (CLAD) remains a barrier to LTx survival. This study aimed to measure the association between DQ REM and the risk of CLAD and death after LTx. A retrospective analysis of LTx recipients at a single center was conducted between January 2014 and April 2019. Molecular typing at human leucocyte antigen-DQA/DQB identified DQ REM. Multivariable competing risk and Cox regression models were used to measure the association between DQ REM, time-to-CLAD, and time-to-death. DQ REM was detected in 96/268 (35.8%), and DQ REM de novo donor specific antibodies were detected in 34/96 (35.4%). CLAD occurred in 78 (29.1%), and 98 (36.6%) recipients died during follow-up. When analyzed as a baseline predictor, DQ REM status was associated with CLAD (subdistribution hazard ratio (SHR), 2.19; 95% confidence interval [CI], 1.40-3.43; P = .001). After adjustment for time-dependent variables, DQ REM dn-DSA (SHR, 2.43; 95% CI, 1.10-5.38; P = .029) and A-grade rejection score (SHR, 1.22; 95% CI, 1.11-1.35; P = <.001), DQ REM status was not independently associated with CLAD. DQ REM was not associated with death (hazard ratio, 1.18; 95% CI, 0.72-1.93; P = .51). Classification of DQ REM may identify patients at risk of poor outcomes and should be incorporated into clinical decision-making.

Plasma formation in holmium:YAG laser lithotripsy.

OBJECTIVES: During holmium:yttrium-aluminum-garnet (holmium:YAG) laser lithotripsy to break urinary stones, urologists frequently see flashes of light. As infrared laser pulses are invisible, what is the source of light? Here we studied the origin, characteristics, and some effects of flashes of light in laser lithotripsy. METHODS: Ultrahigh-speed video-microscopy was used to record single laser pulses at 0.2-1.0 J energy lasered with 242 µm glass-core-diameter fibers in contact with whole surgically retrieved urinary stones and hydroxyapatite (HA)-coated glass slides in air and water. Acoustic transients were measured with a hydrophone. Visible-light and infrared photodetectors resolved temporal profiles of visible-light emission and infrared-laser pulses. RESULTS: Temporal profiles of laser pulses showed intensity spikes of various duration and amplitude. The pulses were seen to produce dim light and bright sparks with submicrosecond risetime. The spark produced by the intensity spike at the beginning of laser pulse generated a shock wave in the surrounding liquid. The subsequent sparks were in a vapor bubble and generated no shock waves. Sparks enhanced absorption of laser radiation, indicative of plasma formation and optical breakdown. The occurrence and number of sparks varied even with the same urinary stone. Sparks were consistently observed at laser energy >0.5 J with HA-coated glass slides. The slides broke or cracked by cavitation with sparks in 63 ± 15% of pulses (1.0 J, N = 60). No glass-slide breakage occurred without sparks (1.0 J, N = 500). CONCLUSION: Unappreciated in previous studies, plasma formation with free-running long-pulse holmium:YAG lasers can be an additional physical mechanism of action in laser procedures.

Clinical and postoperative characteristics of stentless ureteroscopy patients: a prospective analysis from ReSKU.

INTRODUCTION: To evaluate the clinical characteristics as well as the postoperative course of urolithiasis patients undergoing a ureteroscopy (URS) without stent placement. MATERIALS AND METHODS: This was a prospective case cohort study utilizing data collected in the Registry for Stones of the Kidney and Ureter (ReSKU) from a single institution between October 2015 and December 2020. We identified all consecutive patients undergoing URS for stone disease and analyzed data encompassing demographics, medical history, intra and postoperative characteristics, including complications and postoperative symptoms. Univariate and multivariate logistic regression analyses were performed based on the presence or absence of an indwelling ureteral stent. RESULTS: A total of 470 patients were included for analysis, 92 patients in the stentless group (19.5%). Factors associated with stentless ureteroscopy were a lower stone burden (p < 0.001), the pre-existence of a ureteral stent (37.4% vs. 27.9% p = 0.011), absence of an access sheath (14.6% vs. 69.5% p < 0.001), and a shorter operative time (31 vs. 58 min p < 0.001). Postoperative gross hematuria and lower urinary tract symptoms (LUTS) were reported less frequently in stentless patients (p = 0.02, p = 0.01, respectively). There was no difference in postoperative complications between both groups (15.2% vs. 12.0%, p = 0.385). On multivariate analysis, the risk of postoperative complications was associated with obesity, stone burden ≥ 1 cm, and positive preoperative urine culture. There was no patient who required emergent stent placement in the stentless group. CONCLUSION: Our data show that, in well selected patients, omitting ureteral stent placement after URS can decrease postoperative gross hematuria and LUTS without increasing postoperative complications.

