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Background & Aims Almost one third of adults in the West have increased plasma levels of triglycerides. Even mild to moderate hypertriglyceridemia (2–10 mmol/L or 177–886 mg/dL) is associated with an increased risk of acute pancreatitis. However, it is not clear whether hypertriglyceridemia is a cause or result of acute pancreatitis. Lipoprotein lipase degrades plasma triglycerides. Variants in LPL, APOA5, APOC3, ANGPTL3, and ANGPTL4, which regulate the lipoprotein lipase pathway, result in increased or reduced plasma triglyceride levels. We investigated associations between these variants and acute pancreatitis in a study of the general population. Methods In a prospective cohort study, men and women randomly selected from the population of Denmark were invited to complete a questionnaire, undergo a physical examination, and provide blood samples for biochemical and genetic analyses, from 2003 through 2015. We obtained triglyceride measurements from 117,427 participants. We examined for 15 genetic variants that associate with lipoprotein lipase function in DNA samples from 102,888 participants and analyzed data from 117,427 participants in observational analyses. Diagnoses of acute pancreatitis (970 diagnoses among participants in the genetic analysis and 527 among participants in the observational study) were obtained from Danish registries. We performed a 1-sample Mendelian randomization analysis in which specific variants were used as markers of plasma level of triglycerides to determine the association between plasma level of triglyceride and acute pancreatitis. We calculated unweighted, internally weighted, and externally weighted allele scores for each participant by adding numbers of triglyceride-increasing alleles. Results The highest genetic allele score correlated with a higher plasma level of triglycerides of 0.54 mmol/L (48 mg/dL). Among participants with the highest vs the lowest genetic allele score, the odds ratio for acute pancreatitis was 1.55 (95% CI, 1.08-2.23). Using instrumental variable analysis, integrating the effect of genotype on both triglycerides levels and risk of acute pancreatitis, we associated higher unweighted allele scores (level of triglycerides 1 mmol/L or 89 mg/dL higher) with increased risk of acute pancreatitis (OR, 1.76; 95% CI, 1.16–2.65), as well as internally weighted higher allele scores (OR, 1.41; 95% CI, 1.01–1.97) and externally weighted higher allele scores (OR, 1.44; 95% CI, 1.01–2.04). Every 1 mmol/L (89 mg/dL) increase in triglycerides was observationally associated with an increase in OR of 1.09 (95% CI, 1.05–1.14) after multivariable adjustment. Conclusions Based on an analysis of individuals with genetic variants associated with an increased level of triglycerides, via their effects on the lipoprotein lipase pathway, we associated increased plasma levels of triglycerides with increased risk of acute pancreatitis. Strategies to reduce plasma levels of triglyceride, by increasing lipoprotein lipase function, might be developed for prevention of acute pancreatitis.

Background N-methyl-D-aspartate receptors are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro-β-lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known N-methyl-D-aspartate receptor agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid, or ifenprodil. Methods The in vitro and in vivo pharmacological properties of NYX-2925 were examined. Results NYX-2925 has a low potential for “off-target” activity, as it did not exhibit any significant affinity for a large panel of neuroactive receptors, including hERG receptors. NYX-2925 increased MK-801 binding to human N-methyl-D-aspartate receptor NR2A-D subtypes expressed in HEK cells and enhanced N-methyl-D-aspartate receptor current and long-term potentiation (LTP) in rat hippocampal slices (100–500 nM). Single dose ex vivo studies showed increased metaplasticity in a hippocampal LTP paradigm and structural plasticity 24 hours after administration (1 mg/kg p.o.). Significant learning enhancement in both novel object recognition and positive emotional learning paradigms were observed (0.01–1 mg/kg p.o.), and these effects were blocked by the N-methyl-D-aspartate receptor antagonist CPP. NYX-2925 does not show any addictive or sedative/ataxic side effects and has a therapeutic index of >1000. NYX-2925 (1 mg/kg p.o.) has a cerebrospinal fluid half-life of 1.2 hours with a Cmax of 44 nM at 1 hour. Conclusions NYX-2925, like rapastinel, activates an NMDA receptor-mediated synaptic plasticity process and may have therapeutic potential for a variety of NMDA receptor-mediated central nervous system disorders.

Background and Purpose The GPCR Epstein–Barr virus-induced gene 2 (EBI2, also known as GPR183) is activated by oxysterols and plays a pivotal role in the regulation of B cell migration during immune responses. While the molecular basis of agonist binding has been addressed in several studies, the concept of biased agonism of the EBI2 receptor has not been explored. Experimental Approach We investigated the effects of the EBI2 endogenous agonist 7α,25-dihydroxycholesterol (7α,25-OHC) on G protein-dependent and -independent pathways as well as sodium ion allosterism using site-directed mutagenesis and functional studies. Moreover, we generated a homology model of the EBI2 receptor to investigate the structural basis of the allosteric modulation by sodium. Key Results Residue N114, located in the middle of transmembrane-III at position III:11/3.35, was found to function as an efficacy switch. Thus, substituting N114 with an alanine (N114A) completely abolished heterotrimeric G protein subunit Gi α activation by 7α,25-OHC even though the specific binding of [3H]-7α,25-OHC increased. In contrast, the N114A mutant was still able to recruit β-arrestin and even had an enhanced potency (18.7-fold) compared with EBI2 wild type. Sodium had a negative allosteric effect on oxysterol binding that was mediated via N114, verifying the key role of N114. This was further supported by molecular modelling of the ion binding site based on a EBI2 receptor homology model. Conclusions and Implications Collectively, our data point to N114 as a key residue for EBI2 signalling controlling the balance between G protein-dependent and -independent pathways and facilitating sodium binding.

While the percentage of women head coaches of collegiate teams has consistently declined since 1972, the number of women assistant coaches continues to rise and currently represents the largest gro...

Abnormal plasma concentrations of potassium in the form of hyper- and hypokalemia are frequent among hospitalized patients and have been linked to poor outcomes. In this study, we examined the prevalence of hypo- and hyperkalemia in patients admitted with a fractured hip as well as the association with 30-day mortality in these patients. A total of 7293 hip fracture patients (aged 60 years or above) with admission plasma potassium measurements were included. Data on comorbidity, medication, and death was retrieved from national registries. The association between plasma potassium and mortality was examined using Cox proportional hazards models adjusted for age, sex, and comorbidities. The prevalence of hypo- and hyperkalemia on admission was 19.8% and 6.6%, respectively. The 30-day mortality rates were increased for patients with hyperkalemia (21.0%, p < 0.0001) compared to normokalemic patients (9.5%), whereas hypokalemia was not significantly associated with mortality. After adjustment for age, sex, and individual comorbidities, hyperkalemia was still associated with increased risk of death 30 days after admission (HR = 1.93 [1.55–2.40], p < 0.0001). After the same adjustments, hypokalemia remained non-associated with increased risk of 30-day mortality (HR = 1.06 [0.87–1.29], p = 0.6). Hyperkalemia, but not hypokalemia, at admission is associated with increased 30-day mortality after a hip fracture.

