Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.

Rare genetic variants impact muscle strength.

Muscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We show that the exome-wide burden of rare protein-truncating and damaging missense variants is associated with a reduction in hand grip strength. We identify six significant hand grip strength genes, KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, and EIF3J. In the example of the titin (TTN) locus we demonstrate a convergence of rare with common variant association signals and uncover genetic relationships between reduced hand grip strength and disease. Finally, we identify shared mechanisms between brain and muscle function and uncover additive effects between rare and common genetic variation on muscle strength.

The impact of rare protein coding genetic variation on adult cognitive function.

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.

Inconsistent Surgical Implant Documentation: A Case Study in Total Knee and Hip Arthroplasty.

Value-based care initiatives require accurate quantification of resource utilization. This study explores hospital resource documentation performance for total knee and hip arthroplasty (TKA, THA) implants and how this may differ between hospitals. This retrospective study utilized the Premier discharge database, years 2006 to 2020. TKA/THA cases were categorized into 5 tiers based upon the completeness of implant component documentation: Platinum, Gold, Silver, Bronze, Poor. Correlation between TKA and THA documentation performance (per-hospital percentage of Platinum cases) was assessed. Logistic regression analyses measured the association between hospital characteristics (region, teaching status, bed size, urban/rural) and satisfactory documentation. TKA/THA implant documentation performance was compared to documentation for endovascular stent procedures. Individual hospitals tended to have very complete (Platinum) or very incomplete (Poor) documentation for both TKA and THA. TKA and THA documentation performance were correlated (correlation coefficient = .70). Teaching hospitals were less likely to have satisfactory documentation for both TKA (P = .002) and THA (P = .029). Documentation for endovascular stent procedures was superior compared to TKA/THA. Hospitals' TKA and THA-related implant documentation performance is generally either very proficient or very poor, in contrast with often well-documented endovascular stent procedures. Hospital characteristics, other than teaching status, do not appear to impact TKA/THA documentation completeness.

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Identifying and understanding determinants of high healthcare costs for breast cancer: a quantile regression machine learning approach.

BACKGROUND: To identify and rank the importance of key determinants of high medical expenses among breast cancer patients and to understand the underlying effects of these determinants. METHODS: The Oncology Care Model (OCM) developed by the Center for Medicare & Medicaid Innovation were used. The OCM data provided to Mount Sinai on 2938 breast-cancer episodes included both baseline periods and three performance periods between Jan 1, 2012 and Jan 1, 2018. We included 11 variables representing information on treatment, demography and socio-economics status, in addition to episode expenditures. OCM data were collected from participating practices and payers. We applied a principled variable selection algorithm using a flexible tree-based machine learning technique, Quantile Regression Forests. RESULTS: We found that the use of chemotherapy drugs (versus hormonal therapy) and interval of days without chemotherapy predominantly affected medical expenses among high-cost breast cancer patients. The second-tier major determinants were comorbidities and age. Receipt of surgery or radiation, geographically adjusted relative cost and insurance type were also identified as important high-cost drivers. These factors had disproportionally larger effects upon the high-cost patients. CONCLUSIONS: Data-driven machine learning methods provide insights into the underlying web of factors driving up the costs for breast cancer care management. Results from our study may help inform population health management initiatives and allow policymakers to develop tailored interventions to meet the needs of those high-cost patients and to avoid waste of scarce resource.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Estimating cost implications of potentially avoidable hospitalizations among Oncology Care Model patients with prostate cancer.

PURPOSE/OBJECTIVES: We sought to estimate the expected cost savings generated if a set of potentially avoidable hospitalizations (PAHs) among oncology care model (OCM) patients with prostate cancer were shifted to an acute care model in the outpatient setting. METHODS: We previously identified a set of 28 PAHs among OCM prostate cancer patients. Outpatient management costs for a characteristically similar cohort of cancer patients were obtained from our institution's ambulatory acute-care Oncology Care Unit (OCU). We excluded OCU visits resulting in hospitalization, involving non-cancer diagnoses, and those missing clinical/financial information. Exact-matching based on the strata of age, categorically-defined presenting complaint, and systemic disease was used to match PAHs to OCU acute care visits. PAH costs obtained from OCM data were compared to costs from matched OCU visits. RESULTS: We identified 130 acute care OCU visits, of which 47 met inclusion criteria. Twenty-four PAHs (89%) matched to 26 of these OCU visits. PAHs accounted for 5.8% of OCM expenditures during our study period. The mean inpatient cost among matched PAHs was $15,885 compared to $6,227 for matched OCU visits. Boot strapping within each match stratum produced a mean estimated cost savings of $12,151 (95% CI $10,488 to $13,814) per PAH. We estimate this per event savings to yield a 4.4% (95% CI 3.8% to 5.0%) an overall spending decrement for OCM prostate cancer episodes. CONCLUSIONS: PAHs contribute meaningfully to costs of care in oncology. Investment in specialized ambulatory acute care services for oncology patients could lead to substantial cost savings.

