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Functional magnetic resonance imaging (fMRI) has been widely used to examine the relationships between brain function and phenotypic features in neurodevelopmental disorders. Techniques such as resting-state functional connectivity (FC) have enabled the identification of the primary networks of the brain. One fMRI network, in particular, the default mode network (DMN), has been implicated in social-cognitive deficits in autism spectrum disorders (ASD) and attentional deficits in attention deficit hyperactivity disorder (ADHD). Given the significant clinical and genetic overlap between ASD and ADHD, surprisingly, no reviews have compared the clinical, developmental, and genetic correlates of DMN in ASD and ADHD and here we address this knowledge gap. We find that, compared with matched controls, ASD studies show a mixed pattern of both stronger and weaker FC in the DMN and ADHD studies mostly show stronger FC. Factors such as age, intelligence quotient, medication status, and heredity affect DMN FC in both ASD and ADHD. We also note that most DMN studies make ASD versus ADHD group comparisons and fail to consider ASD+ADHD comorbidity. We conclude, by identifying areas for improvement and by discussing the importance of using transdiagnostic approaches such as the Research Domain Criteria (RDoC) to fully account for the phenotypic and genotypic heterogeneity and overlap of ASD and ADHD. Impact statement In this work, we review the default mode network in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), as well as comorbid ASD+ADHD literature. Such a review has not been constructed in the field of cognitive neuroscience at this time, and it would greatly aid other behavioral and cognitive neuroscientists in identifying gaps in the field. In addition, the need to consider disorders to be on a continuum, as suggested by the Research Domain Criteria (RDoC), is important while identifying abnormal patterns in resting-state functional connectivity. This timely review will impact the field in a meaningful way, such that more research on the overlaps between ASD and ADHD is conducted along a spectrum.

BACKGROUND CONTEXT Emerging literature has identified the importance of pretreatment health and functional status as influential in the prognostication of survival. A comprehensive, accessible, predictive model for survival following cervical spine fracture has yet to be developed. PURPOSE To develop an accessible and intuitive predictive model for survival in individuals aged 50 and older treated for cervical spine fractures. STUDY DESIGN Retrospective review of records from two tertiary care centers (2009–2016). PATIENT SAMPLE Patients age 50 and older who received operative or nonoperative management for cervical fractures. OUTCOME MEASURES One-year mortality was the primary outcome with 3-month and 2-year mortality considered secondarily. METHODS Multivariable logistic regression was used to identify factors independently associated with mortality. The magnitude and precision of the relationship with 1-year mortality for statistically significant variables determined weighting in the scoring system subsequently developed. Score performance was tested through multivariable regression and bootstrap simulation. In a sensitivity test, the performance of the score developed for 1-year mortality was assessed using figures for the 3-month and 2-year time-points. RESULTS We included 1,758 patients. Mortality rates were 12% at 3 months, 17% at 1 year, and 21% at 2 years. Following multivariable testing age, injury severity score and Glasgow coma scale demonstrated the strongest predictive values for a base score, followed by serum albumin and ambulatory status. The resultant composite score ranged from 0 (base score≤4, albumin≤3.5 g/dL, and dependent/nonambulator at presentation) to a maximum of 4 (base score≥5, albumin>3.5 g/dL, and independent ambulator at presentation). Following multivariable analysis, when compared to patients with a score of 4, significantly increased odds of 1-year mortality were appreciated for those with scores of 3 (odds ratio [OR] 7.35; 95% confidence interval [CI] 3.77, 14.32), 2 (OR 8.43; 95% CI 4.66, 15.25), 1 (OR 17.47; 95% CI 9.81, 31.11), and 0 (OR 26.58; 95% CI 13.87, 50.92). Score performance was unchanged in bootstrap testing and sensitivity analyses. CONCLUSIONS We have developed a useful prognostic utility capable of informing survival in individuals age 50 and older, following cervical spine fractures. The score can be applied to adjust patient expectations, anticipate outcomes, and as an adjunct to decision-making in the postinjury period.