I test whether the anticipation of earnings news stimulates acquisition of customer information and mitigates returns to the customer–supplier anomaly documented by Cohen and Frazzini (“Economic Links and Predictable Returns.” The Journal of Finance 63 (2008): 1977–2011). I find that attention to a firm's publicly disclosed customers increases shortly before the firm announces earnings, and that customer stock returns predict supplier stock returns shortly before, but not after, the supplier's earnings announcement. I further find some evidence that these predictable returns are increasing in the level of customer information acquisition. These results are unique to anticipated disclosure events and suggest that anticipation of supplier earnings announcements resolves investor limited attention to customer information and accelerates price discovery of customer news.

We investigate whether unpleasant environmental conditions affect stock market participants’ responses to information events. We draw from psychology research to develop a new prediction that weather-induced negative moods reduce market participants’ activity levels. Exploiting geographic variation in equity analysts’ locations, we find compelling evidence that analysts experiencing unpleasant weather are slower or less likely to respond to an earnings announcement relative to analysts responding to the same announcement but experiencing pleasant weather. Price association tests find evidence consistent with reduced activity due to weather-induced moods delaying equilibrium price adjustments following earnings announcements. We also use our analyst-based research design to re-examine an existing prediction that unpleasant weather induces investor pessimism, and find evidence of both analyst pessimism and reduced activity in the presence of unpleasant weather. Together, our study provides new evidence that both extends and reaffirms findings of a relation between unpleasant weather and market activities, and contributes to the broader psychology and economics literature on the impact of weather-induced mood on labor productivity. This article is protected by copyright. All rights reserved

OBJECTIVES Our objective was to describe trends in hysteropexy and apical support for uterovaginal prolapse (UVP) from 2002 to 2012 in the United States. We identified patient and hospital variables associated with hysteropexy and apical support. METHODS We used the Nationwide Inpatient Sample and International Classification of Diseases, Ninth Revision codes to identify a population of women 18 years or older with UVP undergoing pelvic organ prolapse surgery from January 1, 2002, to December 31, 2012. Procedures were categorized as (1) hysteropexy, (2) obliterative with uterine preservation, (3) hysterectomy with apical support, (4) hysterectomy without apical support, and (5) other reconstruction without apical support. Categories were dichotomized into those with and without apical support. We used survey weights to obtain nationally representative estimates; χ and linear and logistic regression compared procedure groups. RESULTS An estimated 815,184 hospital discharges of pelvic organ prolapse procedures for UVP occurred from 2002 to 2012. During this time, hysteropexies increased from 1.81% to 5.00% (P < 0.0001). From 2002 to 2012, hysterectomies with apical support increased (10.07% to 32.51%, P < 0.0001), hysterectomy without apical support decreased (27.14% to 17.12%, P < 0.0001), and reconstruction without apical support decreased (59.07% to 40.48%, P < 0.0001). In most recent years 2011 to 2012, 60% of women with UVP underwent inpatient surgery without an apical procedure. Age 52 years or older, Medicare payment, Northeast region, and urban teaching hospitals were associated with increased odds of apical support for UVP (P < 0.001 for all). CONCLUSIONS Hysteropexy significantly increased in the United States from 2002 to 2012, although the overall proportion remains low. While hysterectomy without apical support is decreasing, approximately 60% of inpatient procedures performed for UVP do not address the apex.

Background Despite the greater prevalence of familial hypercholesterolemia (FH) in subjects with ischemic heart disease (IHD), premature IHD, and severe hypercholesterolemia (low-density lipoprotein ≥190 mg/dl), overall prevalence estimates are not available. Objectives The aim of this study was to provide worldwide estimates of FH prevalence in subjects with IHD, premature IHD, and severe hypercholesterolemia compared with those in the general population. Methods In this systematic review and meta-analyses, Embase, PubMed, and the Web of Science were searched until June 3, 2019, for peer-reviewed papers and conference abstracts reporting heterozygous FH prevalence in nonfounder populations, revealing 104 studies eligible for inclusion. Results Estimates of FH prevalence were pooled using random-effects meta-analyses and were 0.32% (95% confidence interval [CI]: 0.26% to 0.39% [corresponding to 1:313]) among 10,921,310 unique subjects in the general population (33,036 patients with FH) on the basis of 44 studies, 3.2% (95% CI: 2.2% to 4.3% [1:31]) among 84,479 unique subjects with IHD (2,103 patients with FH) on the basis of 28 studies, 6.7% (95% CI: 4.9% to 8.7% [1:15]) among 31,316 unique subjects with premature IHD (1,471 patients with FH) on the basis of 32 studies, and 7.2% (95% CI: 4.6% to 10.8% [1:14]) among 17,728 unique subjects with severe hypercholesterolemia (920 patients with FH) on the basis of 7 studies. FH prevalence in the general population was similar using genetic versus clinical diagnoses. Seventeen of 195 countries (9%) in the world have reported FH prevalence for the general population, leaving 178 (91%) countries in the world with unknown prevalence. Conclusions Compared with 1:313 among subjects in the general population, FH prevalence is 10-fold higher among those with IHD, 20-fold higher among those with premature IHD, and 23-fold higher among those with severe hypercholesterolemia. The prevalence of FH is unknown in 90% of countries in the world.

