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OBJECTIVE The authors’ objective was to determine whether preoperative administration of tamsulosin decreases postoperative urinary retention after spine surgery. METHODS In this randomized, double-blind, placebo-controlled clinical trial performed at a single institution between 2016 and 2019, eligible males aged 50 to 85 years were administered tamsulosin or placebo for 5 days prior to elective spine surgery. Patients were excluded if they were taking alpha adrenergic blocking drugs; were allergic to tamsulosin, lactose, or sulfa drugs; had a preexisting indwelling urinary catheter, orthostatic hypotension, history of urological surgery, or renal failure; or were scheduled for cataract surgery within 2 weeks. Screening identified 1051 eligible patients (140 declined participation, 150 did not meet the inclusion criteria, and 151 did not enroll for other reasons). A total of 610 patients were randomly assigned to receive 0.4 mg oral tamsulosin or an identical placebo capsule for 5 days preoperatively and 2 days postoperatively. RESULTS A total of 497 patients were included in the final statistical analysis. The overall rate of postoperative urinary retention was 9.7%, and tamsulosin had no observed effect on reducing the rate of postoperative urinary retention as compared with placebo (9.4% vs 9.9%, p = 0.96). There were no significant differences in the reported adverse events between groups. Multivariate logistic regression was performed to model the effects of patient, surgical, and anesthetic factors on postoperative urinary retention, and the study drug remained an insignificant factor. CONCLUSIONS This study did not detect an effect of perioperative tamsulosin on reducing the rate of postoperative urinary retention in male patients aged 50 to 85 years who underwent elective spine surgery. This study does not support the routine use of tamsulosin to reduce postoperative urinary retention in patients without a previous prescription. It is unknown if subpopulations exist for which prophylactic tamsulosin may reduce postoperative urinary retention.

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Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma.Significance:This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising “epidemic” of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks (N=16/group). Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI, Ct.Por.) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in males, but not females, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic.

BackgroundForkhead transcription factors control cell growth in multiple cancer types.Foxd1is essential for kidney development and mitochondrial metabolism, but its significance in renal cell carcinoma (ccRCC) has not been reported.MethodsTranscriptome data from the TCGA database was used to correlateFOXD1expression with patient survival.FOXD1was knocked out in the 786-O cell line and known targets were analyzed. Reduced cell growth was observed and investigated in vitro using growth rate and Seahorse XF metabolic assays and in vivo using a xenograft model. Cell cycle characteristics were determined by flow cytometry and immunoblotting. Immunostaining for TUNEL and γH2AX was used to measure DNA damage. Association of theFOXD1pathway with cell cycle progression was investigated through correlation analysis using the TCGA database.ResultsFOXD1expression level in ccRCC correlated inversely with patient survival. Knockout ofFOXD1in 786-O cells altered expression of FOXD1 targets, particularly genes involved in metabolism (MICU1) and cell cycle progression. Investigation of metabolic state revealed significant alterations in mitochondrial metabolism and glycolysis, but no net change in energy production. In vitro growth rate assays showed a significant reduction in growth of 786-OFOXD1null. In vivo, xenografted 786-OFOXD1nullshowed reduced capacity for tumor formation and reduced tumor size. Cell cycle analysis showed that 786-OFOXD1nullhad an extended G2/M phase. Investigation of mitosis revealed a deficiency in phosphorylation of histone H3 in 786-OFOXD1null, and increased DNA damage. Genes correlate withFOXD1in the TCGA dataset associate with several aspects of mitosis, including histone H3 phosphorylation.ConclusionsWe show that FOXD1 regulates the cell cycle in ccRCC cells by control of histone H3 phosphorylation, and that FOXD1 expression governs tumor formation and tumor growth. Transcriptome analysis supports this role for FOXD1 in ccRCC patient tumors and provides an explanation for the inverse correlation between tumor expression ofFOXD1and patient survival. Our findings reveal an important role for FOXD1 in maintaining chromatin stability and promoting cell cycle progression and provide a new tool with which to study the biology of FOXD1 in ccRCC.