Evaluation of the national governmental efforts between 1997 and 2010 in reducing health inequalities in England.

OBJECTIVES: The pandemic has compounded existing inequalities. In the UK, there have been calls for a new cross-government health inequalities strategy. This study aims to evaluate the effectiveness of national governmental efforts between 1997 and 2010, referred to as the National Health Inequalities Strategy (NHIS). STUDY DESIGN: population-based observational study. METHODS: Using Global Burden of Disease data, age-standardised years of life lost due to premature mortality (YLL) rates per 10,000 were extracted for 150 Upper Tier Local Authority (UTLA) regions in England for every year between 1990 and 2019. The slope index of inequality was calculated using YLL rates for all causes, individual conditions, and risk factors. Joinpoint regression was used to assess the trends of any changes which arose before, during or after the NHIS. RESULTS: Absolute inequalities in YLL rates for all causes remained stable between 1990 and 2000, before decreasing over the following 10 years. After 2010, improvements slowed. A similar trend can be observed amongst inequalities in YLLs for individual causes, including ischaemic heart disease, stroke, breast cancer and lung cancer amongst females, and ischaemic heart disease stroke, diabetes and self-harm amongst males. This trend was also observed amongst certain risk factors, notably blood pressure, cholesterol, tobacco and dietary risks. Inequalities were generally greater in males than in females; however, trends were similar across both sexes. The NHIS coincided with significant reductions in inequalities in YLLs due to ischaemic heart disease and lung cancer. CONCLUSIONS: The findings suggest that the NHIS coincided with a reduction in health inequalities in England. Policy makers should consider a new cross-government strategy to tackle health inequalities drawing from the success of the previous NHIS.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster.

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.

National Variation in Congenital Heart Surgery Outcomes.

BACKGROUND: Optimal strategies to improve national congenital heart surgery outcomes and reduce variability across hospitals remain unclear. Many policy and quality improvement efforts have focused primarily on higher-risk patients and mortality alone. Improving our understanding of both morbidity and mortality and current variation across the spectrum of complexity would better inform future efforts. METHODS: Hospitals participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2014-2017) were included. Case mix-adjusted operative mortality, major complications, and postoperative length of stay were evaluated using Bayesian models. Hospital variation was quantified by the interdecile ratio (IDR, upper versus lower 10%) and 95% credible intervals (CrIs). Stratified analyses were performed by risk group (Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery [STAT] category) and simulations evaluated the potential impact of reductions in variation. RESULTS: A total of 102 hospitals (n=84 407) were included, representing ≈85% of US congenital heart programs. STAT category 1 to 3 (lower risk) operations comprised 74% of cases. All outcomes varied significantly across hospitals: adjusted mortality by 3-fold (upper versus lower decile 5.0% versus 1.6%, IDR 3.1 [95% CrI 2.5-3.7]), mean length of stay by 1.8-fold (19.2 versus 10.5 days, IDR 1.8 [95% CrI 1.8-1.9]), and major complications by >3-fold (23.5% versus 7.0%, IDR 3.4 [95% CrI 3.0-3.8]). The degree of variation was similar or greater for low- versus high-risk cases across outcomes, eg, ≈3-fold mortality variation across hospitals for STAT 1 to 3 (IDR 3.0 [95% CrI 2.1-4.2]) and STAT 4 or 5 (IDR 3.1 [95% CrI 2.4-3.9]) cases. High-volume hospitals had less variability across outcomes and risk categories. Simulations suggested potential reductions in deaths (n=282), major complications (n=1539), and length of stay (101 183 days) over the 4-year study period if all hospitals were to perform at the current median or better, with 37% to 60% of the improvement related to the STAT 1 to 3 (lower risk) group across outcomes. CONCLUSIONS: We demonstrate significant hospital variation in morbidity and mortality after congenital heart surgery. Contrary to traditional thinking, a substantial portion of potential improvements that could be realized on a national scale were related to variability among lower-risk cases. These findings suggest modifications to our current approaches to optimize care and outcomes in this population are needed.

