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PURPOSE: This study aimed to detect supratentorial cortical and subcortical morphological changes in pediatric patients with infratentorial tumors. METHODS: The study included 24 patients aged 4–18 years who were diagnosed with primary infratentorial tumors and 41 age- and gender-matched healthy controls. Synthetic magnetization-prepared rapid gradient echo images of brain magnetic resonance imaging were generated using deep learning algorithms applied to T2-axial images. The cortical thickness, surface area, volume, and local gyrification index (LGI), as well as subcortical gray matter volumes, were automatically calculated. Surface-based morphometry parameters for the patient and control groups were compared using the general linear model, and volumes between subcortical structures were compared using the t-test and Mann–Whitney U test. RESULTS: In the patient group, cortical thinning was observed in the left supramarginal, and cortical thickening was observed in the left caudal middle frontal (CMF), left fusiform, left lateral orbitofrontal, left lingual gyrus, right CMF, right posterior cingulate, and right superior frontal (P < 0.050). The patient group showed a volume reduction in the pars triangularis, paracentral, precentral, and supramarginal gyri of the left hemisphere (P < 0.05). A decreased surface area was observed in the bilateral superior frontal and cingulate gyri (P < 0.05). The patient group exhibited a decreased LGI in the right precentral and superior temporal gyri, left supramarginal, and posterior cingulate gyri and showed an increased volume in the bilateral caudate nucleus and hippocampus, while a volume reduction was observed in the bilateral putamen, pallidum, and amygdala (P < 0.05). The ventricular volume and tumor volume showed a positive correlation with the cortical thickness in the bilateral CMF while demonstrating a negative correlation with areas exhibiting a decreased LGI (P < 0.05). CONCLUSION: Posterior fossa tumors lead to widespread morphological changes in cortical structures, with the most prominent pattern being hypogyria. CLINICAL SIGNIFICANCE: This study illuminates the neurological impacts of infratentorial tumors in children, providing a foundation for future therapeutic strategies aimed at mitigating these adverse cortical and subcortical changes and improving patient outcomes.

Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a significant reduction in astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.

Abstract Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.

Abstract Background Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies. Methods Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP‐43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU‐9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses. Results Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU‐9 has drug‐like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU‐9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP‐43 pathology, two distinct and important overarching causes of motor neuron degeneration. Conclusions Mechanism‐focused and cell‐based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU‐9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.

Abstract Background Recent evidence indicates the importance of innate immunity and neuroinflammation with microgliosis in amyotrophic lateral sclerosis (ALS) pathology. The MCP1 (monocyte chemoattractant protein-1) and CCR2 (CC chemokine receptor 2) signaling system has been strongly associated with the innate immune responses observed in ALS patients, but the motor cortex has not been studied in detail. Methods After revealing the presence of MCP1 and CCR2 in the motor cortex of ALS patients, to elucidate, visualize, and define the timing, location and the extent of immune response in relation to upper motor neuron vulnerability and progressive degeneration in ALS, we developed MCP1-CCR2-hSOD1G93A mice, an ALS reporter line, in which cells expressing MCP1 and CCR2 are genetically labeled by monomeric red fluorescent protein-1 and enhanced green fluorescent protein, respectively. Results In the motor cortex of MCP1-CCR2-hSOD1G93A mice, unlike in the spinal cord, there was an early increase in the numbers of MCP1+ cells, which displayed microglial morphology and selectively expressed microglia markers. Even though fewer CCR2+ cells were present throughout the motor cortex, they were mainly infiltrating monocytes. Interestingly, MCP1+ cells were found in close proximity to the apical dendrites and cell bodies of corticospinal motor neurons (CSMN), further implicating the importance of their cellular interaction to neuronal pathology. Similar findings were observed in the motor cortex of ALS patients, where MCP1+ microglia were especially in close proximity to the degenerating apical dendrites of Betz cells. Conclusions Our findings reveal that the intricate cellular interplay between immune cells and upper motor neurons observed in the motor cortex of ALS mice is indeed recapitulated in ALS patients. We generated and characterized a novel model system, to study the cellular and molecular basis of this close cellular interaction and how that relates to motor neuron vulnerability and progressive degeneration in ALS.

Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

Background and aims: The 2019 European Society of Cardiology guidelines for the management of dyslipidemia consider the use of high-dose marine omega-3 fatty acid (FA) eicosapentaenoic acid (EPA) supplementation (icosapent ethyl 2 × 2g/day) to lower residual cardiovascular risk in high-risk patients with hypertriglyceridemia. This study aimed to assess the eligibility for omega-3 FA-EPA supplementation in patients with acute coronary syndromes (ACS). Methods: In a prospective Swiss cohort of patients hospitalized for ACS, eligibility for marine omega-3 FA-EPA, defined as plasma triglyceride levels ranging from 1.5 to 5.6 mmol/l, was assessed at baseline and one-year follow-up and compared across subgroups. Lipid-lowering therapy intensification with statin and ezetimibe was modelled to simulate a hypothetical systematic treatment and its effect on omega-3 FA-EPA supplementation eligibility. Results: Of 2643 patients, 98 % were prescribed statin therapy at discharge, including 62 % at a high-intensity regimen; 93 % maintained it after one year, including 53 % at a high-intensity regimen. The use of ezetimibe was 3 % at discharge and 7 % at one year. Eligibility was observed in 32 % (32 % men, 29 % women) one year post-ACS. After modelling systematic treatment with statins, ezetimibe, and both, eligibility decreased to 31 %, 25 % and 24 %, respectively. Eligibility was higher in individuals aged

Diabetes mellitus (DM) promotes atherosclerosis, leading to increased risk for cardiovascular morbidity and mortality. Diabetics represent a challenging subset of patients undergoing percutaneous coronary intervention (PCI) or who have experienced an acute coronary syndrome (ACS), a subset characterized by higher rates of recurrent ischemic events compared with non-diabetics. These events are caused by both patient-related accelerated atherosclerotic disease progression and worse stent-related adverse clinical outcomes translating into a higher risk for repeat revascularization. In addition, DM is paradoxically associated with an increased risk of major bleeding following PCI or an ACS. Secondary prevention therapies following PCI or an ACS in diabetic patients are therefore of paramount importance. This mini review focuses on the currently available evidence regarding short- and long-term secondary prevention treatments for diabetic patients undergoing PCI or who have experienced an ACS.

Objective: To assess how inadequate reporting of cointerventions influences estimated treatment effects in recent cardiovascular trials. Methods: Medline/Embase were systematically searched from January 1, 2011 to July 1, 2021 for trials evaluating pharmacologic interventions on clinical cardiovascular outcomes published in 5 high-impact journals. Information on adequate vs inadequate reporting of cointerventions, blinding, risk of bias due to deviations of intended interventions (low vs high/some concerns), funding (nonindustry vs industry), design (superiority vs noninferiority), and results were assessed by 2 reviewers. The association with effect sizes was assessed using meta-regression random-effect analysis, expressed as ratios of odds ratios (ROR). RORs of >1.0 indicated that trials with the methodological factor pointing to lower quality report larger treatment estimates. Results: In total, 164 trials were included. Of the 164 trials, 124 (74%) did not adequately report cointerventions; 89 of the 164 trials (54%) provided no information regarding cointerventions, and 70 of the 164 (43%) were at risk of bias due to inadequate blinding. Moreover, 86 of the 164 (53%) were at risk of bias due to deviation of intended interventions. Of the 164 trials, 144 (88%) were funded by the industries. Trials with inadequate reporting of cointerventions had larger treatment estimates for the primary end point (ROR, 1.08; 95% CI, 1.01-1.15; I2=0%). No significant association with results for blinding (ROR, 0.97; 95% CI, 0.91-1.03; I2=66%), deviation of intended interventions (ROR, 0.98; 95% CI, 0.92-1.04; I2=0%), or funding (ROR, 1.01; 95% CI, 0.93-1.09; I2=0%) was found. Conclusion: We conclude that trials with inadequate reporting of cointerventions showed larger treatment effect estimates, potentially indicating overestimation of therapeutic benefit. Trial Registration: Prospero Identifier: CRD42017072522

