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BACKGROUND Percutaneous coronary intervention (PCI) of diseased saphenous vein grafts (SVG) continues to pose a clinical challenge. Current PCI guidelines give a class III recommendation against performing PCI on chronically occluded SVG. However, contemporary outcomes after SVG intervention have incrementally improved with distal protection devices, intracoronary vasodilators, drug-eluting stents, and prolonged dual antiplatelet therapy. AIM To reassess the procedural and long-term outcomes of PCI for totally occluded SVG with contemporary techniques. METHODS This was a retrospective observational study conducted at a single university hospital. The study population consisted of 35 consecutive patients undergoing PCI of totally occluded SVG. Post-procedure dual antiplatelet therapy was continued for a minimum of one year and aspirin was continued indefinitely. Clinical outcomes were assessed at a mean follow-up of 1221 ± 1038 d. The primary outcome was freedom from a major adverse cardiac event (MACE) defined as the occurrence of any of the following: death, myocardial infarction, stroke, repeat bypass surgery, repeat PCI, or graft reocclusion. RESULTS The study group included 29 men and 6 women with a mean age of 69 ± 12 years. Diabetes was present in 14 (40%) patients. All patients had Canadian Heart Classification class III or IV angina. Clinical presentation was an acute coronary syndrome in 34 (97%) patients. Mean SVG age was 12 ± 5 years. Estimated duration of occlusion was acute (< 24 h) in 34% of patients, subacute (> 24 h to 30 d) in 26%, and late (> 30 d) in 40%. PCI was initially successful in 29/35 SVG occlusions (83%). Total stent length was 52 ± 35 mm. Intraprocedural complications of distal embolization or no-reflow occurred in 6 (17%) patients. During longer term follow-up, MACE-free survival was only 30% at 3 years and 17% at 5 years. CONCLUSION PCI of totally occluded SVG can be performed with a high procedural success rate. However, its clinical utility remains limited by poor follow-up outcomes.

PURPOSE OF REVIEW Pelvic floor disorders are common among gynecologic cancer survivors. With improvements in survivorship, quality of life conditions in these women need greater attention and care. This review focuses specifically on vulvovaginal symptoms, which are common and have a negative impact on sexual health and quality of life in women affected by gynecologic cancer. RECENT FINDINGS We review publications on treatment-specific sexual health outcomes, screening and treatment of vulvovaginal symptoms and sexual pain, and surgical management options. Recent evidence regarding the safety of concomitant prolapse repair at the time of surgery for gynecologic malignancies and CO2 laser therapy is discussed and areas needing further research and innovation are highlighted. SUMMARY Pelvic floor disorders, including vaginal and sexual health concerns, are common in women affected by gynecologic cancer due to both common risk factors and as a side effects of cancer treatment. Gynecologists play a critical role in screening, treatment, and collaboration with other specialists to provide comprehensive care for these women throughout their lifetime.

Incidences of pancreatic cancer and acute and chronic pancreatitis are rising globally, and often no curative treatment is available at the time of diagnosis. We tested the hypothesis that low and high plasma concentrations of pancreatic amylase are associated with increased risk of pancreatic cancer, acute pancreatitis, and chronic pancreatitis in the general population. We included 101,765 individuals (55% women) aged 20–100 years from the Copenhagen General Population Study with baseline measurements of plasma pancreatic amylase. After recruitment in 2004–2015 during a median 9 years of follow-up (range 0–15), we collected information about diagnoses of pancreatic cancer, acute pancreatitis, and chronic pancreatitis from the national Danish Patient Registry, the national Danish Cancer Registry, and the national Danish Causes of Death Registry. The median age was 58 years (interquartile range: 48–67) and the median plasma pancreatic amylase 32 U/L (26–40). During follow-up, 442 individuals were diagnosed with pancreatic cancer, 282 with chronic pancreatitis, and 401 with acute pancreatitis. Compared to individuals with pancreatic amylase levels in the 41st–60th percentiles, those with extreme low (1st–2.5th percentiles) and extreme high (97.5th–100th percentiles) pancreatic amylase had hazard ratios of 2.4 (95% confidence interval; 1.6–3.6) and 2.2 (1.4–3.7) for pancreatic cancer, of 1.8 (1.1–3.3) and 3.2 (1.8–5.6) for chronic pancreatitis, and of 1.1 (0.6–1.8) and 1.5 (0.8–2.7) for acute pancreatitis, respectively. In apparently healthy individuals from the general population, extreme low and extreme high plasma pancreatic amylase were associated with 2–threefold higher risk of both pancreatic cancer and chronic pancreatitis.