Integration of a vertebral fracture identification service into a fracture liaison service: a quality improvement project.

Integration of a vertebral fracture identification service into a Fracture Liaison Service is possible. Almost one-fifth of computerised tomography scans performed identified an individual with a fracture. This increase in workload needs to be considered by any FLS that wants to utilise such a service. INTRODUCTION: This service improvement project aimed to improve detection of incidental vertebral fractures on routine imaging. It embedded a vertebral fracture identification service (Optasia Medical, OM) on routine computerised tomography (CT) scans performed in this hospital as part of its Fracture Liaison Service (FLS). METHODS: The service was integrated into the hospital's CT workstream. Scans of patients aged ≥ 50 years for 3 months were prospectively retrieved, alongside their clinical history and the CT report. Fractures were identified via OM's machine learning algorithm and cross-checked by the OM radiologist. Fractures identified were then added as an addendum to the original CT report and the hospital FLS informed. The FLS made recommendations based on an agreed algorithm. RESULTS: In total, 4461 patients with CT scans were retrieved over the 3-month period of which 850 patients had vertebra fractures identified (19.1%). Only 49% had the fractures described on hospital radiology report. On average, 61 patients were identified each week with a median of two fractures. Thirty-six percent were identified by the FLS for further action and recommendations were made to either primary care or the community osteoporosis team within 3 months of fracture detection. Of the 64% not identified for further action, almost half was because the CT was part of cancer assessment or treatment. The remaining were due to a combination of only ≤ 2 mild fractures; already known to a bone health specialist; in the terminal stages of any chronic illness; significant dependency for activities of daily living; or a life expectancy of less than 12 months CONCLUSION: It was feasible to integrate a commercial vertebral fracture identification service into the daily working of a FLS. There was a significant increase in workload which needs to be considered by any future FLS planning to incorporate such a service into their clinical practice.

Watching others in a positive state does not induce optimism bias in common marmosets (Callithrix jacchus), but leads to behaviour indicative of competition.

Emotional contagion is suggested to facilitate group life by enhancing synchronized responses to the environment. Cooperative breeders are an example of a social system that requires such intricate coordination between individuals. Therefore, we studied emotional contagion in common marmosets by means of a judgement bias test. Demonstrators were exposed to an emotion manipulation (i.e., positive, negative, control), and observers perceived only the demonstrator's behaviour. We predicted that the positive or negative states of the demonstrator would induce matching states in the observer, indicating emotional contagion. All subjects' emotional states were assessed through behaviour and cognition, the latter by means of a judgement bias test. Behavioural results showed a successful emotion manipulation of demonstrators, with manipulation-congruent expressions (i.e., positive calls in the positive condition, and negative calls and pilo-erect tail in the negative condition). Observers showed no manipulation-congruent expressions, but showed more scratching and arousal after the positive manipulation. Concerning the judgement bias test, we predicted that subjects in a positive state should increase their response to ambiguous cues (i.e., optimism bias), and subjects in a negative state should decrease their response (i.e., pessimism bias). This prediction was not supported as neither demonstrators nor observers showed such bias in either manipulation. Yet, demonstrators showed an increased response to the near-positive cue, and additional analyses showed unexpected responses to the reference cues, as well as a researcher identity effect. We discuss all results combined, including recently raised validation concerns of the judgement bias test, and inherent challenges to empirically studying emotional contagion.

Intraoperative Methadone Use in Cardiac Surgery: A Systematic Review.