The comparative effects of zoledronic acid, denosumab, and teriparatide for preventing hip fractures in frail older adults, especially those in nursing homes, were unknown. We found that denosumab and zoledronic acid may be as effective as teriparatide for hip fracture prevention in nursing home residents. Several non-oral drugs exist for osteoporosis treatment, including zoledronic acid (ZA), denosumab, and teriparatide. Little data exist on the comparative effectiveness of these drugs for hip fracture prevention in frail older adults. We examined their comparative effectiveness in one of the frailest segments of the US population—nursing home (NH) residents. We conducted a national retrospective cohort study of NH residents aged ≥ 65 years using 2012 to 2016 national US Minimum Data Set clinical assessment data and linked Medicare claims. New parenteral ZA, denosumab, and teriparatide use was assessed via Medicare Parts B and D; hip fracture outcomes via Part A; and 125 covariates for confounding adjustment via several datasets. We used inverse probability weighted (IPW) competing risk regression models to compare hip fracture risk between groups with teriparatide as the reference. The study cohort (N = 2019) included 1046 denosumab, 578 teriparatide, and 395 ZA initiators. Mean age was 85 years, 90% were female, and 68% had at least moderate functional impairment. Seventy-two residents (3.6%) had a hip fracture and 1100 (54.5%) died over a mean follow-up of 1.5 years. Compared to teriparatide use, denosumab use was associated with a 46% lower risk of hip fracture (HR 0.54, 95% CI 0.29–1.00) and no difference was observed for ZA (HR 0.70, 95% CI 0.26–1.85). Denosumab and ZA may be as effective as teriparatide for hip fracture prevention in frail older adults. Given their lower cost and easier administration, denosumab and ZA are likely preferable non-oral treatments for most frail, older adults.

Novel medical technologies, like large-panel genomic tumor testing (GTT), offer great promise but also substantial uncertainty regarding their clinical value and appropriate use. The goal of this study was to understand how clinicians' perceived uncertainty about GTT, and uncertainty tolerance (UT), a construct that describes trait-level differences in individuals' responses to uncertainty, influence attitudes and self-efficacy regarding GTT. Community-based oncologists participating in a study of large-panel GTT completed surveys assessing their perceptions of uncertainty about GTT, and their attitudes and self-efficacy regarding GTT. Multivariable regression analyses examined the relationship between oncologists' perceived uncertainty of GTT and their GTT-related attitudes and self-efficacy, and the potential moderating effect of individual differences in UT. Fifty-seven oncologists completed surveys. Greater perceived uncertainty about GTT was associated with more negative attitudes towards it. This association was moderated by UT, such that lower UT was associated with a stronger negative relationship between perceived uncertainty and attitudes. That is, oncologists who perceive GTT as uncertain, tended to have more negative attitudes, particularly if they were low in the trait of uncertainty tolerance. More research is warranted to understand how uncertainty and uncertainty tolerance influence clinicians' responses to GTT and other novel medical interventions.

Studies evaluating bathing frequency in pediatric atopic dermatitis (AD) are limited. Parents of children with AD often receive conflicting information, leading to frustration and confusion.To evaluate efficacy of twice-daily soaking baths, followed by immediate application of an occlusive moisturizer (ie, soak-and-seal [SS]), versus twice-weekly SS baths, in the acute management of pediatric AD.We conducted a randomized, single-blind, crossover-controlled trial comparing frequent versus infrequent SS baths, in children 6 months to 11 years of age with moderate-to-severe AD. Children were randomized 1:1 into 2 groups: group 1 underwent twice-weekly SS baths, for 10 minutes or less, over 2 weeks ("dry method" [DM]) followed by twice-daily SS baths, for 15 to 20 minutes, over 2 weeks ("wet method" [WM]). Group 2 did the inverse. Patients received the same moisturizer, cleanser, and low-potency topical corticosteroid (TCS). Primary outcome was AD severity evaluated using the SCORing Atopic Dermatitis (SCORAD) index. Caregiver assessment of AD severity (Atopic Dermatitis Quickscore [ADQ]), quality of life, Staphylococcal aureus colonization, skin hydration, moisturizer, and TCS usage were assessed.Of the 63 children screened, 42 fulfilled inclusion criteria and were randomized. Forty (95%) completed the study. WM decreased SCORAD by 21.2 compared with DM (95% confidence interval [CI], 14.9-27.6; P.0001). Secondary analysis showed a greater than 30% SCORAD improvement for WM versus DM (McNemar's χAs an acute treatment intervention, WM is superior to DM at improving disease severity in moderate-to-severe pediatric AD.