The perception of high-density lipoprotein (HDL) cholesterol as the good cholesterol that protects against atherosclerotic cardiovascular disease (ASCVD) has persisted for decades based largely on the countless observational studies showing high risk of ASCVD in individuals with low concentrations of HDL cholesterol.1 The notion has been the higher the better and the faith in HDL cholesterol–elevating drugs as a new treatment option for ASCVD so great, that >70 000 patients worldwide have been randomized in phase III outcome trials with the 4 major cholesteryl ester transfer protein inhibitors.2–5 Cholesteryl ester transfer protein inhibitors effectively increase HDL cholesterol, but to date none of these compounds have been marketed because of disappointing effects on the risk of ASCVD, and one drug even increased ASCVD risk as well as all-cause mortality.2 Despite the failures of HDL cholesterol–elevating drugs, which in addition to cholesteryl ester transfer protein inhibitors include niacin,6 and genetic studies showing that genetically elevated HDL cholesterol does not confer lower risk of ASCVD,7–12 the perception of HDL cholesterol as the good cholesterol is still deeply believed among many physicians, scientists, and individuals in the general public. See accompanying article on page 669 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Hamer et al13 provide further data to …

BACKGROUND Remnant cholesterol in triglyceride-rich lipoproteins is associated observationally and genetic, causally with increased risk of atherosclerotic cardiovascular disease in healthy individuals. OBJECTIVES We tested the hypothesis that an unmet medical need exists in individuals with high nonfasting remnant cholesterol and prior atherosclerotic cardiovascular disease. METHODS From amongst 109 574 individuals in a prospective cohort study of the Danish general population, we included 2973 individuals aged 20-80 with baseline diagnoses of myocardial infarction/ischaemic stroke ascertained from national Danish health registries. RESULTS The recurrent major cardiovascular event (MACE) incidence rates per 1000 person-years were 39 (95% confidence interval: 30-50) for individuals with remnant cholesterol levels ≥ 1.5 mmol L-1 (≥58 mg dL-1 ), 31 (26-37) for 1-1.49 mmol L-1 (39-57 mg dL-1 ), 27 (24-31) for 0.5-0.99 mmol L-1 (19-38 mg dL-1 ) and 23 (19-27) for individuals with remnant cholesterol

Despite the greater prevalence of familial hypercholesterolemia (FH) in subjects with ischemic heart disease (IHD), premature IHD, and severe hypercholesterolemia (low-density lipoprotein ≥190 mg/dl), overall prevalence estimates are not available.The aim of this study was to provide worldwide estimates of FH prevalence in subjects with IHD, premature IHD, and severe hypercholesterolemia compared with those in the general population.In this systematic review and meta-analyses, Embase, PubMed, and the Web of Science were searched until June 3, 2019, for peer-reviewed papers and conference abstracts reporting heterozygous FH prevalence in nonfounder populations, revealing 104 studies eligible for inclusion.Estimates of FH prevalence were pooled using random-effects meta-analyses and were 0.32% (95% confidence interval [CI]: 0.26% to 0.39% [corresponding to 1:313]) among 10,921,310 unique subjects in the general population (33,036 patients with FH) on the basis of 44 studies, 3.2% (95% CI: 2.2% to 4.3% [1:31]) among 84,479 unique subjects with IHD (2,103 patients with FH) on the basis of 28 studies, 6.7% (95% CI: 4.9% to 8.7% [1:15]) among 31,316 unique subjects with premature IHD (1,471 patients with FH) on the basis of 32 studies, and 7.2% (95% CI: 4.6% to 10.8% [1:14]) among 17,728 unique subjects with severe hypercholesterolemia (920 patients with FH) on the basis of 7 studies. FH prevalence in the general population was similar using genetic versus clinical diagnoses. Seventeen of 195 countries (9%) in the world have reported FH prevalence for the general population, leaving 178 (91%) countries in the world with unknown prevalence.Compared with 1:313 among subjects in the general population, FH prevalence is 10-fold higher among those with IHD, 20-fold higher among those with premature IHD, and 23-fold higher among those with severe hypercholesterolemia. The prevalence of FH is unknown in 90% of countries in the world.

Background There is strong evidence linking high lipoprotein(a) (Lp(a)) to development of incident cardiovascular disease (CVD), but it is not clear whether Lp(a) is associated with risk of recurrent CVD events in individuals from the general population with preexisting CVD. This is of importance as the first drugs specifically aimed at lowering Lp(a) are currently in development, and these would likely be used primarily in individuals with established CVD for secondary prevention of recurrent CVD events. Purpose We tested the hypothesis that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD. Methods From the Copenhagen General Population Study (CGPS) (2003–2015) of 58,527 individuals with measurements of Lp(a) at baseline, 2,527 aged 20–79 with a history of CVD were studied. The primary endpoint was major adverse cardiovascular event (MACE). We also studied 1,115 individuals with CVD at baseline from the Copenhagen City Heart Study (CCHS) (1991–1994) and the Copenhagen Ischemic Heart Disease Study (CIHDS) (1991–1993). Results During a median follow-up of 5 years (range: 0–13, 13,974 person-years), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1,000 person-years were 29 (95% CI: 25–34) for individuals with Lp(a) Conclusion High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD. This points to a possible unmet need for secondary prevention in individuals with increased Lp(a), and such individuals could be a target group for upcoming randomized cardiovascular outcome trials. Acknowledgement/Funding The Novo Nordisk Foundation, Herlev and Gentofte Hospital, Chief Physician Johan Boserup and Lise Boserup's Fund

Summary: Hip fractures are associated with increased mortality and it is important to identify risk factors. This study demonstrates that preexisting cardiovascular disease as well as cardiovascular biomarkers that are associated with increased 30-day mortality. These findings can be used to identify high-risk patients who might benefit from specialized care. Introduction: This study investigates the association between cardiovascular disease (CVD), cardiovascular biomarkers, and 30-day mortality following a hip fracture. Methods: The Danish National Patient Registry was used to investigate the association between CVD and mortality following hip fracture in a nationwide population-based cohort study. In a subset of the included patients (n = 355), blood samples were available from a local biobank. These samples were used for analyzing the association between specific biochemical markers and mortality. The primary outcome was 30-day mortality. Results: A total of 113,211 patients were included in the population-based cohort study. Among these, heart failure was present in 9.4%, ischemic heart disease in 15.9%, and ischemic stroke in 12.0%. Within 30 days after the hip fracture, 11,488 patients died, resulting in an overall 30-day mortality of 10.1%. The 30-day mortality was significantly increased in individuals with preexisting CVD with multivariably adjusted odds ratios of 1.69 (95% confidence interval, 1.60–1.78) for heart failure, 1.23 (1.17–1.29) for ischemic heart disease, and 1.06 (1.00–1.12) for ischemic stroke. In the local database including 355 patients, 41 (11.5%) died within 30 days. The multivariably adjusted odds ratio for 30-day mortality increased with increasing NT-proBNP (2.36 [1.53–3.64] per quartile) and decreased with increasing HDL cholesterol (0.58 [0.41–0.82] per quartile). On this basis, we established a model for predicting the probability of death based on the biochemical markers. Conclusion: Preexisting CVD was associated with increased 30-day mortality after a hip fracture. Furthermore, high levels of NT-proBNP and low levels of HDL cholesterol were associated with increased 30-day mortality.