OBJECTIVE: To investigate the effects of intraoperative methadone in comparison with those of standard-of-care intraoperative opioids, such as fentanyl and morphine, on pain scores, opioid consumption, and adverse effects in adults undergoing cardiothoracic surgery. METHODS: The literature was reviewed in PubMed, Embase, Cochrane Library, and Google Scholar, followed by a manual search of the reference lists of the identified articles. Search terms included a combination of "intraoperative methadone," "methadone," and "cardiac surgery." Our review includes four studies published between 2011 and 2020. Quality assessment of the studies was performed. RESULTS: The initial search identified 715 articles, from which 461 duplicates were removed and 236 were eliminated on the basis of inclusion and exclusion criteria. Eighteen articles underwent full-text review. Four studies evaluating a total of 435 patients with various cardiothoracic procedures were included in this review. We found that intraoperative methadone decreased acute postoperative pain and reduced postoperative opioid consumption in the first 24 postoperative hours in patients who received 0.1-0.3 mg/kg intraoperative methadone in comparison with morphine and fentanyl. No difference was found in adverse effects between the groups. Quality assessment of the studies showed a low risk of bias in three of the randomized controlled trials and a high risk of bias in the retrospective review because of the baseline confounding bias in the study design. CONCLUSIONS: Intraoperative methadone use reduces acute postoperative pain and lowers opioid consumption in comparison with morphine and fentanyl. Initial results suggest that methadone may be an equivalent opioid to be administered during cardiothoracic procedures to reduce acute postsurgical pain, though further research is warranted.

Postoperative Hematocrit and Adverse Outcomes in Pediatric Cardiac Surgery Patients: A Cross-Sectional Study From the Society of Thoracic Surgeons and Congenital Cardiac Anesthesia Society Database Collaboration.

BACKGROUND: We sought to examine potential associations between pediatric postcardiac surgical hematocrit values and postoperative complications or mortality. METHODS: A retrospective, cross-sectional study from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) and Congenital Cardiac Anesthesia Society Database Module (2014-2019) was completed. Multivariable logistic regression models, adjusting for covariates in the STS-CHSD mortality risk model, were used to assess the relationship between postoperative hematocrit and the primary outcomes of operative mortality or any major complication. Hematocrit was assessed as a continuous variable using linear splines to account for nonlinear relationships with outcomes. Operations after which the oxygen saturation is typically observed to be <92% were classified as cyanotic and ≥92% as acyanotic. RESULTS: In total, 27,462 index operations were included, with 4909 (17.9%) being cyanotic and 22,553 (82.1%) acyanotic. For cyanotic patients, each 5% incremental increase in hematocrit over 42% was associated with a 1.31-fold (95% confidence interval [CI], 1.10-1.55; P = .003) increase in the odds of operative mortality and a 1.22-fold (95% CI, 1.10-1.36; P < .001) increase in the odds of a major complication. For acyanotic patients, each 5% incremental increase in hematocrit >38% was associated with a 1.45-fold (95% CI, 1.28-1.65; P < .001) increase in the odds of operative mortality and a 1.21-fold (95% CI, 1.14-1.29; P < .001) increase in the odds of a major complication. CONCLUSIONS: High hematocrit on arrival to the intensive care unit (ICU) is associated with increased operative mortality and major complications in pediatric patients following cardiac surgery.

Improving the prediction of long-term readmission and mortality using a novel biomarker panel.

OBJECTIVE: Several short-term readmission and mortality prediction models have been developed using clinical risk factors or biomarkers among patients undergoing coronary artery bypass graft (CABG) surgery. The use of biomarkers for long-term prediction of readmission and mortality is less well understood. Given the established association of cardiac biomarkers with short-term adverse outcomes, we hypothesized that 5-year prediction of readmission or mortality may be significantly improved using cardiac biomarkers. MATERIALS AND METHODS: Plasma biomarkers from 1149 patients discharged alive after isolated CABG surgery from eight medical centers were measured in a cohort from the Northern New England Cardiovascular Disease Study Group between 2004 and 2007. We assessed the added predictive value of a biomarker panel with a clinical model against the clinical model alone and compared the model discrimination using the area under the receiver operating characteristic (AUROC) curves. RESULTS: In our cohort, 461 (40%) patients were readmitted or died within 5 years. Long-term outcomes were predicted by applying the STS ASCERT clinical model with an AUROC of 0.69. The biomarker panel with the clinical model resulted in a significantly improved AUROC of 0.74 (p value <.0001). Across 5 years, the hazard ratio for patients in the second to fifth quintile predicted probabilities from the biomarker augmented STS ASCERT model ranged from 2.2 to 7.9 (p values <.001). CONCLUSIONS: We report that a panel of biomarkers significantly improved prediction of long-term readmission or mortality risk following CABG surgery. Our findings suggest biomarkers help clinical care teams better assess the long-term risk of readmission or mortality.