Objective Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis. Measurements A linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups. Results The proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups. Conclusions High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG.

Background Physical molecular interactions are the basis of intracellular signalling and gene regulatory networks, and comprehensive, accessible databases are needed for their discovery. Highly correlated transcripts may reflect important functional associations, but identification of such associations from primary data are cumbersome. Therefore, we have constructed a user-friendly online browser supporting identification of putative macromolecular interactions in human peripheral blood based on significant correlations at the transcriptional level. Methods The blood transcriptome was characterized by quantification of 17,328 RNA species, including ~341 mature microRNAs in 105 clinically well-characterized postmenopausal women. Intercorrelation of detected transcripts signal levels generated a matrix with >150 million correlations recognizing the human blood RNA interactome. The correlations with calculated adjusted p-values were made easily accessible by a freely available online browser. Results We document that significant transcript correlations within the giant matrix reflect experimentally documented interactions between select ubiquitous blood relevant transcription factors CREB1, GATA1, and the glucocorticoid receptor (GR, NR3C1). Their responsive genes recapitulated up to 91% of these as significant correlations, and were replicated in a separate cohort of 1204 individual blood samples from the Framingham Heart Study. Furthermore, experimentally documented mRNAs/miRNA associations were also reproduced in the matrix, and their predicted functional co-expression described. The blood transcript correlation browser is freely available at http://app.uio.no/med/klinmed/correlation-browser/blood/index.php and works on all commonly used internet browsers. Conclusions The matrix and web browser ought to be a valuable tool for easy access to the human blood transcriptome and molecular interactions documented as significant correlations at the RNA-level. This application should also be useful as a hypothesis generating tool for identification of regulatory mechanisms.

CONTEXT: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects., OBJECTIVE: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study’s (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study., METHODS: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD., RESULTS: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings., CONCLUSION: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures., peer-reviewed

Background. Low-dose computed tomography (LDCT) screening for lung cancer is a preference-sensitive intervention that should ideally be individualized according to patients’ likelihood of benefit and personal values. Personalized cancer risk information (PCRI) may facilitate this goal, but its effects are unknown. Objective. To evaluate the effects of providing PCRI to patients referred for LDCT screening. Design. Mixed-methods, pre-post study using surveys administered to patients before and after provision of PCRI—calculated by the PLCOm2012 risk prediction model—in shared decision-making consultations, and postvisit qualitative interviews. Setting. Centralized specialty-based LDCT screening program at a tertiary care hospital. Participants. Convenience sample of eligible patients referred for LDCT screening. Measurements. Pre- and postvisit surveys assessed patients’ 1) perceived lung cancer risk, 2) uncertainty about their risk, 3) minimum risk threshold for wanting screening, 4) interest in LDCT screening, and 5) interest in smoking cessation. Qualitative interviews explored patients’ perceptions of the value of PCRI. Screening uptake was assessed by chart review. Results. Sixty of 70 (86%) patients received PCRI and completed pre-post surveys, and 17 patients (28%) completed qualitative interviews. Perceived lung cancer risk decreased from 52% previsit to 31% postvisit ( P < 0.0001). However, patients’ minimum risk thresholds for screening decreased, their screening interest increased, and all patients completed screening. Qualitative interviews corroborated these effects, suggesting that patients discount and interpret PCRI according to preexisting beliefs and attitudes. Limitations. The study population was a relatively small, single-institution sample of patients referred for screening. Conclusions. Personalized cancer risk information decreases cancer risk perceptions of patients referred for LDCT screening, but has complex effects on screening-related judgments and decisions. The value of PCRI for patients considering LDCT screening requires further investigation.