The aim of this study is to assess the possible association between thyroid-stimulating hormone (TSH) and mortality in hip fracture patients.The study is based on a hip fracture database from Bispebjerg University Hospital (Copenhagen, Denmark). This database includes all hip fracture patients (ICD-10 codes DS720 (femoral neck), DS721 (pertrochanteric), and DS722 (subtrochanteric)) admitted to Bispebjerg Hospital from 1996 to 2012. From this database, we identified all surgically treated hip fracture patients aged 60 years with available plasma TSH-measurements at admission.Of the 914 included patients (24% men and 76% women), 10.5% died within 30 days. At inclusion, 161 (17.6%) of the patients were hyperthyroid (TSH 0.65 mIU/L), 58 (6.4%) were hypothyroid (TSH 4.8 mIU/L), while 695 (76.0%) were euthyroid (0.65 TSH 4.80 mIU/L), p = 0.03. Mortality was significantly higher in the two higher quartiles of TSH [Q3 (13.0%) and Q4 (15.4%)] compared to the two lower quartiles [Q1 (7.4%) and Q2 (6.2%), p = 0.0003. After adjustment for age, sex and Charlson Comorbidity Index (CCI) in a Cox proportional hazard model, the risk of 30-day mortality continued to be increased in patients with TSH above the median as compared to patients with TSH below the median (HR 2.1 (1.4-3.3), p = 0.0006].The study demonstrates increased 30-day mortality in surgically treated hip fracture patients with plasma TSH levels above the median (1.41 mIU/L) at admission, even after adjusting for age, sex and CCI.

Study Objectives The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. Methods Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day–night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings. Results NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by facilitating the transitions from sleep to rough-and-tumble play and back to sleep. In contrast to NYX-2925, the NMDAR antagonist ketamine acutely (1–4 hours post-dosing) suppressed REM and non-REM sleep, increased delta power during wake, and blunted the amplitude of the sleep-wake activity rhythm. Discussion These data suggest that NYX-2925 could enhance behavioral plasticity via improved sleep quality as well as vigilance during wake. As such, the facilitation of sleep by NYX-2925 has the potential to both reduce symptom burden on neurological and psychiatric disorders as well as serve as a biomarker for drug effects through restoration of sleep architecture.

The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in oligodendrocytes in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.

Objective The incidence of acute pancreatitis is rising worldwide and currently no curative treatment exists. Clarification of preventable risk factors is important for the reduction of morbidity and mortality from acute pancreatitis. In this study, we tested the hypothesis that the risk of acute pancreatitis associated with body mass index (BMI) is partly mediated through elevated triglycerides. Design We included 118 085 individuals from 2 prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, with BMI measured at baseline. Diagnosis of acute pancreatitis was assessed from the national Danish registries, as hospitalization or death due to acute pancreatitis. Results Higher BMI was associated with higher risk of acute pancreatitis with a multivariable-adjusted hazard ratio of 1.4 (95% CI, 1.1–1.8) for BMI of 25–29.9, 2.1 (1.6–2.9) for BMI of 30–34.9, and 2.8 (1.8–4.3) for BMI > 35, compared with individuals with BMI of 18.5–24.9. Triglycerides mediated 29% (95% CI, 12%–46%; P = 0.001) of the association between BMI and risk of acute pancreatitis in the age- and sex-adjusted model and 22% (6%–39%; P = 0.008) in the multivariable-adjusted model. Conclusion Higher BMI is associated with higher risk of acute pancreatitis in individuals from the general population, partly mediated through higher triglycerides. This indicates a potential for preventing acute pancreatitis by reducing BMI and triglycerides in individuals with high values.

The benefits of peer support for pelvic floor disorders are unclear. We hypothesize that perioperative peer support might be associated with greater preoperative preparedness compared with usual care in women undergoing pelvic reconstruction. A multicenter prospective cohort study of women undergoing pelvic reconstruction compared peer support (group or one-to-one) with usual care. The primary outcome was preparedness, measured by a Preoperative Preparedness Questionnaire at baseline and before surgery. Assuming 48% preparedness in usual care preoperatively, 44 women per group (Group, One-to-One, or Usual care) would detect a 30% difference in preparedness (alpha = 0.05, 80% power). Chi-squared or Fisher’s exact test compared categorical variables, t test and analysis of variance compared continuous variables, independent sample tests compared changes in mean or composite scores, and multiple logistic regression estimated the effect. One hundred and sixty-eight patients were included (113 with peer support, 55 undergoing usual care). A greater proportion of women in peer support had college or higher education versus usual care (78 vs 58%, P = 0.02). After the intervention, the proportion of women feeling prepared was not different between groups (66 vs 63%, P = 0.9). However, a greater proportion in peer support reported improved preparedness from baseline compared with usual care (71 vs 44%, P = 0.001). Peer support was associated with improved preparedness on multiple regression adjusting for age, study site, education, and surgery type (OR 4.14, 95% CI 1.69, 10.14). Peer support was associated with improved preoperative preparedness compared with usual care, but did not result in a greater proportion of women feeling prepared before surgery.

Some lactic acid bacteria, especially Lactobacillus spp., possess adhesive properties enabling colonization of the human gastrointestinal tract. Two probiotic Lactobacillus plantarum strains, WCSF1 and 299v, display highly different mannose-specific adhesion, with L. plantarum 299v being superior to L. plantarum WCFS1 based on a yeast agglutination assay. A straightforward correlation between the mannose adhesion capacity and domain composition of the mannose-specific adhesin (Msa) in the two strains has not been demonstrated previously. In this study, we analyzed the promoter regions upstream of the msa gene encoding a mannose-specific adhesin in these two strains. The promoter region was mapped by primer extension and DNA sequence analysis, and only a single nucleotide change was identified between the two strains. However, Northern blot analysis showed a stronger msa transcript band in 299v than in WCFS1 correlating with the different adhesion capacities. During the establishment of a high-throughput yeast agglutination assay, we isolated variants of WCFS1 that displayed a very strong mannose-specific adhesion phenotype. The region upstream of the msa gene in these variants showed an inversion of a 104-bp fragment located between two perfectly inverted repeats present in the untranslated leader region. The inversion disrupts a strong hairpin structure that otherwise most likely would terminate the msa transcript. In addition, the ribosome binding site upstream of the msa gene, which is also masked within this hairpin structure, becomes accessible upon inversion, thereby increasing the frequency of translation initiation in the variant strains. Furthermore, Northern blot analysis showed a higher abundance of the msa transcript in the variants than in the wild type, correlating with a strong-Msa phenotype.IMPORTANCE Probiotic strains possess adhesive properties enabling colonization of the human intestinal tract through interactions between molecules present on the probiotic bacteria and components of the epithelial surface. In Lactobacillus plantarum, interaction is mediated through bacterial surface proteins like Msa, which binds to mannose residues present on the intestinal cells. Such interactions are believed to be important for the health-promoting effects of probiotics, including displacement of pathogens, immunomodulation, and protective effects on the intestinal barrier function. In this study, we have identified a new molecular switch controlling expression of the msa gene in L. plantarum strain WCFS1. Strains with increased msa expression could be valuable in the development and manufacture of improved probiotic products.