Fatty acid-binding protein 4 downregulation drives calcification in the development of kidney stone disease.

Nephrolithiasis is a significant source of morbidity, and its incidence has increased significantly over the last decades. This rise has been attributed to concurrent increasing rates of obesity, associated with a 3-time risk of developing NL. To date, the mechanism by which obesity is linked to stone formation has not been elucidated. We aimed to utilize a transcriptomics approach to discover the missing link between these two epidemic diseases. We investigated gene expression profiling of nephrolithiasis patients by two RNA-sequencing approaches: comparison between renal papilla tissue with and without the presence of calcified Randall's plaques (RP), and comparison between the papilla, medulla, and cortex regions from within a single recurrent stone forming kidney. Results were overlaid between differently expressed genes found in the patient cohort and in the severely lithogenic kidney to identify common genes. Overlay of these two RNA-sequencing datasets demonstrated there is impairment of lipid metabolism in renal papilla tissue containing RP linked to downregulation of fatty acid binding protein (FABP) 4. Immunohistochemistry of human kidney specimens and microarray analysis of renal tissue from a nephrolithiasis mouse model confirmed that FABP4 downregulation is associated with renal stone formation. In a FABP4 knockout mouse model, FABP4 deficiency resulted in development of both renal and urinary crystals. Our study revealed that FABP4 plays an important, previously unrecognized role in kidney stone formation, providing a feasible mechanism to explain the link between nephrolithiasis and metabolic syndrome.

Associations between anthropometric indices and outcomes of congenital heart operations in infants and young children: An analysis of data from the Society of Thoracic Surgeons Database.

BACKGROUND: Children with congenital heart disease are at risk for growth failure due to inadequate nutrient intake and increased metabolic demands. We examined the relationship between anthropometric indices of nutrition (height-for-age z-score [HAZ], weight-for-age z-score [WAZ], weight-for-height z-score [WHZ]) and outcomes in a large sample of children undergoing surgery for congenital heart disease. METHODS: Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database having index cardiac surgery at age 1 month to 10 years were included. Indices were calculated by comparing patients' weight and height to population norms from the World Health Organization and Centers for Disease Control and Prevention. Outcomes included operative mortality, composite mortality or major complication, major postoperative infection, and postoperative length of stay. For each outcome and index, the adjusted odds ratio (aOR) (for mortality, composite outcome, and infection) and adjusted relative change in median (for postoperative length of stay) for a 1-unit decrease in index were estimated using mixed-effects logistic and log-linear regression models. RESULTS: Every unit decrease in HAZ was associated with 1.40 aOR of mortality (95% CI 1.32-1.48), and every unit decrease in WAZ was associated with 1.33 aOR for mortality (95% CI 1.25-1.41). The relationship between WHZ and outcome was nonlinear, with aOR of mortality of 0.84 (95% CI 0.76-0.93) for 1-unit decrease when WHZ ≥ 0 and a nonsignificant association for WHZ < 0. Trends for other outcomes were similar. Overall, the incidence of low nutritional indices was similar for 1-ventricle and 2-ventricle patients. Children between the age of 1 month and 1 year and those with lesions associated with pulmonary overcirculation had the highest incidence of low nutritional indices. CONCLUSIONS: Lower HAZ and WAZ, suggestive of malnutrition, are associated with increased mortality and other adverse outcomes after cardiac surgery in infants and young children. Higher WHZ over zero, suggestive of obesity, is also associated with adverse outcomes.

Overcoming underpowering: Trial simulations and a global rank end point to optimize clinical trials in children with heart disease.

