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Chemotherapy-induced peripheral neuropathy is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 × 4 mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (.5 and 1.8 mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin ( .5 and 1.8 mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), reduced the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin 43 protein expression in the dorsal root ganglion. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for chemotherapy-induced peripheral neuropathy treatment. PERSPECTIVE: Chemotherapy neuropathy is a major clinical problem that decreases quality of life for cancer patients and survivors. Our experiments demonstrate that Meteorin treatment alleviates pain-related behaviors, and signs of neurotoxicity in a mouse model of paclitaxel neuropathy.

Previous research regarding the intraseasonal variability of the wintertime Pacific jet has employed empirical orthogonal function (EOF)/principal component (PC) analysis to characterize two leading modes of variability: a zonal extension or retraction and a ∼20° meridional shift of the jet exit region. These leading modes are intimately tied to the large-scale structure, sensible weather phenomena, and forecast skill in and around the vast North Pacific basin. However, variability within the wintertime Pacific jet and the relative importance of tropical and extratropical processes in driving such variability, is poorly understood. Here, a self-organizing maps (SOM) analysis is applied to 73 Northern Hemisphere cold seasons of 250-hPa zonal winds from the NCEP–NCAR reanalysis data to identify 12 characteristic physical jet states, some of which resemble the leading EOF Pacific jet patterns and combinations of them. Examination of teleconnection patterns such as El Niño–Southern Oscillation (ENSO) and the Madden–Julian oscillation (MJO) provide insight into the varying nature of the 12 SOM nodes at inter- and intraseasonal time scales. These relationships suggest that the hitherto more common EOF/PC analysis of jet variability obscures important subtleties of jet structure, revealed by the SOM analysis, which bear on the underlying physical processes associated with Pacific jet variability as well as the nature of its downstream impacts.

Postpartum urinary retention is a relatively common condition that can have a marked impact on women in the immediate days following childbirth. If left untreated, postpartum urinary retention can lead to repetitive overdistention injury that may damage the detrusor muscle and the parasympathetic nerve fibers within the bladder wall. In rare circumstances, postpartum urinary retention may even lead to bladder rupture, which is a potentially life-threatening yet entirely preventable complication. Early diagnosis and timely intervention are necessary to decrease long-term consequences. There are 3 types of postpartum urinary retention: overt, covert, and persistent. Overt retention is associated with an inability to void, whereas covert retention is associated with incomplete bladder emptying. Persistent urinary retention continues beyond the third postpartum day and can persist for several weeks in rare cases. Recognition of risk factors and prompt diagnosis are important for proper management and prevention of negative sequelae. However, lack of knowledge by providers and patients alike creates barriers to accessing and receiving evidence-based care, and may further delay diagnosis for patients, especially those who experience covert postpartum urinary retention. Nationally accepted definitions and management algorithms for postpartum urinary retention are lacking, and development of such guidelines is essential for both patient care and research design. We propose intrapartum recommendations and a standardized postpartum bladder management protocol that will improve patient outcomes and contribute to the growing body of evidence-based practice in this field.

The chemotactic G protein–coupled receptor GPR183 and its most potent endogenous oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) are important for immune cell positioning in secondary lymphoid tissues. This receptor-ligand pair is associated with various diseases, in some cases contributing favorably and in other cases adversely, making GPR183 an attractive target for therapeutic intervention. We investigated the mechanisms underlying GPR183 internalization and the role of internalization in the main biological function of the receptor, chemotaxis. We found that the C terminus of the receptor was important for ligand-induced internalization but less so for constitutive (ligand-independent) internalization. β-arrestin potentiated ligand-induced internalization but was not required for ligand-induced or constitutive internalization. Caveolin and dynamin were the main mediators of both constitutive and ligand-induced receptor internalization in a mechanism independent of G protein activation. Clathrin-mediated endocytosis also contributed to constitutive GPR183 internalization in a β-arrestin–independent manner, suggesting the existence of different pools of surface-localized GPR183. Chemotaxis mediated by GPR183 depended on receptor desensitization by β-arrestins but could be uncoupled from internalization, highlighting an important biological role for the recruitment of β-arrestin to GPR183. The role of distinct pathways in internalization and chemotaxis may aid in the development of GPR183-targeting drugs for specific disease contexts.

Behavioral interventions are an increasingly popular tool for encouraging socially desirable behavior. While they are expressly designed to seize people's attention, little consideration has been given to the costs of doing so. We estimate the consequences of seizing attention in the context of a widespread highway traffic safety campaign that displays roadside fatality counts on highway dynamic message signs (DMSs). We exploit detailed data on DMS and crash locations, DMS log files, and a unique setting in Texas where fatality messages are displayed only for one week each month. We find that this behavioral intervention significantly increases the number of traffic crashes. This increase is immediate, dissipates over 7 km, and increases with the displayed fatality count. Furthermore, drivers do not habituate to these messages, even after five years, and the effects do not persist beyond the treated weeks. Crashes increase statewide during treated weeks, inconsistent with any benefits. Our results show that behavioral interventions, designed to be salient, can crowd out more important considerations, causing interventions to backfire with costly consequences.