To evaluate the reporting quality of systematic reviews (SRs) underpinning the American Urologic Association (AUA) clinical practice guidelines (CPGs).We searched the AUA for CPGs from 2015-2021. We extracted all SRs from the reference sections and two independent investigators evaluated eligible SR/meta-analysis using the PRISMA (Preferred Reporting Instrument for Systematic Reviews and Meta-Analyses) and AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews 2) instruments. We compared SRs conducted by the Cochrane group to non-Cochrane SRs using a Mann-Whitney test. A multivariate regression was used to compare study characteristics.Eighteen CPG's met inclusion criteria. We extracted 120 unique SRs, which accounted for 5.1% (n = 120/2346) of all citations. Mean percent adherence to PRISMA and AMSTAR-2 was 65.4% -d 55.2% respectively. SRs conducted by the Cochrane Collaboration scored higher on AMSTAR-2 compared to non-Cochrane (z = -4.41, P.01) and a positive correlation between PRISMA and AMSTAR-2 scores (r = 0.56, P.001) was determined.Our study indicated the quality of SRs used to develop AUA CPGs across both PRISMA and AMSTAR-2 was variable. Despite higher evaluations, Cochrane SRs accounted for less than 15% of SRs underpinning CPG recommendations. Given the importance placed on CPGs within clinical practice, we recommended a synergistic relationship between the AUA and the Cochrane Collaboration to increase the number of quality urologic SRs.

INTRODUCTION: Distinct PSA kinetics have been reported across the breadth of radiation modalities used to definitively treat prostate cancer. This study uses a patient-specific model to characterize and compare ideal PSA kinetics for low- and intermediate-risk prostate cancer following definitive treatment with conventionally fractionated (CFRT), hypofractionated (HFRT), ultra-hypofractionated or stereotactic body radiation therapy (SbRT), or brachytherapy, both high-dose-rate (HDR) and low-dose-rate (LDR). METHODS: This retrospective analysis includes patients with low- or intermediate-risk prostate cancer treated with definitive radiation between 1998 and 2018 at a single, NCI-designated Comprehensive Cancer Center. Patient demographics, treatment characteristics, and follow-up information were prospectively collected in an institutional database. Eligible patients had at least two PSA measurements within 24-months of treatment and were free from biochemical recurrence and receipt of androgen deprivation therapy. The incidence of, time to, and risk factors for PSA nadir (nPSA) and bounce (bPSA) were analyzed by radiation modality. Ideal PSA kinetics were characterized for each modality and compared. RESULTS: Of 1,047 patients included, 45% had low-risk prostate cancer, 37% had favorable intermediate-risk, and 19% had unfavorable intermediate-risk. The majority of patients were treated with CFRT or LDR; the smallest subset was 52 patients (5%) who received SbRT. nPSA measurements within the two-year follow-up period were significantly higher for those treated with ablative modalities, both as absolute nPSA values and relative to initial PSA (iPSA). Median time to nPSA ranged from 14.8 to 17.1 months. Over 50% of those treated with non-ablative therapy (CFRT, HFRT, and LDR) reached a critical nPSA threshold of ≤0.5 ng/mL, while only 23% of SbRT and 33% of HDR cohorts achieved the same threshold. The overall incidence of bPSA was 13.3% and was not affected by treatment modality, Gleason Score, or prostate volume. A piecewise linear regression showed no statistically significant difference in the PSA decay rates between radiation modalities over time, though there was a trend toward faster PSA decay in ablative therapies between the 6–24-month period. CONCLUSION: Ablative therapies, such as HDR and SbRT, are associated with a latent PSA response and higher nPSA when compared to non-ablative therapies. Multivariate logistics modeling revealed younger age, iPSA above the mean, presence of bPSA, and receipt of ablative therapy as significant predictors for not achieving an nPSA ≤0.5 ng/mL. Understanding the different PSA kinetic profiles for the various radiation modalities is critical to assess treatment response and survey for disease recurrence.

Osteomyelitis is an infection of the bone marrow. MRI with gadolinium-based contrast is frequently performed for cases of suspected osteomyelitis. The objective of this systematic review is to examine the diagnostic accuracy of contrast-enhanced vs non-contrast–enhanced MRI for osteomyelitis in the appendicular skeleton. We conducted a systematic review of MRI in the diagnosis of osteomyelitis by searching MEDLINE and EMBASE from January 2000 to March 2020. There were 21 studies that met the inclusion criteria for the systematic review for a total of 1095 patients. Analytic methods were based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Evidence was evaluated using the STARD criteria for evaluation of completeness and transparency of reporting. For diagnosing osteomyelitis in the appendicular skeleton, MRI with gadolinium-based contrast has 89% sensitivity (95% CI, 86–92%), 79% specificity (95% CI, 75–83%), and 90% overall diagnostic accuracy ([SE] = 0.03). For diagnosing osteomyelitis in the appendicular skeleton, MRI without gadolinium-based contrast has a 92% sensitivity (95% CI, 87–96%), 89% specificity (95% CI, 84–93%), and 96% overall diagnostic accuracy ([SE] = 0.03). The median score of included studies was 85% utilizing the STARD criteria with excellent interobserver agreement of 83.4%. Limitations included small sample size of studies, with retrospective designs. No evidence was found to suggest an added diagnostic value of gadolinium contrast for the diagnosis of osteomyelitis in the appendicular skeleton. For routine cases of suspected non-spinal osteomyelitis, non-contrast MRI of the area of interest is the next most appropriate study after radiographs.