Premature overexposure to thyroid hormone causes profound effects on testis growth, spermatogenesis, and male fertility. We used genetic mouse models of type 3 deiodinase (DIO3) deficiency to determine the genetic programs affected by premature thyroid hormone action and to define the role of DIO3 in regulating thyroid hormone economy in testicular cells. Gene expression profiling in the neonatal testis of DIO3-deficient mice identified 5699 differentially expressed genes. Upregulated and downregulated genes were, respectively, involved according to DAVID analysis with cell differentiation and proliferation. They included anti-Müllerian hormone and genes involved in the formation of the blood–testis barrier, which are specific to Sertoli cells (SCs). They also included steroidogenic genes, which are specific to Leydig cells. Comparison with published data sets of genes enriched in SCs and spermatogonia, and responsive to retinoic acid (RA), identified a subset of genes that were regulated similarly by RA and thyroid hormone. This subset of genes showed an expression bias, as they were downregulated when enriched in spermatogonia and upregulated when enriched in SCs. Furthermore, using a genetic approach, we found that DIO3 is not expressed in SCs, but spermatogonia-specific inactivation of DIO3 led to impaired testis growth, reduced SC number, decreased cell proliferation and, especially during neonatal development, altered gene expression specific to somatic cells. These findings indicate that spermatogonial DIO3 protects testicular cells from untimely thyroid hormone signaling and demonstrate a mechanism of cross-talk between somatic and germ cells in the neonatal testis that involves the regulation of thyroid hormone availability and action.

OBJECTIVES Bisphosphonates are effective at preventing hip fractures among older adults, yet many patients still fracture while on treatment and may benefit from additional preventive interventions. Little data are specifically available to target such efforts among bisphosphonate users. We aimed to identify predictors of hip fracture unique to frail older adults initiating pharmacologic treatment for osteoporosis. DESIGN Retrospective cohort using 2008-2013 linked national Minimum Data Set assessments, Medicare claims, and nursing home (NH) facility data. SETTING NHs in the United States. PARTICIPANTS Long-stay NH residents 65 years or older who initiated treatment with a bisphosphonate (N = 17 753). Estimates for bisphosphonate initiators were contrasted with those for calcitonin initiators (control group; N = 5348). MEASUREMENTS Hospitalized hip fracture outcomes were measured using Part A claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for 36 a priori selected potential predictors. RESULTS The mean (SD) age of the study population was 84 (8) years, 85% were women, and 51% had moderate to severe cognitive impairment. Predictors associated with a higher risk of hip fracture despite bisphosphonate use included age 75 years or older to 85 years (vs ≥65 to

The growth and spread of malignant tumors, such as ovarian carcinomas, are governed in part by complex interconnected signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms. Herein, we provide evidence that blocking cellular interactions with an RGDKGE-containing collagen peptide that selectively binds integrin β3 on ovarian tumor cells enhances the phosphorylation of the hippo effector kinase large tumor suppressor kinase-1 and reduces nuclear accumulation of yes-associated protein and its target gene c-Myc. Selectively targeting this RGDKGE-containing collagen fragment inhibited ovarian tumor growth and the development of ascites fluid in vivo. These findings suggest that this bioactive collagen fragment may represent a previously unknown regulator of the hippo effector kinase large tumor suppressor kinase-1 and regulate ovarian tumor growth by a yes-associated protein–dependent mechanism. Taken together, these data not only provide new mechanistic insight into how a unique collagen fragment may regulate ovarian cancer, but in addition may help provide a useful new alternative strategy to control ovarian tumor progression based on selectively disrupting a previously unappreciated signaling cascade.

Osteoporosis is a debilitating and costly disease that causes fractures in 33% of women and 20% of men over the age of 50 years. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture compared with non-users. The mechanism underlying this association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however, the mechanism in humans is unknown. Also, several miRNAs are associated with adrenergic signaling and BMD in separate studies. To investigate potential miRNA mechanisms, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry (DXA) scans, and miRNA and mRNA profiling of whole blood from the Framingham Study's Offspring Cohort. We found nine miRNAs associated with BB use and increased BMD. In parallel network analyses, we discovered a subnetwork associated with BMD and BB use containing two of these nine miRNAs, miR-19a-3p and miR-186-5p. To strengthen this finding, we showed that these two miRNAs had significantly higher expression in individuals without incident fracture compared with those with fracture in an external data set. We also noted a similar trend in association between these miRNA and Z-score as calculated from heel ultrasound measures in two external cohorts (SOS-Hip and SHIP-TREND). Because miR-19a directly targets the ADRB1 mRNA transcript, we propose BB use may downregulate ADRB1 expression in osteoblasts through increased miR-19a-3p expression. We used enrichment analysis of miRNA targets to find potential indirect effects through insulin and parathyroid hormone signaling. This analysis provides a starting point for delineating the role of miRNA on the association between BB use and BMD. © 2020 American Society for Bone and Mineral Research (ASBMR).