Comparison of statistical and machine learning models for healthcare cost data: a simulation study motivated by Oncology Care Model (OCM) data.

BACKGROUND: The Oncology Care Model (OCM) was developed as a payment model to encourage participating practices to provide better-quality care for cancer patients at a lower cost. The risk-adjustment model used in OCM is a Gamma generalized linear model (Gamma GLM) with log-link. The predicted value of expense for the episodes identified for our academic medical center (AMC), based on the model fitted to the national data, did not correlate well with our observed expense. This motivated us to fit the Gamma GLM to our AMC data and compare it with two other flexible modeling methods: Random Forest (RF) and Partially Linear Additive Quantile Regression (PLAQR). We also performed a simulation study to assess comparative performance of these methods and examined the impact of non-linearity and interaction effects, two understudied aspects in the field of cost prediction. METHODS: The simulation was designed with an outcome of cost generated from four distributions: Gamma, Weibull, Log-normal with a heteroscedastic error term, and heavy-tailed. Simulation parameters both similar to and different from OCM data were considered. The performance metrics considered were the root mean square error (RMSE), mean absolute prediction error (MAPE), and cost accuracy (CA). Bootstrap resampling was utilized to estimate the operating characteristics of the performance metrics, which were described by boxplots. RESULTS: RF attained the best performance with lowest RMSE, MAPE, and highest CA for most of the scenarios. When the models were misspecified, their performance was further differentiated. Model performance differed more for non-exponential than exponential outcome distributions. CONCLUSIONS: RF outperformed Gamma GLM and PLAQR in predicting overall and top decile costs. RF demonstrated improved prediction under various scenarios common in healthcare cost modeling. Additionally, RF did not require prespecification of outcome distribution, nonlinearity effect, or interaction terms. Therefore, RF appears to be the best tool to predict average cost. However, when the goal is to estimate extreme expenses, e.g., high cost episodes, the accuracy gained by RF versus its computational costs may need to be considered.

Physical fitness training for stroke patients.

BACKGROUND: Levels of physical activity and physical fitness are low after stroke. Interventions to increase physical fitness could reduce mortality and reduce disability through increased function. OBJECTIVES: The primary objectives of this updated review were to determine whether fitness training after stroke reduces death, death or dependence, and disability. The secondary objectives were to determine the effects of training on adverse events, risk factors, physical fitness, mobility, physical function, health status and quality of life, mood, and cognitive function. SEARCH METHODS: In July 2018 we searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, SPORTDiscus, PsycINFO, and four additional databases. We also searched ongoing trials registers and conference proceedings, screened reference lists, and contacted experts in the field. SELECTION CRITERIA: Randomised trials comparing either cardiorespiratory training or resistance training, or both (mixed training), with usual care, no intervention, or a non-exercise intervention in stroke survivors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed quality and risk of bias, and extracted data. We analysed data using random-effects meta-analyses and assessed the quality of the evidence using the GRADE approach. Diverse outcome measures limited the intended analyses. MAIN RESULTS: We included 75 studies, involving 3017 mostly ambulatory participants, which comprised cardiorespiratory (32 studies, 1631 participants), resistance (20 studies, 779 participants), and mixed training interventions (23 studies, 1207 participants). Death was not influenced by any intervention; risk differences were all 0.00 (low-certainty evidence). There were few deaths overall (19/3017 at end of intervention and 19/1469 at end of follow-up). None of the studies assessed death or dependence as a composite outcome. Disability scores were improved at end of intervention by cardiorespiratory training (standardised mean difference (SMD) 0.52, 95% CI 0.19 to 0.84; 8 studies, 462 participants; P = 0.002; moderate-certainty evidence) and mixed training (SMD 0.23, 95% CI 0.03 to 0.42; 9 studies, 604 participants; P = 0.02; low-certainty evidence). There were too few data to assess the effects of resistance training on disability. Secondary outcomes showed multiple benefits for physical fitness (VO2 peak and strength), mobility (walking speed) and physical function (balance). These physical effects tended to be intervention-specific with the evidence mostly low or moderate certainty. Risk factor data were limited or showed no effects apart from cardiorespiratory fitness (VO2 peak), which increased after cardiorespiratory training (mean difference (MD) 3.40 mL/kg/min, 95% CI 2.98 to 3.83; 9 studies, 438 participants; moderate-certainty evidence). There was no evidence of any serious adverse events. Lack of data prevents conclusions about effects of training on mood, quality of life, and cognition. Lack of data also meant benefits at follow-up (i.e. after training had stopped) were unclear but some mobility benefits did persist. Risk of bias varied across studies but imbalanced amounts of exposure in control and intervention groups was a common issue affecting many comparisons. AUTHORS' CONCLUSIONS: Few deaths overall suggest exercise is a safe intervention but means we cannot determine whether exercise reduces mortality or the chance of death or dependency. Cardiorespiratory training and, to a lesser extent mixed training, reduce disability during or after usual stroke care; this could be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programmes to improve fitness, balance and the speed and capacity of walking. The magnitude of VO2 peak increase after cardiorespiratory training has been suggested to reduce risk of stroke hospitalisation by ˜7%. Cognitive function is under-investigated despite being a key outcome of interest for patients. Further well-designed randomised trials are needed to determine the optimal exercise prescription, the range of benefits and any long-term benefits.