Multidisciplinary care (MDC) yields proven benefits for patients with cancer, although it may be underused in the complex management of head and neck squamous cell carcinoma (HNSCC).To characterize the patterns of MDC in the treatment of HNSCC among elderly patients in the US.This nationwide, population-based, retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from January 1, 1991, to December 31, 2011, to identify patients 66 years or older diagnosed with head and neck cancer and determine the dates of diagnosis, oncology consultations, treatment initiation, and speech therapy evaluation in addition to MDC completion. Multidisciplinary care was defined in a stage-dependent manner: localized disease necessitated consultations with radiation and surgical oncologists, and advanced-stage disease also included a medical oncology consultation, all before definitive treatment. Data were analyzed between December 2016 and September 2020.Rates of MDC across all subsites of head and neck cancer as measured by the presence of an evaluation for each oncologist on the MDC team and its effect on treatment initiation.This cohort study assessed 28 293 patients with HNSCC (mean [SD] age, 75.1 [6.6] years; 67% male; 87% White) from the SEER-Medicare linked database. The HNSCC subsites included larynx (40%), oral cavity (30%), oropharynx (21%), hypopharynx (7%), and nasopharynx (2%). Overall, the practice of MDC significantly increased over time, from 24% in 1991 to 52% in 2011 (P .001). For patients with localized (stage 0-II) tumors, 60% received care in the multidisciplinary setting, whereas 28% of those with advanced-stage disease did. A total of 18 181 patients (64%) were treated with initial definitive nonsurgical therapy across all stages. Regardless of stage and subsite, few patients (2%) underwent evaluation by a speech-language pathologist before definitive therapy. Multidisciplinary care prolonged the time to initiation of definitive treatment by 11 days for localized disease and 10 days for advanced disease.This cohort study found that most elderly patients with localized HNSCC received MDC, whereas few patients with advanced-stage disease received such care, although a significant proportion received adjuvant therapy. Multidisciplinary care may prolong time to initiation of definitive treatment with an uncertain impact. Consultation with a speech-language pathologist before definitive therapy was rare.

Introduction COVID-19 has disrupted how ophthalmic practice is conducted worldwide. One patient population that may suffer from poor outcomes during the pandemic are those with age-related macular degeneration (AMD). Many practices are performing some form of tele-ophthalmology services for their patients, and guidance is needed on how to maintain continuity of care amongst patients with AMD using tele-ophthalmology. Methods A literature search was conducted, ending 1 August 2020, to identify AMD outcomes and telecare management strategies that could be used during the COVID-19 pandemic Results 237 total articles were retrieved, 56 of which were included for analysis. Four American Academy of Ophthalmology and Center for Disease Control web resources were also included. Discussion Risk-stratification models have been developed that let providers readily screen existing patients for their future risk of neovascular AMD (nAMD). When used with at-home monitoring devices to detect nAMD, providers may be able to determine who should be contacted via tele-ophthalmology for screening. Telemedicine triage can be used for new complaints of vision loss to determine who should be referred to a retinal specialist for management of suspected nAMD. To increase access and provider flexibility, smartphone fundus photography images sent to a centralized tele-ophthalmology service can aid in the detection of nAMD. Considerations should also be made for COVID-19 transmission, and tele-ophthalmology can be used to screen patients for the presence of COVID-19 prior to in-person office visits. Tele-ophthalmology has additional utility in connecting with nursing home, rural, and socioeconomically disadvantaged patients in the post-pandemic period.