Some, but not all, prior observational studies have shown that beta blocker (BB) use is associated with lower fracture risk and higher bone mineral density (BMD). Rodent studies show the mechanism to involve the reduction in the effects of beta‐adrenergic signaling on bone remodeling. Because previous studies did not have detailed information on dose, duration, and beta‐1 selectivity, we examined these in a cross‐sectional analysis of the association between BB use and hip and spine BMD using DXA with the Offspring Cohort of the Framingham Heart Study. The sample size was n = 1520, and 397 individuals used BBs. We used propensity score modeling to balance a comprehensive set of covariates using inverse probability of treatment weighting (IPTW) to minimize bias due to treatment indication. We found significant differences in BMD between BB users and non‐users for three of four BMD measurements (femoral neck: 3.1%, 95% CI, 1.1% to 5.0%; total femur: 2.9%, 95% CI, 0.9% to 4.9%; femoral trochanter: 2.4%, 95% CI, −0.1% to 5.0%; and lumbar spine: 2.7%, 95% CI, 0.2% to 5.0%). Results were found to be similar between sexes although the magnitude of association was larger for women. Similar differences were estimated for beta‐1 selective and nonselective BBs compared with no BB use. We modeled dose in categories (no BB use, low‐dose, high‐dose) and as a continuous variable and found an increasing dose response that levels off at higher doses. Finally, associations were similar for short‐term versus long‐term (≤4 years versus >4 years) use. In summary, this large comprehensive study shows that BB use is associated with higher BMD in a dose‐related manner regardless of beta‐1 specificity and duration of use, which supports the conduct of a randomized clinical trial of BBs for achieving improvements in BMD for individuals at risk of bone loss with aging. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., Predicted bone mineral density (BMD) in g/cm2 as a function of standardized dose (defined daily dose [DDD]) in polynomial dose response models with sample weighing by inverse probability of treatment weights (IPTW).

Aims To assess whether meeting both fasting plasma glucose (FPG) and HbA1c criteria for prediabetes in people at high risk indicates with near certainty the presence of dysglycemia on repeat testing. Methods Observational study using data from Vitamin D and Type 2 Diabetes (D2d) study. HbA1c, FPG were measured at screening visit 1; FPG, HbA1c and 2 h plasma glucose (2hPG) measured at screening visit 2 (a median of 21 days later); participants classified as having normal glucose regulation (all 3 tests in normal range), prediabetes or diabetes (at least 1 of 3 tests in diabetes range). A predictive model was developed to estimate the probability of confirming dysglycemia and for detecting diabetes at screening visit 2 based on values of FPG and HbA1c at screening visit 1. Results Of 1271 participants who met both FPG and HbA1c criteria for prediabetes at screening visit 1, 98.6% exhibited dysglycemia (defined as prediabetes or diabetes) on repeat testing (84.5% were classified as having prediabetes, 14.1% were reclassified as having diabetes). Of those with diabetes, 62.6% were identified by 2hPG alone. Conclusions Combined measurement of FPG and HbA1c is a reliable and reproducible measure to identify presence of dysglycemia among people at high risk. A prediction model is provided to help clinicians decide whether an oral glucose tolerance test will provide value in detecting diabetes based on the 2hPG criterion., Highlights • FPG and HbA1c were tested simultaneously to identify patients with prediabetes. • Median 21 days later, repeat evaluation with FPG, HbA1c and an OGTT to measure the 2hPG criterion was done. • 98.6% of the subjects exhibited dysglycemia (prediabetes (84.5%) or diabetes (14.1%)) on repeat testing. • A prediction model to assess additional value of OGTT in detecting diabetes based on the 2hPG criterion is provided.