OBJECTIVE Precise measurements of fluid status lack valid methods. Bioimpedance is an attractive diagnostic tool because it is noninvasive, quick, and relatively cheap. This systematic review aims to assess the existing evidence of bioimpedance as an accurate measure of fluid status in critically ill patients. DATA SOURCES PubMed and Embase up till March 2021 were systematically searched (PROSPERO: CRD42020157436). STUDY SELECTION Eligibility criteria were studies reporting original data from cohorts of adult patients in intensive care units and doing at least one whole-body bioimpedance and one reference test. In addition, studies assessing internal reproducibility were included. DATA EXTRACTION An extraction form was designed for the purpose. DATA SYNTHESIS Nine hundred five studies were screened for eligibility, and 28 studies, comprising 1482 individual patients, were included in the final analysis. Eight studies compared bioimpedance with a gold standard, and two of those reported the results adequate. We found a low mean difference, but the 95% limits of agreements had wide limits. The remaining studies applied different surrogates as reference tests. Correlations ranged from 0.05 to 0.99. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) certainty of evidence for all outcomes was very low. CONCLUSIONS The accuracy of bioimpedance as a measure for fluids in critically ill patients in the intensive care unit cannot be determined. Due to the lack of a gold standard, numerous studies compared bioimpedance with surrogate outcomes with great variability in both designs and results. Assessing the internal reproducibility of bioimpedance had the same limitations, but the studies overall reported good internal reproducibility.

BACKGROUND: Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate.METHODS: All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in 75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied.RESULTS: No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45-3.90, p CONCLUSION: No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

OBJECTIVES Peer counseling may improve upon provider counseling and enhance patient preparedness for midurethral sling (MUS) surgery. We aimed to compare the impact of peer-centered versus standard preoperative video counseling by assessing patient preparedness for MUS surgery. METHODS Women undergoing MUS were randomized to view either a peer-centered (PEER) or standard physician preoperative counseling video (PHYS). The PEER video featured a woman who had undergone MUS surgery and included the standard risks and benefits as well as additional information identified in prior work as important to patients. The PHYS video featured a surgeon discussing risks and benefits. Patients viewed either video at their preoperative visit and completed the Patient Preparedness Questionnaire (PPQ), Surgical Decision Satisfaction, Decisional Regret Scale, and the Urogenital Distress Inventory Short Form. Patients then underwent standard in-person surgeon counseling. Sessions were timed and compared with historical timed sessions. Our primary outcome was between-group differences in 6-week postoperative PPQ scores. RESULTS Patient Preparedness Questionnaire scores did not differ between groups (postoperative PPQ scores: median [interquartile range], 95 [84, 100] vs 92 [80, 100]; P=0.50). The PEER group reported higher decisional regret (15 [0, 28.75] vs 0 [0, 10], P=0.02) and less symptom improvement on Urogenital Distress Inventory Short Form change scores compared with the PHYS group (47.2 [37.2, 62.5] vs 36.1 [16.5, 50], P=0.03); secondary outcomes were not different between groups. In-person counseling times decreased after watching either video compared with the institution's historical standard (8:27 minutes [08:56, 17:14] vs 11:34 minutes [5:22, 13:07]; P < 0.005). CONCLUSION Patient preparedness did not differ between groups. Decision regret did not differ between groups once adjusted for urinary symptoms.

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.