Objective: To summarize and critically appraise the evidence regarding oral vancomycin prophylaxis (OVP) to prevent recurrent Clostridium difficile infections (RCDIs), identify potential consequences of this emerging practice, and highlight future directions of study. Data Sources: A MEDLINE literature search of English-language publications from 1947 through September 2018 was performed using the search terms vancomycin and C difficile and prophylaxis. Clinical trials were identified on the National Library of Medicine clinical trials registry. Study Selection and Data Extraction: All clinical studies (n = 3) assessing oral vancomycin for secondary prophylaxis of C difficile infection (CDI) were evaluated by all authors. Other search results and references in selected publications were used for background and discussion. Data Synthesis: OVP reduced the risk of RCDI in high-risk patients taking systemic antibiotics. Variable dosing regimens and lack of safety data are limitations. OVP may have an adverse impact on the gastrointestinal microbiome, but this was not examined in the clinical studies. Relevance to Patient Care and Clinical Practice: Although current studies are limited by methodological concerns, clinicians can consider vancomycin 125 mg orally once or twice daily in high-risk patients receiving broad-spectrum antibacterial agents. Results of ongoing trials will define the most appropriate regimen and its impact on outcomes, including collateral damage. Conclusions: OVP reduces the risk of RCDIs and should be considered on a case-by-case basis. Caution is warranted before routine use is implemented because the impact on long-term outcomes has not been assessed and the optimal regimen has not been defined.

Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15(−/−) mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15(−/−) mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15(−/−) mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides [DNA-TG]) in an MP dose–dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15(−/−) mice and largely eliminated Nudt15 deficiency–mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15(−/−) mice receiving a reduced MP dose compared with Nudt15(+/+) counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype–guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants’ effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

How intracellular organelles acquire their characteristic sizes is a fundamental question in cell biology. Given stereotypical changes in nuclear size in cancer, it is important to understand the mechanisms that control nuclear size in human cells. Using a high-throughput imaging RNAi screen, we identify and mechanistically characterize ELYS, a nucleoporin required for post-mitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. ELYS knockdown results in small nuclei, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import. Increasing nuclear import by importin α overexpression rescues nuclear size and lamin B2 import, while inhibiting importin α/β-mediated nuclear import decreases nuclear size. Conversely, ELYS overexpression increases nuclear size, enriches nuclear lamin B2 at the nuclear periphery, and elevates NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. Thus, we identify ELYS as a novel positive effector of mammalian nuclear size and propose that nuclear size is sensitive to NPC density and nuclear import capacity.

SUMMARY Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis., In Brief Vijayaraj et al. describe the generation and characterization of an in vitro progressive fibrosis model that is broadly applicable to progressive organ fibrosis. They use it to identify a promising anti-fibrotic therapy that acts by activating normal tissue repair., Graphical Abstract

OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n = 412) or empagliflozin 25 mg (n = 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% [–15 vs. –9 mmol/mol], ETD –0.5% [95% CI –0.7, –0.4] [–6 mmol/mol (–7, –5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product −4.7 vs. −3.8 kg; P = 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

Hypercalcaemia is a common diagnosis with the majority of cases resulting from hyperparathyroidism or malignancy. We report a rare case of persistent symptomatic hypervitaminosis D-induced hypercalcaemia in an individual taking 50 000 IU of vitamin D supplement daily for several months following a diagnosis of vitamin D deficiency. His hypercalcaemia was initially treated with calcitonin and intravenous fluids, but due to recurrent symptomatic hypercalcaemia after discharge, additional treatment with glucocorticoids and bisphosphonates was warranted during his second admission. The pathophysiology of hypercalcaemia from vitamin D intoxication results from the long-term effects of vitamin D storage in adipose tissue. In the present case, we discuss this pathophysiology and treatment approaches in the context of increasing awareness of and testing for vitamin D deficiency, and growing access to over-the-counter supplements.

ASD and ADHD are regarded as distinct disorders in the current DSM-5. However, recent research and the RDoC initiative are recognizing considerable overlap in the clinical presentation of ASD, ADHD, and other neurodevelopmental disorders. In spite of numerous neuroimaging findings in ASD and ADHD, the extent to which either of the above views are supported remains equivocal. Here we compare structural MRI and DTI literature in ASD and ADHD. Our main findings reveal both distinct and shared neural features. Distinct expressions were in total brain volume (ASD: increased volume, ADHD: decreased volume), amygdala (ASD: overgrowth, ADHD: normal), and internal capsule (ASD: unclear, ADHD: reduced FA in DTI). Considerable overlap was noted in the corpus callosum and cerebellum (lower volume in structural MRI and decreased FA in DTI), and superior longitudinal fasciculus (reduced FA in DTI). In addition, we identify brain regions which have not been studied in depth and require more research. We discuss relationships between brain features and symptomatology. We conclude by addressing limitations of current neuroimaging research and offer approaches that account for clinical heterogeneity to better distinguish brain-behavior relationships.