Objectives Clostridioides difficile infection is a major source of morbidity and mortality among frail older adults, especially those in nursing homes (NHs). Safety reports have signaled that bisphosphonate use may be a contributing cause. We therefore evaluated the risk of C difficile hospitalization associated with oral bisphosphonate use in the NH. Design Observational, retrospective new-user cohort study. Setting The cohort included US NH residents aged ≥65 years who became a long-stay resident (>100 days in the NH) between January 1, 2008 and December 31, 2009. Methods We conducted a study of NH residents using linked Medicare claims and Minimum Data Set records. Residents were new users of an oral bisphosphonate 1:1 matched to new calcitonin users (“active” comparator) on propensity scores controlling for more than 100 covariates. The outcome was risk of hospitalization for C difficile infection in a Cox proportional hazards model adjusted for previous antibiotic and proton pump inhibitor use. Results Our final analytical cohort included 17,753 bisphosphonate and 5348 calcitonin users. In the matched cohort, 84/5209 (1.6%) vs 71/5209 (1.4%) C difficile–related hospitalizations occurred in bisphosphonate and calcitonin users, respectively. We observed no significant difference in the risk of hospitalization among bisphosphonate users (hazard ratio: 1.11, 95% confidence interval: 0.80-1.51). Antibiotic and proton pump inhibitor exposure before and after osteoporosis treatment was also similar between bisphosphonate and calcitonin users. Conclusions and Implications C difficile infection should not be a consideration when prescribing bisphosphonates to frail older adults given the lack of a significant association.

Atypical antipsychotic (AA) medications including risperidone (RIS) and olanzapine (OLAN) are FDA approved for the treatment of psychiatric disorders including schizophrenia, bipolar disorder and depression. Clinical side effects of AA medications include obesity, insulin resistance, dyslipidemia, hypertension and increased cardiovascular disease risk. Despite the known pharmacology of these AA medications, however, the mechanisms contributing to adverse metabolic side-effects are not well understood. To evaluate drug-associated effects on the heart, we assessed changes in the cardiac proteomic signature in mice administered for 4 weeks with clinically relevant exposure of RIS or OLAN. Using proteomic and gene enrichment analysis, we identified differentially expressed (DE) proteins in both RIS- and OLAN-treated mouse hearts (p

Caloric restriction (CR) improves survival in nonhuman primates and delays the onset of age-related morbidities including sarcopenia, which is characterized by the age-related loss of muscle mass and function. A shift in metabolism anticipates the onset of muscle-aging phenotypes in nonhuman primates, suggesting a potential role for metabolism in the protective effects of CR. Here, we show that CR induced profound changes in muscle composition and the cellular metabolic environment. Bioinformatic analysis linked these adaptations to proteostasis, RNA processing, and lipid synthetic pathways. At the tissue level, CR maintained contractile content and attenuated age-related metabolic shifts among individual fiber types with higher mitochondrial activity, altered redox metabolism, and smaller lipid droplet size. Biometric and metabolic rate data confirm preserved metabolic efficiency in CR animals that correlated with the attenuation of age-related muscle mass and physical activity. These data suggest that CR-induced reprogramming of metabolism plays a role in delayed aging of skeletal muscle in rhesus monkeys.

PURPOSE: Functional outcomes vary between centers after out of hospital cardiac arrest (OHCA) and are partially explained by preexisting health status and arrest characteristics, while the effects of in-hospital treatments on functional outcome are less understood. We examined variation in functional outcomes by center after adjusting for patient and arrest-specific characteristics and evaluated how in-hospital management differs between high and low performing centers. METHODS: Analysis of observational registry data within the International Cardiac Arrest Registry (INTCAR) was used to perform a hierarchical model of center-specific risk standardized rates for good outcome, adjusted for demographics, pre-existing functional status, arrest related factors with treatment center as a random effect variable. We described the variability in treatments and diagnostic tests that may influence outcome at centers with adjusted rates significantly above and below registry average. RESULTS: 3855 patients admitted to an ICU following cardiac arrest with return of spontaneous circulation. The overall prevalence of good outcome was 11–63% among centers. After adjustment, center-specific risk standardized rates for good functional outcome ranged from 0.47 (0.37–0.58) to 0.20 (0.12–0.26). High performing centers had faster time to goal temperature, were more likely to have goal temperature of 33°C, more likely to perform unconscious cardiac catheterization and percutaneous coronary intervention, and had differing prognostication practices that low performing centers. CONCLUSIONS: Center-specific differences in outcomes after OHCA after adjusting for patient-specific factors exist. This variation could partially be explained by in-hospital management differences. Future research should address the contribution of these factors to the differences in outcomes after resuscitation. ‘TAKE HOME MESSAGE’: There are significant center-specific differences in outcomes after out of hospital cardiac arrest after adjusting for patient-specific factors. These differences are partially explained by in-hospital treatment decisions. TWEET: Largest study evaluating center-specific outcomes for out-of-hospital cardiac arrest; finding significant center-specific differences after adjustment