BACKGROUND Prior suicide attempts are a strong risk factor for future attempts. There is growing interest in using longitudinal electronic health record (EHR) data to derive risk prediction models for suicidal behavior. However, model performance may be inflated by an unrecognized form of “data leakage” during model training: codes for suicide attempt outcomes may refer to prior attempts also included as predictors. OBJECTIVE We aimed to develop an automated rule for determining when documented suicide attempt codes identify distinct events. METHODS From a large healthcare system’s EHR, patients with at least two suicide attempt codes were randomly sampled (N = 369). Chart reviewers assigned clinical setting, attempt method, and inter-code interval to each pair of suicide attempt codes. The probability that the second code in a pair referred to a distinct attempt from its preceding code was calculated by setting, method, and inter-code interval. RESULTS Of the 1,253 code pairs reviewed, 78% were non-independent (i.e., two codes referred to the same event). When the second code in a pair was assigned in a setting other than the emergency department (ED), it represented a distinct event less than 15% of the time. Code pairs in which the second code was assigned in the ED at least 5 days after its preceding code had a positive predictive value (PPV) of 0.90. CONCLUSIONS Suicide attempt codes documented in an ED setting at least 5 days after a preceding code can be confidently treated as new events in EHR-based suicide risk prediction models. CLINICALTRIAL NA

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit.Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives.Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy.Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT05486195

In their implementation of Basel III, U.S. bank regulators are again including changes in the fair value of available-for-sale (AFS) debt securities in Tier 1 capital, but only for the largest U.S. banks. This paper investigates a potential impact of expanding this regulation by examining bank investment decisions in the 1990's when changes in the fair value of AFS debt securities were included in regulatory capital for all banks. Using a matched sample difference-in differences research design, we find evidence that low-capitalized banks reduced their investments in more volatile asset classes (e.g., corporate bonds, non-agency MBS) and increased their investments in less volatile asset classes (e.g., treasuries and municipal bonds) after changes in fair value were included in regulatory capital. We also find that low-capitalized banks change their holdings of these asset classes in the opposite direction after regulators subsequently excluded changes in fair value from regulatory capital. These findings inform regulators worldwide regarding a possible consequence of Basel III. We also contribute to prior research by suggesting that changes in maturity and credit risk around the passage of SFAS 115 (Beatty 1995; Hodder, Kohlbeck, and McAnally 2002) were partially obtained by changing the composition of asset classes within banks' investment portfolios.

Objective Suicide is one of the leading causes of death worldwide, yet clinicians find it difficult to reliably identify individuals at high risk for suicide. Algorithmic approaches for suicide risk detection have been developed in recent years, mostly based on data from electronic health records (EHRs). Significant room for improvement remains in the way these models take advantage of temporal information to improve predictions. Materials and Methods We propose a temporally enhanced variant of the random forest (RF) model—Omni-Temporal Balanced Random Forests (OT-BRFs)—that incorporates temporal information in every tree within the forest. We develop and validate this model using longitudinal EHRs and clinician notes from the Mass General Brigham Health System recorded between 1998 and 2018, and compare its performance to a baseline Naive Bayes Classifier and 2 standard versions of balanced RFs. Results Temporal variables were found to be associated with suicide risk: Elevated suicide risk was observed in individuals with a higher total number of visits as well as those with a low rate of visits over time, while lower suicide risk was observed in individuals with a longer period of EHR coverage. RF models were more accurate than Naive Bayesian classifiers at predicting suicide risk in advance (area under the receiver operating curve = 0.824 vs. 0.754, respectively). The proposed OT-BRF model performed best among all RF approaches, yielding a sensitivity of 0.339 at 95% specificity, compared to 0.290 and 0.286 for the other 2 RF models. Temporal variables were assigned high importance by the models that incorporated them. Discussion We demonstrate that temporal variables have an important role to play in suicide risk detection and that requiring their inclusion in all RF trees leads to increased predictive performance. Integrating temporal information into risk prediction models helps the models interpret patient data in temporal context, improving predictive performance.

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.

Chemotherapy-induced peripheral neuropathy (CIPN) is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 x 4mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (0.5 and 1.8mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin (0.5 and 1.8mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), blocked the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin43 protein expression in the DRG. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for CIPN treatment.HighlightsMeteorin produces an antinociceptive effect in both male and female mice treated with paclitaxel.Satellite glial cell reactivity induced by paclitaxel treatment is reversed by Meteorin.Retraction of intraepidermal nerve fibre (IENF) is blocked by Meteorin treatment in paclitaxel treated mice.Findings suggest a disease modifying effect of Meteorin in the mouse model of paclitaxel-induced peripheral neuropathy.

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.

Rationale: Bioimpedance may be a useful tool to guide fluid treatment and avoid organ dysfunction related to fluid overload. Objective: We examined the correlation between bioimpedance and organ dysfunction in patients with septic shock. Methods: Prospective observational study of adult intensive care unit patients fulfilling the sepsis-3 criteria. Bioimpedance was measured using a body composition monitor (BCM) and BioScan Touch i8 (MBS). We measured impedance at inclusion and after 24 h and reported the impedance, change in impedance, bioimpedance-derived fluid balance, and changes in bioimpedance-derived fluid balance. Organ markers on respiratory, circulatory, and kidney function and overall disease severity were ascertained on days 1–7. The effect of bioimpedance on the change in organ function was assessed by mixed effects linear models. We considered P

Given the high volume of hysterectomies performed, the contribution of gynecologists to the opioid crisis is potentially significant. Following a hysterectomy, most patients are over-prescribed opioids, are vulnerable to developing new persistent opioid use, and can be the source of misuse, diversion, or accidental exposure. People who misuse opioids are at risk of an overdose related death, which is now one of the leading causes of death in the United States and is rising in other countries. It is the physician's responsibility to reduce opioid use by making impactful practice changes, such as 1) using pre-emptive opioid sparing strategies, 2) optimizing multimodal nonopioid pain management, 3) restricting postoperative opioid prescribing, and 4) educating patients on proper disposal of unused opioids. These changes can be implemented with an enhanced recovery after surgery protocol, shared decision-making, and patient education strategies related to opioids.

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.