The Isometric Horizontal Push Test: Test-Retest Reliability and Validation Study.

PURPOSE: To investigate the test-retest reliability and criterion validity of the isometric horizontal push test (IHPT), a newly designed test that selectively measures the horizontal component of maximal isometric force. METHODS: Twenty-four active males with ≥3 years of resistance training experience performed 2 testing sessions of the IHPT, separated by 3 to 4 days of rest. In each session, subjects performed 3 maximal trials of the IHPT with 3 minutes of rest between them. The peak force outputs were collected simultaneously using a strain gauge and the criterion equipment consisting of a floor-embedded force plate. RESULTS: The test-retest reliability of peak force values was nearly perfect (intraclass correlation coefficient = ∼.99). Bland-Altman analysis showed excellent agreement between days with nearly no bias for strain gauge 1.2 N (95% confidence interval [CI], -3 to 6 N) and force plate 0.8 N (95% CI, -4 to 6 N). A nearly perfect correlation was observed between the strain gauge and force plate (r = .98, P < .001), with a small bias of 8 N (95% CI, 1.2 to 15 N) in favor of the force plate. The sensitivity of the IHPT was also good, with smallest worthwhile change greater than standard error of measurement for both the strain gauge (smallest worthwhile change: 29 N; standard error of measurement: 17 N; 95% CI, 14 to 20 N) and the force plate (smallest worthwhile change: 29 N; standard error of measurement: 18 N; 95% CI, 14 to 19 N) devices. CONCLUSIONS: The high degree of validity, reliability, and sensitivity of the IHPT, coupled with its affordability, portability, ease of use, and time efficacy, point to the potential of the test for assessment and monitoring purposes.

The Emergent Evaluation and Treatment of Hand and Wrist Injuries: An Update.

Injury patterns of the hand and wrist can be complex and challenging for the emergency physician to diagnose and treat. The ability of the hand to perform delicate maneuvers requires a very intricate interplay of bones, ligaments, and tendons. Unfortunately, due to the omnipresence of the hand, the hand and wrist are commonly injured. These injuries can be debilitating if not treated correctly and can be both time-consuming and fraught with medicolegal risk. This article provides the necessary knowledge to diagnose and treat common hand and wrist injuries encountered in the emergency department.

Epinephrine in cardiac arrest: The PARAMEDIC2 trial.

Link:http://www.nejm.org/doi/10.1056/NEJMoa1806842Full citation: Perkins GD, Ji C, Deakin CD, et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest. N Engl J Med 2018; epub, NEJMoa1806842.Article type: TherapyRatings: Methods - 4/5 Usefulness - 3.5/5.

Identifying Potentially Avoidable Hospitalizations in Medicare Patients With Prostate Cancer: A Retrospective Analysis.