A questionnaire-based study was conducted to assess long-term patient reported outcomes (PROs) following definitive IMRT-based treatment for early stage carcinomas of the tonsillar fossa.Participants had received IMRT with or without systemic therapy for squamous carcinoma of the tonsillar fossa (T1-2 and N0-2b) with a minimum follow-up of 2years. Patients completed a validated head and neck cancer-specific PRO instrument, the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Symptoms were compared between treatment groups of interest and overall symptom burden was evaluated.Of 139 participants analyzed, 51% had received ipsilateral neck IMRT, and 62% single modality IMRT alone (no systemic therapy). There were no differences in mean severity ratings for the top-ranked individual symptoms or symptom interference for those treated with bilateral versus ipsilateral neck IMRT alone. However, 40% of those treated with bilateral versus 25% of those treated with ipsilateral neck RT alone reported moderate-to-severe levels of dry mouth (p=0.03). Fatigue, numbness/tingling, and constipation were rated more severe for those who had received systemic therapy (p0.05 for each), but absolute differences were small. Overall, 51% had no more than mild symptom ratings across all 22 symptoms assessed.The long-term patient reported symptom profile in this cohort of tonsil cancer survivors treated with definitive IMRT-based treatment showed a majority of patients with no more than mild symptoms, low symptom interference, and provides an opportunity for future comparison studies with other treatment approaches.

Using patient-reported and objective assessment tools, we sought to quantify cognitive symptoms and objective cognitive dysfunction in patients irradiated for skull base cancer.Participants were assessed using the Telephone Interview for Cognitive Status (TICS) and the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN), with subsequent analysis.Of the 122 participants analyzed, the majority (63%) had no frank detectable cognitive impairment by TICS, with frank impairment in 6%. Overall, mean patient-reported problems with memory (MDASIApproximately one third of patients had ambiguous results by TICS assessment, for whom more rigorous testing may be warranted. Moderate to severe levels of patient-reported memory complaints on the MDASI-HN module may have utility as a screening tool for cognitive dysfunction in this population.

Stroke remains one of the leading causes of death in the United States. Current evidence identified electrocardiographic abnormalities and cardiac arrhythmias in 50% of patients with an acute stroke. The purpose of this study was to assess whether the presence of ventricular arrhythmia (VA) in adult patients hospitalized in Florida with acute stroke increased the risk of in-hospital mortality. Secondary data analysis of 215,150 patients with ischemic and hemorrhagic stroke hospitalized in the state of Florida collected by the Florida Agency for Healthcare Administration from 2008 to 2012. The main outcome for this study was in-hospital mortality. The main exposure of this study was defined as the presence of VA. VA included the ICD-9 CM codes: paroxysmal ventricular tachycardia (427.1), ventricular fibrillation (427.41), ventricular flutter (427.42), ventricular fibrillation and flutter (427.4), and other – includes premature ventricular beats, contractions, or systoles (427.69). Differences in demographic and clinical characteristics and hospital outcomes were assessed between patients who developed versus did not develop VA during hospitalization (χ2 and t tests). Binary logistic regression was used to estimate unadjusted and adjusted odds ratios and 95% confidence intervals (CIs) between VA and in-hospital mortality. VA was associated with an increased risk of in-hospital mortality after adjusting for all covariates (odds ratio [OR]: 1.75; 95% CI: 1.6–1.2). There was an increased in-hospital mortality in women compared to men (OR: 1.1; 95% CI: 1.1–1.14), age greater than 85 years (OR: 3.9, 95% CI: 3.5–4.3), African Americans compared to Whites (OR: 1.1; 95% CI: 1.04–1.2), diagnosis of congestive heart failure (OR: 2.1; 95% CI: 2.0–2.3), and atrial arrhythmias (OR: 2.1, 95% CI: 2.0–2.2). Patients with hemorrhagic stroke had increased odds of in-hospital mortality (OR: 9.0; 95% CI: 8.6–9.4) compared to ischemic stroke. Identifying VAs in stroke patients may help in better target at risk populations for closer cardiac monitoring during hospitalization. The impact of implementing methods of quick assessment could potentially reduce VA associated sudden cardiac death.