BackgroundElectroconvulsive therapy (ECT) is a highly effective and fast-acting treatment for depression used in the clinic. Its mechanism of therapeutic action remains uncertain. Previous studies have focused on documenting neuroplasticity in the early phase following electroconvulsive seizures (ECS), an animal model of ECT. Here, we investigate whether changes in synaptic plasticity and nonneuronal plasticity (vascular and mitochondria) are sustained 3 months after repeated ECS trials.MethodsECS or sham treatment was given daily for 1 day or 10 days to a genetic animal model of depression: the Flinders Sensitive and Resistant Line rats. Stereological principles were employed to quantify numbers of synapses and mitochondria as well as length of microvessels in the hippocampus 24 hours after a single ECS. Three months after 10 ECS treatments (1 per day for 10 days) and sham-treatment, brain-derived neurotrophic factor and vascular endothelial growth factor protein levels were quantified with immunohistochemistry.ResultsA single ECS treatment significantly increased the volume of hippocampal CA1-stratum radiatum, the total length of microvessels, mitochondria number, and synapse number. Observed changes were sustained as shown in the multiple ECS treatment group analyzed 3 months after the last of 10 ECS treatments.ConclusionA single ECS caused rapid effects of synaptic plasticity and nonneuronal plasticity, while repeated ECS induced long-lasting changes in the efficacy of synaptic plasticity and nonneuronal plasticity at least up to 3 months after ECS.

Objective: High Lp(a) (lipoprotein[a]) cause cardiovascular disease (CVD) in a primary prevention setting; however, it is debated whether high Lp(a) lead to recurrent CVD events. We tested the latter hypothesis and estimated the Lp(a)-lowering needed for 5 years to reduce CVD events in a secondary prevention setting. Approach and Results: From the CGPS (Copenhagen General Population Study; 2003–2015) of 58 527 individuals with measurements of Lp(a), 2527 aged 20 to 79 with a history of CVD were studied. The primary end point was major adverse cardiovascular event (MACE). We also studied 1115 individuals with CVD from the CCHS (Copenhagen City Heart Study; 1991–1994) and the CIHDS (Copenhagen Ischemic Heart Disease Study; 1991–1993). During a median follow-up of 5 years (range, 0–13), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1000 person-years were 29 (95% CI, 25–34) for individuals with Lp(a) Conclusions: High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population. This study suggests that Lp(a)-lowering by 50 mg/dL (105 nmol/L) short-term (ie, 5 years) may reduce CVD by 20% in a secondary prevention setting.

Often considered a condition of aging women, pelvic floor disorders may initially present in pregnancy and postpartum, having a negative impact on quality of life during this important time in a woman's life. This review outlines the clinical approach to implementing pelvic health into obstetric care through education and promotion of pelvic health in pregnancy, screening for pelvic floor disorders routinely, and providing support through resources, treatment, and referrals if pelvic floor disorders develop during pregnancy and postpartum.

Purpose of review Transvaginal mesh kits were widely used to treat pelvic organ prolapse for over a 10-year period in the early 2000s. Due to safety concerns and FDA regulations, these mesh kits are no longer available for use. Thus, current Obstetricians and Gynecologists are likely to encounter these meshes, but may have no previous experience or exposure to the devices making it difficult to adequately monitor, counsel, and care for patients that underwent these types of procedures. This review highlights the most commonly used transvaginal mesh kit types, provides insight into signs and symptoms related to transvaginal mesh complications, and provides guidance for management of mesh complications. Recent findings Not all transvaginal mesh will give rise to a complication. If complications do occur, treatment options range from conservative observation to total mesh excision. Management must be customized to an individual patient's needs and goals. Summary Transvaginal mesh kits promised increased durability of surgical repair for pelvic organ prolapse. Safety concerns over time caused these kits to no longer be available for use. Practicing Obstetricians and Gynecologists should be aware of the history of transvaginal mesh and the signs and symptoms of mesh complications.

Purpose: The aim of this study is to assess the possible association between thyroid-stimulating hormone (TSH) and mortality in hip fracture patients. Patients and methods: 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. Results: 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]. Conclusion: 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.

This nationwide study assessed associations between comorbidity and mortality after hip fracture in young and middle-aged patients. Data on 19,682 patients aged 18 to 65 years were extracted from Danish registries out of 154,047 patients who experienced a hip fracture between 1996 and 2012. Mortality and comorbidity were assessed using information on vital status, hospital admissions, and prescriptions. Of the 19,682 patients 17,722 (90.0%) were middle-aged (40–65 years) and 1960 (10.0%) were young (18–39 years). The 30-day mortality rates were 3.2% (n = 570) and 1.6% (n = 32), respectively. Indicators of multi-trauma (hazard ratio (HR), 3.5 95% confidence interval (CI) [1.6–7.8], n = 2056) and having diabetes (HR, 4.4 [1.2–11.3], n = 59) and heart disease (HR, 4.4[1.3–14.8], n = 57) increased 30-day mortality in the young patients, while having cancer (HR, 5.0 [4.2–5.9], n = 1958) increased 30-day mortality in the middle-aged patients. Heart disease and diabetes were associated with high mortality in the young patients while having cancer was associated with high mortality in the middle-aged patients.