Purpose: To evaluate the predictive value of pre-fracture medication usage on 30-day mortality following a hip fracture. Methods: Information on age, sex, fracture type, time of death and Charlson co-morbidity index (CCI) was collected from the Danish National Patient Registry on all patients above 60 years, sustaining a hip fracture during the period January 1995 to December 2013. Information on drug usage was obtained from the Danish National Prescription Database. Hazard ratios were calculated with 30-day mortality as the outcome. A univariate and 3 multivariate analyses were conducted with increasing adjustments, starting with age, sex and fracture type, adding co-morbidity and dose in the latter. Results: 141,201 patients were included and a total of 12 drugs/drug groups were identified for analysis. Increased mortality was evident in all analyses for antiarrhythmics, beta blockers, proton pump inhibitors, loop diuretics, opioids, acetaminophen and for psycholeptics. For ACE-inhibitors, increased mortality was found in all analyses, except after adjustment for co-morbidity and dose. For thiazide diuretics, a significantly reduced mortality was evident in all but the univariate analyses while NSAIDs and statins were associated with a significantly reduced mortality in all analyses. For calcium channel blockers, an insignificant decrease was found after adjustment for dose. Further analysis showed a dose-response relationship for all drugs except ACE-inhibitors and calcium channel blockers. Conclusion: The study shows a correlation between pre-fracture usage of certain drugs and 30 day mortality after a hip fracture.

Salt marshes respond to sea-level rise through a series of complex and dynamic bio-physical feedbacks. In this study, we found that sea-level rise triggered salt marsh habitat restructuring, with the associated vegetation changes enhancing salt marsh elevation resilience. A continuous record of marsh elevation relative to sea level that includes reconstruction of high-resolution, sub-decadal, marsh elevation over the past century, coupled with a lower-resolution 1500-year record, revealed that relative sea-level rose 1.5 ± 0.4 m, following local glacial isostatic adjustment (1.2 mm/yr). As sea-level rise has rapidly accelerated, the high marsh zone dropped 11 cm within the tidal frame since 1932, leading to greater inundation and a shift to flood- and salt-tolerant low marsh species. Once the marsh platform fell to the elevation favored by low-marsh Spartina alterniflora, the elevation stabilized relative to sea level. Currently low marsh accretion keeps pace with sea-level rise, while present day high marsh zones that have not transitioned to low marsh have a vertical accretion deficit. Greater biomass productivity, and an expanding subsurface accommodation space favorable for salt marsh organic matter preservation, provide a positive feed-back between sea-level rise and marsh platform elevation. Carbon storage was 46 ± 28 g C/m2/yr from 550 to 1800 CE, increasing to 129 ± 50 g C/m2/yr in the last decade. Enhanced carbon storage is controlled by vertical accretion rates, rather than soil carbon density, and is a direct response to anthropogenic eustatic sea-level rise, ultimately providing a negative feedback on climate warming.

Background and purpose - Several studies suggest a global increase of centenarians during the 21st century. We describe temporal trends of hip fracture incidence and mortality in this group and compare these patients with a group of younger hip fracture patients with regards to comorbidities and mortality. Patients and methods - The full study population included all hip fractures that occurred in Denmark (n = 154,047) between 1996 and 2012. Patients aged 100 or above were identified (n = 507) and hip fracture patients between the ages of 70 to 99 years (n = 124,007) were used for comparison. Data were accessed from national registries. Trends in incidence over time were analyzed using a log-linear regression model, mortality was analyzed using the Kaplan-Meier estimator and trends in mortality over time were analyzed using a log-binomial regression model to obtain relative risk estimates. Results and interpretation - The centenarian patients had fewer comorbidities than the younger comparison group, but mortality was higher at all timepoints. There was no statistically significant change in mortality over time but the incidence of hip fracture among centenarians decreased during the same time period. Our findings describe the characteristics of an emerging group of hip fracture patients and could be of use in the planning of healthcare in the years to come.

Vitamin D has been linked to cancer development in both pre-clinical and epidemiological studies. Our study examines the association between serum levels of vitamin D and cancer incidence in the Capital Region of Denmark. Individuals who had vitamin D analyzed at The Copenhagen General Practitioners Laboratory between April 2004 and January 2010 were linked to Danish registries with end of follow-up date at Dec 31st 2014, excluding individuals with pre-existing cancer. Cox regression models adjusted for age in one-year intervals, sex, month of sampling, and Charlson Comorbidity Index were applied. The study population of 217,244 individuals had a median vitamin D level of 46 nmol/L (IQR 27–67 nmol/L). Non-melanoma skin cancer was the most frequent form of cancer, followed by breast-, lung-, and prostate cancers. No associations were found between increments of 10 nmol/L vitamin D and incidence of breast, colorectal, urinary, ovary or corpus uteri cancer. However, higher levels of vitamin D were associated with higher incidence of non-melanoma (HR 1.09 [1.09–1.1]) and melanoma skin cancer (HR 1.1 [1.08–1.13]) as well as prostate (HR 1.05 [1.03–1.07]) and hematological cancers (HR 1.03 [1.01–1.06]), but with lower incidence of lung cancer (HR 0.95 [0.93–0.97]). In our study, vitamin D levels are not associated with the incidence of several major cancer types, but higher levels are significantly associated with a higher incidence of skin, prostate, and hematological cancers as well as a lower incidence of lung cancer. These results do not support an overall protective effect against cancer by vitamin D.