Background Although the different age groups had differences in sensitivity of asthma exacerbations (AEs) to environmental factors, no comprehensive study has examined the age-stratified effects of environmental factors on AEs. Objective We sought to examine the short-term effects in age-stratified groups (infants, preschool children, school-aged children, adults, and the elderly) of outdoor environmental factors (air pollutants, weather conditions, aeroallergens, and respiratory viral epidemics) on AEs. Methods We performed an age-stratified analysis of the short-term effects of 4 groups of outdoor environmental factors on AEs in Seoul Metropolitan City (Korea) from 2008 and 2012. The statistical analysis used a Poisson generalized linear regression model, with a distributed lag nonlinear model for identification of lagged and nonlinear effects and convergent cross-mapping for identification of causal associations. Results Analysis of the total population (n = 10,233,519) indicated there were 28,824 AE events requiring admission to an emergency department during the study period. Diurnal temperature range had significant effects in pediatric (infants, preschool children, and school-aged children) and elderly (relative risk [RR], 1.056-1.078 and 1.016, respectively) subjects. Tree and weed pollen, human rhinovirus, and influenza virus had significant effects in school-aged children (RR, 1.014, 1.040, 1.042, and 1.038, respectively). Tree pollen and influenza virus had significant effects in adults (RR, 1.026 and 1.044, respectively). Outdoor air pollutants (particulate matter of ≤10 μm in diameter, nitrogen dioxide, ozone, carbon monoxide, and sulfur dioxide) had significant short-term effects in all age groups (except for carbon monoxide and sulfur dioxide in infants). Conclusion These findings provide a need for the development of tailored strategies to prevent AE events in different age groups.

Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3 nM; A2780 antiproliferative IC50=70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described.

Background General anaesthesia is usually associated with unconsciousness. 'Awareness' is when patients have postoperative recall of events or experiences during surgery. 'Wakefulness' is when patients become conscious during surgery, but have no postoperative recollection of the period of consciousness. Objectives To evaluate the efficacy of two types of anaesthetic interventions in reducing clinically significant awareness: - anaesthetic drug regimens; and - intraoperative anaesthetic depth monitors. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, ISSUE 4 2016); PubMed from 1950 to April 2016; MEDLINE from 1950 to April 2016; and Embase from 1980 to April 2016. We contacted experts to identify additional studies. We performed a handsearch of the citations in the review. We did not search trial registries. Selection criteria We included randomized controlled trials (RCTs) of either anaesthetic regimens or anaesthetic depth monitors. We excluded volunteer studies, studies of patients prior to skin incision, intensive care unit studies, and studies that only randomized different word presentations for memory tests (not anaesthetic interventions). Anaesthetic drug regimens included studies of induction or maintenance, or both. Anaesthetic depth monitors included the Bispectral Index monitor, M-Entropy, Narcotrend monitor, cerebral function monitor, cerebral state monitor, patient state index, and lower oesophageal contractility monitor. The use of anaesthetic depth monitors allows the titration of anaesthetic drugs to maintain unconsciousness. Data collection and analysis At least two authors independently scanned abstracts, extracted data from the studies, and evaluated studies for risk of bias. We made attempts to contact all authors for additional clarification. We performed meta-analysis statistics in packages of the R language. Main results We included 160 studies with 54,109 enrolled participants; 53,713 participants started the studies and 50,034 completed the studies or data analysis (or both). We could not use 115 RCTs in meta-analytic comparisons because they had zero awareness events. We did not merge 27 of the remaining 45 studies because they had excessive clinical and methodological heterogeneity. We pooled the remaining 18 eligible RCTs in meta-analysis. There are 10 studies awaiting classification which we will process when we update the review. The meta-analyses included 18 trials with 36,034 participants. In the analysis of anaesthetic depth monitoring (either Bispectral Index or M-entropy) versus standard clinical and electronic monitoring, there were nine trials with 34,744 participants. The overall event rate was 0.5%. The effect favoured neither anaesthetic depth monitoring nor standard clinical and electronic monitoring, with little precision in the odds ratio (OR) estimate (OR 0.98, 95% confidence interval (CI) 0.59 to 1.62). In a five-study subset of Bispectral Index monitoring versus standard clinical and electronic monitoring, with 34,181 participants, 503 participants gave awareness reports to a blinded, expert panel who adjudicated or judged the outcome for each patient after reviewing the questionnaires: no awareness, possible awareness, or definite awareness. Experts judged 351 patient awareness reports to have no awareness, 87 to have possible awareness, and 65 to have definite awareness. The effect size favoured neither Bispectral Index monitoring nor standard clinical and electronic monitoring, with little precision in the OR estimate for the combination of definite and possible awareness (OR 0.96, 95% CI 0.35 to 2.65). The effect size favoured Bispectral Index monitoring for definite awareness, but with little precision in the OR estimate (OR 0.60, 95% CI 0.13 to 2.75). We performed three smaller meta-analyses of anaesthetic drugs. There were nine studies with 1290 participants. Wakefulness was reduced by ketamine and etomidate compared to thiopental. Wakefulness was more frequent than awareness. Benzodiazepines reduces awareness compared to thiopental, ketamine, and placebo., Also, higher doses of inhaled anaesthetics versus lower doses reduced the risk of awareness. We graded the quality of the evidence as low or very low in the 'Summary of findings' tables for the five comparisons. Most of the secondary outcomes in this review were not reported in the included RCTs. Authors' conclusions Anaesthetic depth monitors may have similar effects to standard clinical and electrical monitoring on the risk of awareness during surgery. In older studies comparing anaesthetics in a smaller portion of the patient sample, wakefulness occurred more frequently than awareness. Use of etomidate and ketamine lowered the risk of wakefulness compared to thiopental. Benzodiazepines compared to thiopental and ketamine, or higher doses of inhaled anaesthetics versus lower doses, reduced the risk of awareness.