CONTEXT How best to identify families with premature myocardial infarction is unclear. OBJECTIVE We compared approaches to identify familial premature myocardial infarction in the general population using different familial hypercholesterolemia (FH) criteria and low-density lipoprotein (LDL) cholesterol cut-points. DESIGN AND SETTING Clinical and mutation criteria for FH and LDL cholesterol cut-points were applied for identification of familial premature myocardial infarction in 106,732 individuals from the Copenhagen General Population Study. RESULTS FH criteria identified 898 (13%) cases with familial premature myocardial infarction, leaving 5856 (87%) cases undetected. The ORs for familial premature myocardial infarction, compared with the respective remainder groups, were 4.7 (95% CI, 3.7 to 6.0) for clinical FH by Dutch Lipid Clinic Network criteria, 4.4 (4.0 to 4.7) for Simon Broome criteria, 2.1 (95% CI, 1.7 to 3.6) for Make Early Diagnosis to Prevent Early Death criteria, 2.1 (95% CI, 1.4 to 3.3) for FH mutation, and 1.4 (95% CI, 1.3 to1.6) for LDL cholesterol ≥5 mmol/L (193 mg/dL). For these risk groups, the sensitivity (true positive rate) for identification of familial premature myocardial infarction were 1.3%, 13%, 1.6%, 0.9%, and 7.1%, respectively. Compared with universal screening of a similar fraction of the population, the relative increase in sensitivity for these risk groups was 3.8-fold [fraction of population examined: 0.3%, 3.3-fold (4%), 2.0-fold (0.8%), 2.0-fold (0.4%), and 1.4-fold (5.3%), respectively]. CONCLUSION Criteria for FH identify a small fraction of individuals with familial premature myocardial infarction in the general population. Actively identifying families with premature myocardial infarction would be of potential preventive importance, and this study provides data that could be used to choose the best method for such family identification.

BACKGROUND How mild-to-moderate hypertriglyceridemia (2–10 mmol/L; 177–886 mg/dL) potentially causes acute pancreatitis is unknown; however, cellular studies indicate that inflammation might be a driver of disease progression. We tested the hypotheses that (a) mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and that (b) the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis depends on low-grade inflammation. METHODS From the Copenhagen General Population Study and the Copenhagen City Heart Study, 117865 men and women 20–100+ years of age with measurements of nonfasting plasma triglycerides at baseline were followed prospectively for development of acute pancreatitis. RESULTS After multivariable adjustment, a 1 mmol/L (89 mg/dL) higher nonfasting triglyceride concentration was associated with 17% (95% CI, 16%–18%, P = 3 × 10−17) higher plasma C-reactive protein (CRP) and a 4.2% (4.0%–4.4%, P = 6 × 10−17) higher blood leukocyte count. Higher concentrations of nonfasting triglycerides were associated almost linearly with higher risk of acute pancreatitis (P for trend = 5 × 10−6), with hazard ratios of 1.5 (95% CI, 0.9–2.5), 2.0 (95% CI, 1.1–3.6), 2.2 (95% CI, 1.0–4.7), 4.2 (95% CI, 1.6–11.5), and 7.7 (95% CI, 3.0–19.8) in individuals with nonfasting triglycerides of 1.00–1.99 mmol/L (89–176 mg/dL; 46% of the population), 2.00–2.99 mmol/L (177–265 mg/dL; 17%), 3.00–3.99 mmol/L (266–353 mg/dL; 6%), 4.00–4.99 mmol/L (354–442 mg/dL; 2%), and ≥5mmol/L(443 mg/dL; 2%), respectively, vs individuals with CONCLUSIONS Mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and higher risk of acute pancreatitis. The association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis is possibly partly mediated by low-grade inflammation.