The impact of storm events on the sediment dynamics of the shallow groundwater fed estuaries of Cape Cod, Massachusetts, USA is little understood. To address this, the objectives of this study are to assess sediment dynamics during storm passage and determine whether shallow back-barrier lagoons like Waquoit Bay have the preservation potential for a sedimentary archive of hurricanes. When setting out in this study, it was unclear whether paleotempestological methods could be applied successfully to cores collected from the landward reaches of shallow estuaries of southern New England. Water level and bottom current data using Arm-and-Float tide gauges and SeaHorse Tilt Current Meters was collected during Tropical Storm Irene (2011) and coupled with storm surge modeling projections to better elucidate storm-induced sediment transport mechanisms. Three sediment cores were collected at the head of Waquoit Bay, located 2.8 km from the barrier beach. Grain size analysis of sediment cores was conducted with a laser particle size analyzer at 1 cm increments in order to identify coarse grain anomalies, which can act as a storm event proxy. Bayesian statistics were applied to develop age models of two of the cores based on three Pb pollution chronomarkers and 21 continuous flow 14C AMS ages. The results yield variable sediment accumulation rates between 2 mm/yr to 10 mm/yr, with significantly higher rates occurring in the upper 1 m of sediments. Grain size results are highly variable, and contain numerous large amplitude, short duration fluctuations suggesting that during storm passage coarse sand is deposited in the coring site. The sensitivity of the site to both tropical and extratropical storm events, uncertainties in the age model, and the multiple sediment sources and transport pathways limits the utility of using the Waquoit sediments to determine long-term hurricane frequencies. Results nonetheless provide insights into how extreme storm events impact coastal lagoons.

Glutamatergic system and the structural plasticity hypothesis are principal components for rapid and sustained antidepressant effects of novel antidepressant therapeutics. This study represents the first investigation of the structural plasticity of the hippocampus as one of the main contributed mechanisms to the sustained anti-depressive effect of ketamine. Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline 7 days before perfusion-fixed. The optical fractionator method was used to estimate the total number of neurons in the granular cell layer. Microvessel length in the molecular layer of DG was evaluated with global spatial sampling method. By use of the physical disector method, the number of synapses was estimated. The volume of the hippocampus was larger in the FRL-vehicle rats compared with FSL-vehicle group and in FSL-ketamine versus FSL-vehicle rats (P

Background and purpose - Currently, no clear evidence exists on the pattern of use of antithrombotics at admission in hip fracture patients and how this has changed over time. We investigated temporal trends in-and factors associated with-the use of antithrombotics in patients admitted with a fractured hip. Patients and methods - This was a population-based cohort study including all patients aged 18 years or above who were admitted with a hip fracture in Denmark from 1996 to 2012. The Danish national registries were used to collect information on medication use, vital status, and comorbidity. Results - From 1996 to 2012, the proportion of patients using antithrombotics in general increased by a factor of 2.3 from 19% to 43% (p < 0.001). More specifically, the use of anticoagulants increased by a factor of 6.8 and the use of antiplatelets increased by a factor of 2.1. When we adjusted for possible confounders, the use of antithrombotics still increased for every calendar year (relative risk (RR) = 1.03, CI: 1.03-1.04; p < 0.001). Age, sex, and Charlson comorbidity index were all associated with the use of antithrombotics (all p < 0.001). Interpretation - The proportion of hip fracture patients using antithrombotics at admission has increased substantially in Denmark over the last 2 decades. This highlights the need for evidence-based guidelines on how to handle patients using antithrombotics to ensure safe surgery and to avoid surgical delay.

RapidScat, which is a Ku-band scatterometer mounted on the International Space Station, observes the Earth's surface in a non-sun-synchronous orbit allowing for different local time-of-day (LTOD) observations as the orbit progresses. The unique orbit and different LTOD observations provide surface observations that are composited to describe the diurnal variability of Ku-band normalized backscatter $(\sigma^{0})$ measurements over land globally. Previous sun-synchronous scatterometers providing twice-daily surface observations have been used to demonstrate some diurnal changes in $\sigma^{0}$ in several regions globally, but instrument cross-calibration concerns prevent identifying diurnal changes by combining $\sigma^{0}$ observations from multiple sensors. As a result, the full extent of diurnal changes to $\sigma^{0}$ has not been determined until now. In this paper, RapidScat is used to identify diurnal changes to $\sigma^{0}$ globally. Vegetation type is discussed with respect to the diurnal changes in $\sigma^{0}$ regionally. The global diurnal changes to $\sigma^{0}$ are discussed with emphasis on the Amazon, Congo, and Upper Danube river regions. Diurnal cycles are described that could not previously be identified with sun-synchronous instruments. Global means and the magnitude of the diurnal cycle are discussed. With the diurnal changes identified and quantified, RapidScat can be used for future cross-platform calibrations using land targets.

Tumor necrosis factor (TNF) is associated with the pathophysiology of various neurological disorders, including multiple sclerosis. It exists as a transmembrane form tmTNF, signaling via TNF receptor 2 (TNFR2) and TNFR1, and a soluble form, solTNF, signaling via TNFR1. Multiple sclerosis is associated with the detrimental effects of solTNF acting through TNFR1, while tmTNF promotes repair and remyelination. Here we demonstrate that oligodendroglial TNFR2 is a key mediator of tmTNF-dependent protection in experimental autoimmune encephalomyelitis (EAE). CNP-cre:TNFR2fl/flmice with TNFR2 ablation in oligodendrocytes show exacerbation of the disease with increased axon and myelin pathology, reduced remyelination, and increased loss of oligodendrocyte precursor cells and mature oligodendrocytes. The clinical course of EAE is not improved by the solTNF inhibitor XPro1595 in CNP-cre:TNFR2fl/flmice, indicating that for tmTNF to promote recovery TNFR2 in oligodendrocytes is required. We show that TNFR2 drives differentiation of oligodendrocyte precursor cells, but not proliferation or survival. TNFR2 ablation leads to dysregulated expression of microRNAs, among which are regulators of oligodendrocyte differentiation and inflammation, including miR-7a. Our data provide the first directin vivoevidence that TNFR2 in oligodendrocytes is important for oligodendrocyte differentiation, thereby sustaining tmTNF-dependent repair in neuroimmune disease. Our studies identify TNFR2 in the CNS as a molecular target for the development of remyelinating agents, addressing the most pressing need in multiple sclerosis therapy nowadays.SIGNIFICANCE STATEMENTOur study, using novel TNF receptor 2 (TNFR2) conditional KO mice with selective TNFR2 ablation in oligodendrocytes, provides the first direct evidence that TNFR2 is an important signal for oligodendrocyte differentiation. Following activation by transmembrane TNF, TNFR2 initiates pathways that drive oligodendrocytes into a reparative mode contributing to remyelination following disease. This identifies TNFR2 as a new molecular target for the development of therapeutic agents in multiple sclerosis.