PURPOSE:: If identifiable, potentially avoidable hospitalizations (PAHs) can serve as an important target for cost containment efforts in oncology. METHODS:: PAHs among a cohort of Medicare patients with prostate cancer were identified using a two-stage consensus-driven review process. In stage 1, two clinicians independently evaluated admissions records using a case review form, which we modified from a previous study to assess for PAHs. In stage 2, any admissions that the reviewers disagreed on or were unsure of were re-examined in a larger group of clinicians to yield a consensus determination regarding avoidability. Univariable and multivariable regression analyses were performed to identify factors predictive of PAH. RESULTS:: There were 160 admissions among this cohort of 210 patients from January 2012 to June 2015, of which 99 were evaluable. Consensus-driven clinical review yielded an overall PAH rate of 28.3%. Factors associated with increased PAH risk were admission for symptoms related to cancer (odds ratio [OR], 7.33; P < .001), presence of a social contributor to admission (OR, 4.40; P = .014), and history of alcohol or drug abuse (OR, 4.93; P = .025). Admission for a noncancer condition was associated with decreased PAH risk (OR, 0.32; P = .011). On multivariable analysis, presence of a social contributor to admission (OR, 9.35; P = .002) and admission as a result of a noncancer condition (OR, 0.16; P = .038) remained predictive of PAH risk. CONCLUSION:: A significant proportion of hospitalizations among patients with prostate cancer are potentially avoidable. Understanding factors predictive of risk for PAH can help inform programs aimed at avoiding such admissions to improve overall care quality and value.

Interpreting Oncology Care Model Data to Drive Value-Based Care: A Prostate Cancer Analysis.

PURPOSE:: The Oncology Care Model (OCM) must be clinically relevant, accurate, and comprehensible to drive value-based care. METHODS:: We studied OCM data detailing observed and expected expenses for 6-month-long episodes of care for patients with prostate cancer. We constructed seven disease state-treatment dyads into which we grouped each episode on the bases of diagnoses, procedures, and medications in OCM claims data. We used this clinical-administrative stratification model to facilitate a comparative cost analysis, and we evaluated emergency department and hospital utilization and drug therapy as potential drivers of cost. RESULTS:: We examined 377 episodes of care, pertaining to 210 patients, that took place within our health system from January 2012 to June 2015. Ninety-six percent of episodes were assigned to clinically meaningful dyads. Excessive expenses were seen in metastatic, castration-resistant dyads containing second-line hormone therapy (ratio of observed to expected expenses [O/E], 2.66), chemotherapy (O/E, 2.09), and radium-223/sipuleucel-T (O/E, 3.01). An OCM update correcting for castration-resistant prostate cancer led to small differences in observed expenses (0% to +2%) but large changes in expected expenses (-17% to -27% for hormone-sensitive dyads and +136% to +141% for castration-resistant dyads). O/E increased up to 38% for hormone-sensitive dyads and decreased up to 58% for castration-resistant dyads. Emergency department and hospital utilization seems to drive cost for castration-resistant dyads but not for hormone-sensitive dyads. In the revised OCM model, overall O/E for all episodes improved by 22%, from 1.48 to 1.15. CONCLUSION:: Our experience with OCM highlights the limitations of administrative claims data within this model and illustrates a method of translating these data into clinically meaningful information to improve value.

Recruiting Older Men to Walking Football: A Pilot Feasibility Study.

CONTEXT: Walking football (soccer) has recently emerged as a physical activity option targeted at older males to enhance health and wellbeing. DESIGN: This pilot study aimed to examine the feasibility of recruiting and retaining males aged 50 years and over to an 8-week walking football programme in a professional football club. INTERVENTION: Participants were recruited via social media and assigned to an intervention group or a wait-list control group. The intervention group engaged in 1 h of walking football a week led by a community coach from the professional football club, followed by an optional social session in the club facility. Physiological and psychological outcome measures were obtained onsite at the football club facility (aiding compliance and retention) at baseline and following 8-weeks, from both groups. Semi-structured interviews were conducted after the 8-week programme and 1 year later, to explore motivations for engagement and the social impact. RESULTS: The opportunity to engage in football and the link to a professional football club were key attractions. All participants recruited were overweight, sedentary, exhibited blood pressures outside normal ranges, and all but two were hypertensive. Adherence to the programme was 90% over 8 weeks, and of the participants who were contacted after one year, all (n = 6) had maintained engagement in walking football. Walking football is therefore a feasible, cost-effective method of recruiting and retaining males aged 50 years and over to a physical activity programme, though attrition is to be expected.

Quantifying the contribution of recessive coding variation to developmental disorders.

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.