BACKGROUND: Randomized controlled trials (RCTs) in children with heart disease are challenging and therefore infrequently performed. We sought to improve feasibility of perioperative RCTs for this patient cohort using data from a large, multicenter clinical registry. We evaluated potential enrollment and end point frequencies for various inclusion cohorts and developed a novel global rank trial end point. We then performed trial simulations to evaluate power gains with the global rank end point and with use of planned covariate adjustment as an analytic strategy. METHODS: Data from the Society of Thoracic Surgery-Congenital Heart Surgery Database (STS-CHSD, 2011-2016) were used to support development of a consensus-based global rank end point and for trial simulations. For Monte Carlo trial simulations (n = 50,000/outcome), we varied the odds of outcomes for treatment versus placebo and evaluated power based on the proportion of trial data sets with a significant outcome (P < .05). RESULTS: The STS-CHSD study cohort included 35,967 infant index cardiopulmonary bypass operations from 103 STS-CHSD centers, including 11,411 (32%) neonatal cases and 12,243 (34%) high-complexity (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category ≥4) cases. In trial simulations, study power was 21% for a mortality-only end point, 47% for a morbidity and mortality composite, and 78% for the global rank end point. With covariate adjustment, power increased to 94%. Planned covariate adjustment was preferable to restricting to higher-risk cohorts despite higher event rates in these cohorts. CONCLUSIONS: Trial simulations can inform trial design. Our findings, including the newly developed global rank end point, may be informative for future perioperative trials in children with heart disease.

Rationale and design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial.

For decades, physicians have administered corticosteroids in the perioperative period to infants undergoing heart surgery with cardiopulmonary bypass (CPB) to reduce the postoperative systemic inflammatory response to CPB. Some question this practice because steroid efficacy has not been conclusively demonstrated and because some studies indicate that steroids could have harmful effects. STRESS is a randomized, placebo-controlled, double-blind, multicenter trial designed to evaluate safety and efficacy of perioperative steroids in infants (age < 1 year) undergoing heart surgery with CPB. Participants (planned enrollment = 1,200) are randomized 1:1 to methylprednisolone (30 mg/kg) administered into the CPB pump prime versus placebo. The trial is nested within the existing infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database. The primary outcome is a global rank score of mortality, major morbidities, and hospital length of stay with components ranked commensurate with their clinical severity. Secondary outcomes include several measures of major postoperative morbidity, postoperative hospital length of stay, and steroid-related safety outcomes including prevalence of hyperglycemia and postoperative infectious complications. STRESS will be one of the largest trials ever conducted in children with heart disease and will answer a decades-old question related to safety and efficacy of perioperative steroids in infants undergoing heart surgery with CPB. The pragmatic "trial within a registry" design may provide a mechanism for conducting low-cost, high-efficiency trials in a heretofore-understudied patient population.

Kyphosis and 3-year fall risk in community-dwelling older men.

Hyperkyhosis is thought to be a fall risk factor in older adults. This large study of older men found that fall risk increased with greater kyphosis measured with the blocks method, but did not find an association between kyphosis and falls when measured by the commonly used the Cobb angle method. INTRODUCTION: Research suggests an association between hyperkyphosis and falls in community-dwelling older adults, though this has not been investigated within large, population-based studies. This study sought to determine whether two measures of kyphosis prospectively predict fall risk over 3 years among older men. METHODS: Within the Osteoporotic Fractures in Men Study (MrOS), we conducted two 3-year prospective studies of 2346 and 2928 men. The first group had kyphosis measured by the Cobb angle at visit 1, while the second group had kyphosis assessed with the blocks method at visit 3; both groups then self-reported falls tri-annually for 3 years. Poisson regression with GEE was used to obtain relative risks (RR) of falls. RESULTS: The fall rates over 3 years were 651/1000 person-years among the visit 1 sample (mean age 74 ± 6 years) and 839/1000 person-years among the visit 3 sample (mean age 79 ± 5 years). In adjusted models of the visit 3 sample, the risk of falls was increased by 12% for each standard deviation increase (1.4 blocks) in the number of blocks required to achieve a neutral head and neck position (RR = 1.12, 95% CI = 1.06, 1.18). The Cobb angle was not associated with falls in the visit 1 sample. CONCLUSIONS: Although the Cobb angle did not predict falls in community-dwelling older men over 3 years, the blocks method of measuring kyphosis was predictive of falls in this population. This difference could be due to the Cobb angle's focus on thoracic kyphosis, whereas the blocks method may additionally capture abnormal cervical spine curvature.