Introduction: Orthogeriatric service has been shown to improve outcomes in patients with hip fracture. The purpose of this study is to evaluate the effect of orthogeriatrics at Bispebjerg University Hospital, Denmark. The primary outcome is mortality inhospital and after 1, 3, and 12 months for patients with hip fracture. The secondary outcome is mortality for home dwellers and nursing home inhabitants. Materials and Methods: This is a retrospective clinical cohort study with an historic control group including all patients with hip fracture admitted from 2007 to 2011. Patients with hip fracture are registered in a local database, and data are retrieved retrospectively using the Danish Civil Registration Number. Results: We included 993 patients in the intervention group and 989 patients in the control group. A univariate analysis showed only significantly decreased mortality inhospital 6.3% vs 3.1% ( P = .009) after orthogeriatrics. However, when adjusting for age, gender, and American Society of Anaesthesiologists (ASA) score in a multivariate analysis, including all patients with hip fracture, we find significantly reduced mortality inhospital (odds ratio [OR] 0.35), after 30 [OR 0.66] and 90 days [OR 0.72] and 1 year [OR 0.79]). When using a univariate analysis for home-dwelling patients, we found significantly reduced mortality inhospital (8.3-2.0%, P < .0001), after 30 days (12.2-6.8%, P = .004) and 90 days (20.5-13.0%, P = .002). One-year mortality was not significant. Patients from nursing homes had no significant decreasing mortality at any point of time in the univariate analysis. Conclusion: We have shown significant decreases for inhospital, 30 day, 90 day, and 1-year mortality after implementation of orthogeriatric service at Bispebjerg Hospital when adjusting for age, gender, and ASA score. Future trials should include frail patients with other fracture types who can benefit from orthogeriatrics.

Importance Suicide is a leading cause of mortality, with suicide-related deaths increasing in recent years. Automated methods for individualized risk prediction have great potential to address this growing public health threat. To facilitate their adoption, they must first be validated across diverse health care settings. Objective To evaluate the generalizability and cross-site performance of a risk prediction method using readily available structured data from electronic health records in predicting incident suicide attempts across multiple, independent, US health care systems. Design, Setting, and Participants For this prognostic study, data were extracted from longitudinal electronic health record data comprisingInternational Classification of Diseases, Ninth Revisiondiagnoses, laboratory test results, procedures codes, and medications for more than 3.7 million patients from 5 independent health care systems participating in the Accessible Research Commons for Health network. Across sites, 6 to 17 years’ worth of data were available, up to 2018. Outcomes were defined byInternational Classification of Diseases, Ninth Revisioncodes reflecting incident suicide attempts (with positive predictive value >0.70 according to expert clinician medical record review). Models were trained using naive Bayes classifiers in each of the 5 systems. Models were cross-validated in independent data sets at each site, and performance metrics were calculated. Data analysis was performed from November 2017 to August 2019. Main Outcomes and Measures The primary outcome was suicide attempt as defined by a previously validated case definition usingInternational Classification of Diseases, Ninth Revisioncodes. The accuracy and timeliness of the prediction were measured at each site. Results Across the 5 health care systems, of the 3 714 105 patients (2 130 454 female [57.2%]) included in the analysis, 39 162 cases (1.1%) were identified. Predictive features varied by site but, as expected, the most common predictors reflected mental health conditions (eg, borderline personality disorder, with odds ratios of 8.1-12.9, and bipolar disorder, with odds ratios of 0.9-9.1) and substance use disorders (eg, drug withdrawal syndrome, with odds ratios of 7.0-12.9). Despite variation in geographical location, demographic characteristics, and population health characteristics, model performance was similar across sites, with areas under the curve ranging from 0.71 (95% CI, 0.70-0.72) to 0.76 (95% CI, 0.75-0.77). Across sites, at a specificity of 90%, the models detected a mean of 38% of cases a mean of 2.1 years in advance. Conclusions and Relevance Across 5 diverse health care systems, a computationally efficient approach leveraging the full spectrum of structured electronic health record data was able to detect the risk of suicidal behavior in unselected patients. This approach could facilitate the development of clinical decision support tools that inform risk reduction interventions.

Background NYX-2925 is a novel N-methyl-d-aspartate receptor (NMDAR) modulator that has been shown to facilitate both NMDAR-dependent long-term potentiation (LTP) in vitro and learning and memory in vivo. Objective The present studies examine the effects of NYX-2925 on NMDAR-dependent auditory LTP (aLTP) in vivo. Methods NMDAR-dependent aLTP and NMDAR-dependent auditory mismatch negativity (MMN) was measured, as well as changes in resting-state qEEG power. Results NYX-2925 (1, 10 mg/kg PO) increased aLTP 1 h after auditory tetanus measured by the post- minus pre-tetanus difference waveform 140–180 ms post tone onset. NYX-2925 (0.1, 1 mg/kg PO) facilitated MMN measured by the difference waveform (i.e., deviant minus standard tones). NYX-2925 (0.1, 1, 10 mg/kg PO) also enhanced resting-state alpha qEEG power. Conversely, the NMDAR glutamate site antagonist CPP (10 mg/kg IP) reduces alpha power and MMN and produces an opposite effect as NYX-2925 on aLTP. Conclusions Together, these data suggest that the activation of the NMDAR by NYX-2925 enhances synaptic plasticity in vivo, which may both reduce symptoms of neurological disorders and serve as a biomarker for drug effects. This is the first demonstration of a long-lasting (1-h post-tetanus) effect of NMDAR modulation on synaptic plasticity processes in vivo using a noninvasive technique in freely behaving animals.

A respiratory outbreak associated with human adenovirus type 7 (HAdV-7) occurred among unvaccinated officer candidates attending initial military training. Respiratory infections associated with HAdV-7 can be severe, resulting in significant morbidity. Genomic sequencing revealed HAdV-7d, a genome type recently remerging in the United States as a significant respiratory pathogen, following reports from Southeast Asia. Twenty-nine outbreak cases were identified; this likely represents an underestimate. Although the HAdV type 4 and 7 vaccine is currently given to US military enlisted recruit trainees, it is not routinely given to officer candidates. Administration of the HAdV type 4 and 7 vaccine may benefit this cohort.