Background Communicating scientific uncertainty about public health threats such as COVID-19 is an ethically desirable task endorsed by expert guidelines on crisis communication. However, the communication of scientific uncertainty is challenging because of its potential to promote ambiguity aversion—a well-described syndrome of negative psychological responses consisting of heightened risk perceptions, emotional distress, and decision avoidance. Communication strategies that can inform the public about scientific uncertainty while mitigating ambiguity aversion are a critical unmet need. Objective This study aimed to evaluate whether an “uncertainty-normalizing” communication strategy—aimed at reinforcing the expected nature of scientific uncertainty about the COVID-19 pandemic—can reduce ambiguity aversion, and to compare its effectiveness to conventional public communication strategies aimed at promoting hope and prosocial values. Methods In an online factorial experiment conducted from May to June 2020, a national sample of 1497 US adults read one of five versions of an informational message describing the nature, transmission, prevention, and treatment of COVID-19; the versions varied in level of expressed scientific uncertainty and supplemental focus (ie, uncertainty-normalizing, hope-promoting, and prosocial). Participants then completed measures of cognitive, emotional, and behavioral manifestations of ambiguity aversion (ie, perceived likelihood of getting COVID-19, COVID-19 worry, and intentions for COVID-19 risk-reducing behaviors and vaccination). Analyses assessed (1) the extent to which communicating uncertainty produced ambiguity-averse psychological responses; (2) the comparative effectiveness of uncertainty-normalizing, hope-promoting, and prosocial communication strategies in reducing ambiguity-averse responses; and (3) potential moderators of the effects of alternative uncertainty communication strategies. Results The communication of scientific uncertainty about the COVID-19 pandemic increased perceived likelihood of getting COVID-19 and worry about COVID-19, consistent with ambiguity aversion. However, it did not affect intentions for risk-reducing behaviors or vaccination. The uncertainty-normalizing strategy reduced these aversive effects of communicating scientific uncertainty, resulting in levels of both perceived likelihood of getting COVID-19 and worry about COVID-19 that did not differ from the control message that did not communicate uncertainty. In contrast, the hope-promoting and prosocial strategies did not decrease ambiguity-averse responses to scientific uncertainty. Age and political affiliation, respectively, moderated the effects of uncertainty communication strategies on intentions for COVID-19 risk-reducing behaviors and worry about COVID-19. Conclusions Communicating scientific uncertainty about the COVID-19 pandemic produces ambiguity-averse cognitive and emotional, but not behavioral, responses among the general public, and an uncertainty-normalizing communication strategy reduces these responses. Normalizing uncertainty may be an effective strategy for mitigating ambiguity aversion in crisis communication efforts. More research is needed to test uncertainty-normalizing communication strategies and to elucidate the factors that moderate their effectiveness.

The majority of glioma patients experience declines in neurocognitive function (NCF), presumably due to tumor and treatment effects. We sought to understand the natural history of this decline in grade III and grade IV patients. A condensed battery of cognitive tests (HTLV, COWAT, GPT, TMT, and BTA) was administered at three time points: prior (T0) and after (T1) chemoradiation, and during adjuvant chemotherapy (T2). 31 patients were enrolled of which 25, 9 grade III and 16 grade IV, were analyzed. Although our N was too small for statistically significant results, we observed potentially meaningful clinical trends. Changes in HTLV, TMT, and COWAT scores among grade III patients displayed a pattern different from that of grade IV, with a steep decline seen after chemoradiation (T0-T1) followed by improvement several months later (T1-T2), despite ongoing chemotherapy. Grade IV patients, in contrast, showed minimal decline in scores (little change in score between T0-T1 and between T1-T2), perhaps highlighting that NCF is more impacted by disease rather than treatment. We tried to identify a subset of patients who seemed more susceptible to NCF decline. Examination of key clinical features showed that less than gross total resection and less than 4 year degree education level trended to associate with steeper NCF decline (only 40% of those experiencing steep declines in multiple domains had more than 4 yr degree, versus 60% of those with moderate or no decline). This pilot study highlights that assessing neurocognitive function routinely in clinical practice is feasible in a rural academic hospital. Based on patterns of changes in NCF, it appears that grade III and grade IV gliomas are distinct tumor subtypes with respect to NCF decline. Level of education may be a useful biomarker to identify those patients most at risk for neurocognitive decline after treatment.