We report a boy with hypercalcemia due to neonatal severe hyperparathyroidism (NSHPT) caused by a compound heterozygous mutation in the calcium sensing receptor (CaSR) managed successfully on a type II calcimimetic drug. The hypercalcemia was temporarily treated by hyperhydration, bisphosphonate and calcium depleted milk. At 29 days of age cinacalcet was introduced. The starting dose was 0.5 mg/kg/day and was subsequently titrated to the point of efficacy (5.2 mg/kg/day) when a persuasive reduction in parathyroid hormone and calcium concentrations was observed. We propose a trial of type II calcimimetics in newborns with NSHPT irrespective of the genetic mutation and advocate that residual functionality of the CaSR predict the drug efficacy., Highlights • Efficacy of cinacalcet likely depends on residual functionality of the CaSR. • A trial of cinacalcet should be undertaken irrespective of CaSR mutation. • Cinacalcet is safe to use in NSHPT whilst monitoring calcium and PTH concentrations.

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul’s Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22–1.70]; P P =0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P =0.87). Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

Demyelinating disorders of the central white matter are among the most prevalent and disabling conditions in neurology. Since myelin-producing oligodendrocytes comprise the principal cell type deficient or lost in these conditions, their replacement by new cells generated from transplanted bipotential oligodendrocyte-astrocyte progenitor cells has emerged as a therapeutic strategy for a variety of primary dysmyelinating diseases. In this review, we summarize the research and clinical considerations supporting current efforts to bring this treatment approach to patients.

The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic, studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.

Of Duman's many influential findings, the finding that long-term treatment with antidepressant drugs produces an increase in neurogenesis in the subgranular zone of the adult hippocampus may be one of the most enduring and far-reaching. This novel discovery and his decades of continued research in the field led to a new hypothesis about the mechanism of action of antidepressants, providing a critical step in our understanding of the neurotrophic hypothesis of depression and synaptic plasticity. It is now accepted that antidepressant treatments can oppose and even reverse the effects of stress on the brain and on newly born hippocampal cells, possibly via neurotrophic factors, which Duman had continued to explore. Furthermore, ablation studies have shown preclinically that hippocampal neurogenesis may be necessary for some of the clinical effects of antidepressant drugs. Duman's laboratory continued to interrogate neurotrophins and synaptic plasticity, demonstrating that newer clinically approved antidepressant compounds also affect neurogenesis and synaptic plasticity. In this review, we summarize Duman's original findings and discuss the current state of the field of neurogenesis with respect to animal models and human studies and the implications of those findings on the field of drug discovery.

OBJECTIVE To compare outcomes of efficiency, safety, patient, and surgeon satisfaction between absorbable subcuticular staples and subcuticular suture for caesarean section skin closure. DESIGN A prospective, randomised, non-blinded, parallel-group trial. SETTING Mayo Clinic Family Birth Center in Rochester, MN, USA. POPULATION At least 18 years old and 24 weeks' gestation, undergoing caesarean section. Exclusion criteria were body mass index >50, chorioamnionitis, intrauterine fetal death, and multifetal gestation. METHODS Patients were stratified by prior caesarean section, body mass index, and surgeon level and randomised to absorbable subcuticular staples or subcuticular suture. Electronic medical records and surveys were used. MAIN OUTCOME MEASURES Primary outcomes were total operating time, from incision start to close. Secondary outcomes included subcuticular skin closure time, patient and surgeon satisfaction, percutaneous injuries, pain (analgesic use), cosmesis, and wound complications. RESULTS Of 220 randomised patients, 206 were included in the final analysis (103 per group). Baseline characteristics were similar. The primary outcome of total operative time was not significantly different between groups [54.0 (44.9-63.6) versus 58.0 (50.4-68.2) minutes, P = 0.053]. The subcuticular staple group had shorter subcuticular skin closure time [median 2.6 (1.8-4.0) versus 8.5 (6.2-10.5) minutes, P < 0.001]. There were no differences in analgesic use, wound complications, cosmesis or patient satisfaction. One needlestick injury occurred with suture. Surgeons were more likely to recommend (97% versus 85%, P = 0.004) and use (98% versus 82%, P < 0.001) absorbable subcuticular staples. CONCLUSION For caesarean section skin closure, absorbable subcuticular staples did not result in significantly different total operative times compared with sutures. Analgesic use, wound complications, and cosmesis were comparable. Patient and surgeon satisfaction were high with both methods. TWEETABLE ABSTRACT Absorbable subcuticular staples associated with a similar total operative time compared with suture.