Some lactic acid bacteria, especially Lactobacillus spp., possess adhesive properties enabling colonization of the human gastrointestinal tract. Two probiotic Lactobacillus plantarum strains, WCSF1 and 299v, display highly different mannose-specific adhesion, with L. plantarum 299v being superior to L. plantarum WCFS1 based on a yeast agglutination assay. A straightforward correlation between the mannose adhesion capacity and domain composition of the mannose-specific adhesin (Msa) in the two strains has not been demonstrated previously. In this study, we analyzed the promoter regions upstream of the msa gene encoding a mannose-specific adhesin in these two strains. The promoter region was mapped by primer extension and DNA sequence analysis, and only a single nucleotide change was identified between the two strains. However, Northern blot analysis showed a stronger msa transcript band in 299v than in WCFS1 correlating with the different adhesion capacities. During the establishment of a high-throughput yeast agglutination assay, we isolated variants of WCFS1 that displayed a very strong mannose-specific adhesion phenotype. The region upstream of the msa gene in these variants showed an inversion of a 104-bp fragment located between two perfectly inverted repeats present in the untranslated leader region. The inversion disrupts a strong hairpin structure that otherwise most likely would terminate the msa transcript. In addition, the ribosome binding site upstream of the msa gene, which is also masked within this hairpin structure, becomes accessible upon inversion, thereby increasing the frequency of translation initiation in the variant strains. Furthermore, Northern blot analysis showed a higher abundance of the msa transcript in the variants than in the wild type, correlating with a strong-Msa phenotype. IMPORTANCE Probiotic strains possess adhesive properties enabling colonization of the human intestinal tract through interactions between molecules present on the probiotic bacteria and components of the epithelial surface. In Lactobacillus plantarum, interaction is mediated through bacterial surface proteins like Msa, which binds to mannose residues present on the intestinal cells. Such interactions are believed to be important for the health-promoting effects of probiotics, including displacement of pathogens, immunomodulation, and protective effects on the intestinal barrier function. In this study, we have identified a new molecular switch controlling expression of the msa gene in L. plantarum strain WCFS1. Strains with increased msa expression could be valuable in the development and manufacture of improved probiotic products.

OBJECTIVE: to test the hypothesis that excess mortality conferred by diabetes following hip fracture decreases with advancing age.METHODS: a nationwide population-based cohort study including 154,047 patients who were admitted with a hip fracture in Denmark from 1996 to 2012. Information on hip fracture diagnosis, diabetes, other comorbidities, and the primary outcome all-cause mortality was collected using the national Danish health registries. The association between diabetes and all-cause mortality according to age was assessed using Cox proportional hazards regression in the age categories: RESULTS: during a median follow-up of 3 years (interquartile range: 1-6 years, 603,091 person-years) 114,990 died from any cause. In total, 8% (n = 12,158) of the patients had diabetes at baseline and had unadjusted, and age, sex and Charlson Comorbidity Index adjusted hazard ratios for all-cause mortality of 1.19 (95% confidence interval: 1.16-1.21) and 1.14 (1.12-1.17) as compared to patients without diabetes. The sex and Charlson Comorbidity Index adjusted hazard ratios according to age were 1.64 (1.34-2.02) for patients CONCLUSIONS: diabetes is associated with excess mortality following hip fracture across all ages, but the excess mortality decreases with advancing age.

BACKGROUND HDL is quantitatively the most important lipoprotein in most species and mechanistic evidence points toward a role for HDL in normal immune function. We tested the hypothesis that concentrations of HDL cholesterol are associated with risk of autoimmune disease. METHODS From 2 studies of the general population—the Copenhagen General Population Study and the Copenhagen City Heart study—we included 107954 and 9387 individuals with baseline measurements of HDL cholesterol. These were followed with the national Danish Patient Registry from baseline in 2003–2015 or 1991–1994 through 2017, during which time 4078 and 1101 individuals developed autoimmune disease in the 2 studies. RESULTS In the Copenhagen General Population Study, compared to individuals with HDL cholesterol ≥2.0 mmol/L (77 mg/dL), the multifactorially adjusted hazard ratios for any autoimmune disease were 1.06 (95% CI, 0.94–1.19) for individuals with HDL cholesterol of 1.5–1.99 mmol/L (58–77 mg/dL), 1.18 (95% CI, 1.04–1.35) for individuals with HDL cholesterol of 1.0–1.49 mmol/L (39–58 mg/dL), and 1.84 (95% CI, 1.52–2.22) for individuals with HDL cholesterol CONCLUSIONS Low HDL cholesterol level is associated with high risk of autoimmune disease in individuals from the general population. Our observational findings cannot determine causality.

Purpose: The purpose of the study was to evaluate the diagnostic accuracy of core biopsy in small renal masses ≤ 4 cm in response to the rising prevalence of renal masses. Methods: Data from 129 consecutive patients who underwent biopsies of solid renal masses of ≤ 4 cm were prospectively collected between September 2014 and January 2017. In cases with inconclusive biopsies, a repeat biopsy was recommended. Histology from surgical specimens was used as gold standard to evaluate the accuracy of renal biopsies. Results: The initial biopsies revealed malignancy in 77 patients (59.7%) and benign histology in 35 patients (27.1%), whereas 17 (13.2%) were inconclusive. Fifty-six patients with malignant histology underwent either partial or radical nephrectomy according to the physicians’ recommendation, while two patients with benign histology requested surgery. In all cases, the biopsy diagnosis was confirmed upon final histopathology. Of the inconclusive cases, six underwent repeat biopsies all with benign histology. Further, three patients opted for immediate partial nephrectomy with benign oncocytoma in two and renal cell carcinoma in the third. The remaining eight patients opted for follow-up CT scans with no sign of progression with a minimum of 6-month follow-up. No biopsy related complications were reported in the first 30 days after RTB. Overall, the treatment strategy changed in 45 of 129 (35%) patients due to biopsy results. This was either due to benign findings or due to the discovery of non-renal cell cancers. Conclusion: Core needle biopsies of solid renal masses ≤ 4 cm have excellent accuracy and may be used to select the correct treatment. Importantly, they may serve to prevent overtreatment of benign tumors.

This paper proposes a novel measure of noise trading that aims to capture uninformed retail trading. The measure, an indicator of whether the firm placed advertisement(s) in the Wall Street Journal seven calendar days earlier, is motivated by evidence that retail trading spikes seven days after ad days, that firms regularly place ads at weekly intervals, and that weekly ads frequently contain duplicate images. This ad-based measure is positively associated with informed trading and stock price volatility. Collectively, our results provide broad support for the theoretical predictions of Collin-Dufresne and Fos (2016, Econometrica).

We exploit the introduction of a "risks and challenges" (RC) section on the crowdfunding website Kickstarter.com to study the role of disclosure in markets characterized by severe information asymmetries and agency frictions. Although the RC section contains voluntary and unaudited disclosures, after its addition projects with already observably risky characteristics attract fewer backers and are less likely to be funded, and project creators who respond to the prompt to discuss risks and abilities increase their non-risk disclosures and use a financing structure that accommodates greater risk. Risky projects attract relatively more backers and funding when project creators respond to the prompt, consistent with increased disclosure mitigating market frictions. Our findings suggest that crowdfunders change the types of projects they support and that project creators modify their disclosures and financing structure when prompted to consider risks.