Hypothesis Deep infection after shoulder surgery is a rare but devastating problem. This study tested the hypothesis that the home application of a 2% chlorhexidine gluconate cloth before shoulder surgery would be more efficacious than a standard shower of soap and water at decreasing the preoperative cutaneous levels of pathogenic bacteria on the shoulder. Materials and methods This randomized, prospective study evaluated 100 consecutive patients undergoing shoulder surgery. Patients were randomly assigned to use 2% chlorhexidine gluconate–impregnated cloths (treatment group) or to shower with soap and water before surgery (control group). Cutaneous cultures were taken from the patients’shoulders in the preoperative holding area. Patients were monitored for 2 months postoperatively for clinical signs of infection. Results In the treatment group vs the control group, the overall positive culture rate was 66% vs 94% ( P = .0008), and the positive culture rate for coagulase-negative Staphylococcus was 30% vs 70% ( P = .0001). The positive culture rate for Propionibacterium acnes was 46% in the treatment group vs 58% in the control group ( P = .32). No infections occurred in any patients at a minimum of 2-months after surgery. Discussion The use of the 2% chlorhexidine cloth was effective at decreasing overall bacterial culture rates before shoulder surgery and was particularly effective at decreasing the quantity of coagulase-negative Staphylococcus , a known causative agent of postoperative shoulder infections. Conclusion Use of chlorhexidine impregnated cloths prior to shoulder surgery may be a useful adjunct to presently used infection prevention strategies.

Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.

A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

Background: While it is clear that affect is negatively impacted by heavy drinking in adulthood and that it improves with abstinence, little is known about effects of heavy drinking on mood during adolescence. Methods: This study examined negative mood states among 2 groups of 16- to 18-year-old high school students; youth with a history of recent heavy episodic drinking (HED; n = 39) and comparison youth with limited lifetime drinking experience (CON; n = 26). Affect was assessed at 3 time points during a 4- to 6-week period of monitored abstinence using the Hamilton Rating Scales for Anxiety and Depression; self-reports were obtained with the state portion of the State-Trait Anxiety Inventory, and experience sampling of current affect was assessed via daily text messages sent at randomly determined times in the morning, afternoon, and evening. Results: Youth with a recent history of HED reported more negative affect compared with nondrinking youth during early stages of abstinence (days since last HED at assessment 1: M = 6.46; SD = 5.06); however, differences in affect were not observed after 4 to 6 weeks of abstinence. Sex differences were evident, with HED girls reporting greater depression and anxiety than HED male peers. Although not significant, response patterns indicated that boys may experience faster resolution of negative emotional states than girls with sustained abstinence. Conclusions: Findings suggest that high-dose drinking is associated with elevated negative affect for adolescents and that negative mood states may take longer to resolve for girls than for boys following heavy drinking episodes. Future research clarifying naturally occurring changes in affective response during early and sustained abstinence is necessary for improving programs designed to promote adolescent decision-making and to reduce risk for relapse. © 2013 by the Research Society on Alcoholism.

Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).