NYX-2925, a new chemical entity, acts as a co-agonist to glutamate at the N-methyl-D-aspartate receptor (NMDAR). At low concentrations of endogenous agonists (glycine/D-serine), NYX-2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX-2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. In this first-in-human, phase I, single-ascending dose (50-1,200 mg) and multiple-ascending dose (150-900 mg) study, the safety, tolerability, and pharmacokinetics (PKs) of NYX-2925 were evaluated in 84 healthy adult volunteers. No safety concerns emerged, including no dissociative side effects. NYX-2925 exhibited dose-proportional PKs and minimal accumulation following once-daily dosing for 7 days. Cerebrospinal fluid (CSF) measurements confirmed that NYX-2925 crosses the blood brain barrier, with maximum CSF concentrations approximating 6-9% of maximum plasma concentrations at the same dose level. NYX-2925 was safe and well-tolerated in healthy volunteers, and the study results support the continued clinical development for chronic pain conditions.

Background and purpose - While development in hip fracture incidence and mortality is well examined, none has yet looked at the temporal trends regarding prevalence of co-morbidities. Therefore we investigated changes in incidence of first hip fracture, co-morbidity prevalence, 30 day- and 1-year mortality in hip fracture patients in the Danish population during the period 1999 to 2012. Patients and methods - Patients >18 years admitted with a fractured hip in Denmark between 1996 and 2012 were identified with data for the period 1999-2012 being analyzed regarding prevalence of co-morbidities, incidence, and mortality. Results - 122,923 patients were identified. Incidence in the whole population declined but sex-specific analysis showed no changes for men. For the whole study population, 30-day and 1-year mortality remained unchanged. Age at time of first hip fracture also remained unchanged. Of the included co-morbidities a decrease in prevalence of malignancy and dementia in women was found while there was an increase in the prevalence of all remaining co-morbidities, except hemi- or paraplegia for both sexes, rheumatic diseases for women, and for men diabetes with complications, myocardial infarction, AIDS/HIV, and malignancy. Interpretation - While hip fracture incidence declined for women it was unchanged for men; likewise, 30-day and 1-year mortality rates together with age at first fracture remained unchanged. When these results are compared with the relatively large increase in the prevalence of co-morbidities, it does not seem likely that the increased disease burden is affecting either the incidence or the mortality.

Objective To describe obstetrician-gynecologists' (ob-gyns) knowledge and prescribing practices regarding opioid analgesics. Methods We conducted a cross-sectional survey of a national sample of American College of Obstetricians and Gynecologists Fellows and Junior Fellows who are part of the Collaborative Ambulatory Research Network. We used a sequential mixed-method approach. We collected data on opioid knowledge and typical prescribing practices, including number, type, and indication for prescriptions. We determined adherence to four recommended practices: 1) screening for dependence, 2) prescribing the smallest amount required, 3) tailoring prescriptions, and 4) counseling on proper disposal. We also explored variables associated with prescribing practices. Results Sixty percent (179/300) of sampled members responded. Respondents reported prescribing a median of 26 (5-80) pills per patient across all indications combined. Ninety-eight percent prescribed opioids after surgery and a smaller proportion for nonsurgical indications: vaginal birth (22%), ovarian cysts (30%), endometriosis (24%), and chronic pelvic pain of unknown cause (18%). The number prescribed varied only by indication for the prescription. Nineteen percent reported adherence to three or more (of four) recommended practices. There was no significant difference in the median number of pills prescribed between those who reported adherence to at least one compared with those who did not adhere to any recommended practices (25 [interquartile range 25-30] vs 28 [interquartile range 20-30], P=.58). Regarding knowledge, 81% incorrectly identified the main source of misused opioids, which is through diversion from a friend or family member, and 44% did not know how to properly dispose of unused prescription opioids. Conclusion Obstetrician-gynecologists reported prescribing a median of 26 opioid pills across all indications combined. Amount prescribed varied widely by indication but not by reported adherence to recommended prescribing practices. This study highlights an urgent need for increased efforts to improve ob-gyns' knowledge of opioid use, misuse, disposal, and best prescribing practices.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.