Birbiriyle çekişmeli bir mücadele yürüten devlet ve toplumsal hareketler uzun süre ayrı iki alan olarak incelenmiştir. Literatürde yoğunlukla toplumsal hareketlerin devleti ve onun kurumlarını şekillendirmesi ele alınırken devletin bazı unsurlarının da toplumsal hareketler gibi davranması gündeme gelmektedir. Özellikle yerel yönetimlerin tepeden inmeci politikaları/projeleri kabul etmeyerek kent hareketleri ile eşgüdüm halinde, protesto dahil çeşitli toplumsal hareket yöntemlerini kullanarak hak aradıkları çekişmeli bir mücadele yöntemini benimsedikleri gözlemlenmektedir. Yerel Yönetimler bünyelerinde toplumsal hareketlerde kısıtlı olan bazı kaynakları da barındırabilmektedirler. Bu makalede Kamu Yönetimi, Yerel Yönetimler ve Toplumsal Hareketler literatürlerini kesen bir araştırma alanı olarak aktivist belediyeciliğin Türkiye’deki tarihsel arka planı, hangi siyasi, ekonomik ve toplumsal koşullarda şekillendiği ve güncel dinamikleri incelenecektir. Yerel yönetimlerin neden aktivizme yöneldiği, bu tür bir aktivizmin hangi konularda yoğunlaştığı ve hangi eylem repertuarlarına başvurduğu ve hangi devlet kurumlarını neden muhatap aldığı incelenecektir. Aktivist belediyeciliğin merkeziyetçi ve kalkınmacı eğilimlerden, yerel demokrasinin yükselişinden ve son olarak da toplumsal hareketlerin sonuç alıcı etkinliğinden kaynaklandığı öne sürülecektir.

Background There is debate over whether statins increase risk of hemorrhagic stroke, so we assessed current evidence, including data from new statin trials and trials of nonstatin low‐density lipoprotein‐cholesterol (LDL‐C)– and triglyceride‐lowering therapies. Methods and Results We performed a systematic review of large randomized clinical trials (≥1000 patients with ≥2 years follow‐up) of LDL‐C–lowering therapy (statin, ezetimibe, and PCSK‐9 [proprotein convertase subtilisin/kexin type 9] inhibitor) and triglyceride‐lowering therapy (omega‐3 supplements and fibrate) that reported hemorrhagic stroke as an outcome. We searched MEDLINE, Embase, and Cochrane Library up to July 2, 2021 and updated a meta‐analysis of cardiovascular statin trials published in 2012. Among our several subgroup analyses, we looked at difference depending on stroke status and also depending on age. We identified 37 trials for LDL‐C lowering (284 301 participants) and 11 for triglyceride lowering (120 984 participants). Overall, we found a higher risk of hemorrhagic stroke for LDL‐C lowering, risk ratio (RR) 1.16 (95% CI, 1.01–1.32, P=0.03). For statins (33 trials, 216 258 participants), RR=1.17 (95% CI, 1.01–1.36); for PCSK‐9 inhibitors (2 trials, 46 488 participants), RR=0.86 (95% CI, 0.43–1.74); and for ezetimibe (2 trials, 21 555 participants), RR=1.14 (95% CI, 0.64–2.03). In statin trials of patients with previous stroke/transient ischemic attack, RR was 1.46 (95% CI, 1.05–2.04), and in trials with mean age ≥65 years old, RR=1.34 (95% CI, 1.04–1.73) (Pint=0.14 and Pint=0.23 respectively); for triglyceride lowering (11 trials, 120 984 participants), RR=1.05 (95% CI, 0.86–1.30). Conclusions We found evidence for a small increased risk of hemorrhagic stroke events with LDL‐C–lowering therapies but no clear evidence for triglyceride‐lowering therapies. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021275363.

BackgroundLipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk.MethodsWe performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs.ResultsWe included 27 trials with 188'259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97-1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00-1.23), while the RR for CV death was 0.96 (0.91-1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99-1.47).ConclusionLLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations.Prospero registrationCRD42021271658.

BackgroundLongitudinal association studies of atrial fibrillation (AF) and cognitive functions have shown an unclear role of AF-type and often differ in methodological aspects. We therefore aim to investigate longitudinal changes in cognitive functions in association with AF-type (non-paroxysmal vs. paroxysmal) and comorbidities in the Swiss-AF cohort.MethodsSeven cognitive measures were administered up to five times between 2014 and 2022. Age-education standardized scores were calculated and association between longitudinal change in scores and baseline AF-type investigated using linear mixed-effects models. Associations between AF-type and time to cognitive drop, an observed score of at least one standard deviation below individual's age-education standardized cognitive scores at baseline, were studied using Cox proportional hazard models of each cognitive test, censoring patients at their last measurement. Models were adjusted for baseline covariates.Results2,415 AF patients (mean age 73.2 years; 1,080 paroxysmal, 1,335 non-paroxysmal AF) participated in this Swiss multicenter prospective cohort study. Mean cognitive scores increased longitudinally (median follow-up 3.97 years). Non-paroxysmal AF patients showed smaller longitudinal increases in Digit Symbol Substitution Test (DSST), Cognitive Construct Score (CoCo)and Trail Making Test part B (TMT-B) scores vs. paroxysmal AF patients. Diabetes, history of stroke/TIA and depression were associated with worse performance on all cognitive tests. No differences in time to cognitive drop were observed between AF-types in any cognitive test.ConclusionThis study indicated preserved cognitive functioning in AF patients, best explained by practice effects. Smaller practice effects were found in non-paroxysmal AF patients in the DSST, TMT-B and the CoCo and could indicate a marker of subtle cognitive decline. As diabetes, history of stroke/TIA and depression—but not AF-type—were associated with cognitive drop, more attention should be given to risk factors and underlying mechanisms of AF.

Background Randomized clinical trials (RCTs) might not be representative of the real‐world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid‐lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid‐lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We predefined groups: older adults (>70 or >75 years), women, non‐Whites, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, multimorbidity (≥2 chronic diseases), and polypharmacy. We counted the number of RCTs excluding patients of the predefined groups and meta‐analyzed the prevalence of included patients to obtain pooled estimates with a random‐effects model. We included 42 RCTs (298 605 patients). Eighty‐one percent of trials excluded patients with severe and 76% those with moderate kidney failure. Seventy‐one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults. The pooled prevalence for patients >70 years of age was 25% (95% CI, 0%–49%), 11% (3%–18%) for >75 years of age, and 51% (38%–63%) for multimorbidity. Conclusions The majority of lipid‐lowering therapy trials excluded patients with common diseases, such as moderate‐to‐severe kidney disease or heart failure or with immunosuppression. Underrepresenting certain populations, including women and older adults, might lead to limited transportability of study results and uncertainty on possible side‐effects and efficacy in these groups. Future trials should promote diversity in the recruitment strategies and improve equity in cardiovascular research. Registration URL: ClinicalTrials.gov; Unique Identifier: CRD42021253909.