Limitations of conventional uncemented femoral stems persist, including proximal-distal mismatch, nonideal load transfer, loss of bone, and difficulties with minimally invasive surgery. Metaphyseal-engaging short-stem implants have been designed to address these issues in THA. While these devices have been studied in younger patients, it is unclear whether they offer advantages in older patients.We asked whether the stability and bony ingrowth of an off-the-shelf short stem in patients 70 years and older were similar to those achieved in patients younger than 70 years at 2-year followup. Furthermore, we asked whether pain and function scores were affected by age, bone quality, or varus alignment.We retrospectively reviewed 60 patients (65 hips) 70 years and older (mean, 75 years; range, 70-86 years) treated with an uncemented short stem (range, 90-105 mm). We compared radiographic alignment, stability, and bony ingrowth, as well as Harris hip scores and WOMAC pain scores, to a cohort of 89 patients (91 hips) younger than 70 years. Minimum followup was 24 months (mean, 35 months; range, 24-60 months).Radiographs showed proximal bony ingrowth and stable fixation of all implants. Average Harris hip score at last followup was 88 (range, 70-100) for the 70 years and older cohort and 93 (range, 70-100) for younger than 70 years cohort; no patients reported thigh pain. Postoperative WOMAC scores averaged 6 (range, 0-43) and 5 (range, 0-25), respectively.Short-stem implants provide solid, dependable fixation in osteoporotic bone at minimum 2-year followup, while meeting some of the limitations in conventional primary THA.Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

We propose a method for testing any hypothesized association between a candidate allele, for which there is a specific laboratory test, and a common chronic disease. Families in which this allele is segregating are identified through index individuals who are homozygous or heterozygous for the allele. The sample consists of the subset of identified families who also have at least one member with the common disease of interest. For each independent family in this subset, select one person with the disease and determine if he or she is heterozygous for the allele. The observed proportion of heterozygotes in this sample is compared to the proportion expected on the basis of each diseased relative's null probability of being heterozygous for the allele; this null probability depends only on the relative's relationship to the index individual and the population allele frequency. We provide these null probabilities, develop appropriate inference procedures, discuss sample size requirements, and compare this method to a standard case-control design. Results using this method are unlikely to be influenced by confounders, systematic bias, or genetic heterogeneity.

Childbearing and child-rearing by adolescents are associated with suboptimal health and development for both mother and infant. The author summarize research on adolescent pregnancy point out methodologic difficulties and identify questions that remain unanswered. The authors use the term "adolescent" to refer to persons aged 13 through 19 years; if the reference age group is different it is stated. The central issue is whether there are intrinsic biologic and development factors during adolescence that produce poor outcome for mother and child or whether pregnancy during adolescence is a marker for social disadvantage that independently predicts such outcome. Current controversy is focused on whether the youngest mothers (age or = 15 years) and their infants are at greater medical and social risk than older adolescents or adults and their infants. The authors address what is known about biologic soical and behavioral factors that mediate or modify medical and social risks. (authors)

Background While asymmetry in the fusiform gyrus (FFG) has been reported in functional and structural studies in typically developing controls (TDC), few studies have examined FFG asymmetry in autism spectrum disorder (ASD) subjects and those studies are limited by small sample sizes, and confounded by cognitive ability or handedness. No previous work has examined FFG surface area or cortical thickness asymmetry in ASD; nor do we understand the trajectory of FFG asymmetry over time. Finally, it is not known how FFG structural asymmetry relates to ASD symptom severity. Methods In this study, we examined FFG volume, surface area, and cortical thickness asymmetry, as well as their cross-sectional trajectories in a large sample of right-handed males aged 7 to 25 years with 128 ASD and 127 TDC subjects using general linear models. In addition, we examined the relationship between FFG asymmetry and ASD severity using the Autism Diagnostic Observation Schedule (ADOS) and Gotham autism severity scores. Results Findings revealed that while group differences were evident with mean leftward asymmetry in ASD and mean near symmetry in TDC volume and surface area, asymmetry for both groups existed on a spectrum encompassing leftward and rightward asymmetry. In ASD subjects, volume asymmetry was negatively associated with ADOS and autism severity score symptom measures, with a subset of rightward asymmetric patients being most severely affected. We also observed differential trajectory of surface area asymmetry: ASD subjects exhibited a change from leftward asymmetry toward symmetry from age 7 to 25, whereas TDCs exhibited the reverse trend with a change from near symmetry toward leftward symmetry over the observed age range. Conclusions Abnormalities in FFG structural asymmetry are related to symptom severity in ASD and show differential developmental trajectory compared to TDC. This study is the first to note these findings. These results may have important implications for understanding the role of FFG asymmetry in ASD. Electronic supplementary material The online version of this article (doi:10.1186/s13229-016-0089-5) contains supplementary material, which is available to authorized users.