TRIAL DESIGN: In the Special Program University Medicine-Acute Coronary Syndromes (SPUM-ACS) observational study (clinical trial registration: NCT01000701), a multicentre before-after clinical trial, we assessed 5-year outcome after acute coronary syndrome, comparing a systematic with an opportunistic smoking cessation counselling phase. METHODS: We studied smokers who were hospitalised for acute coronary syndromes (ACS), and we assessed self-reported smoking cessation, incidence of cardiovascular events and mortality 5 years after hospital discharge. In the observational phase, from August 2009 to October 2010, only smokers who requested smoking cessation counselling received it during hospitalisation. In the interventional phase, from November 2010 to February 2012, hospitalised smokers with ACS were systematically offered intensive smoking cessation counselling including four telephone calls within 2 months of discharge. Because of the before-after design, the care givers were aware of study phase. The objective was to assess whether systematic counselling to every smoker with ACS has an impact on the long-term smoking cessation rate, incidence of cardiovascular events and mortality. Missing data on smoking cessation were analysed with multiple imputation. The study was not powered to assess differences in 5-year smoking cessation rates or cardiovascular outcomes. RESULTS: Overall, 458 smokers with ACS were included at baseline (225 during the intervention phase and 233 during the observation phase). At 5 years, 286 (62.4%) reported their smoking status (140 for the intervention phase and 146 for the observation phase) and 51 (11.1%) had died. There was no statistically significant difference in the abstinence rate between the interventional phase (75/140, 54%), and the observational phase (68/146, 47%), with a risk ratio with multiple imputation adjusted for age, sex, education and ACS type of 1.13 (95% confidence interval [CI] 0.84–1.51, p = 0.4). The 5-year risk of major acute cardiovascular event was similar in the intervention phase as compared with the observational phase. The multivariate adjusted hazard ratio for all-cause mortality was 0.84 (95% CI 0.45–1.60, p = 0.6). CONCLUSIONS: In this controlled long-term interventional study, systematic intensive smoking cessation counselling in all hospitalised smokers with ACS did not increase 5-year smoking cessation rates, nor decrease cardiovascular event recurrence, as compared with opportunistic smoking cessation counselling during hospitalization.

Background: An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. Objectives: The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Methods: Within IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. Results: In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). Conclusions: Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)

Subclinical thyroid disorders have a high prevalence among older individuals and women. Subclinical hypothyroidism is diagnosed by elevated serum levels of thyroid-stimulating hormone (TSH) with thyroxine levels within the reference range, and subclinical hyperthyroidism is diagnosed by low TSH in conjunction with thyroxine and triiodothyronine levels within reference ranges. Atrial fibrillation is the most commonly diagnosed cardiac arrhythmia and has been associated with an increased risk of mortality, heart failure, stroke, and depression. Mechanistic data from animal and human physiology studies as well as observational data in humans support an association of subclinical hyperthyroidism with atrial fibrillation. Guidelines recommend the measurement of TSH in the evaluation of new-onset atrial fibrillation. All patients with overt hyperthyroidism should be treated, and treatment of subclinical hyperthyroidism should be considered in patients older than 65 years with TSH < 0.4 mlU/L, or in younger patients with TSH < 0.1 mlU/L. Guidelines also recommend screening for AF in patients with known hyperthyroidism. Wearable devices that measure the heart electrical activity continuously may be a novel strategy to detect atrial fibrillation in patients at risk. In this review, we explore the interplay between thyroid hormones and atrial fibrillation, management controversies in subclinical hyperthyroidism, and potential strategies to improve the management of atrial fibrillation in patients with subclinical hyperthyroidism.

Guidelines recommend brief smoking cessation interventions for hospitalized smokers reporting low motivation-to-quit. However, an intensive smoking cessation intervention may improve smoking cessation for these smokers. We conducted a secondary analysis of a pre-post interventional study that tested the efficacy of a proactive approach systematically offering intensive smoking cessation intervention to all hospitalized smokers with acute coronary syndrome (ACS) compared to a reactive approach offering it only to smokers willing to quit.We analyzed data from one study site in Switzerland, which recorded motivation-to-quit smoking at study inclusion between 08.2009 and 02.2012. The primary outcome was smoking cessation at 1- and 5-year. We tested for interaction by participant’s motivation-to-quit score (low vs. high motivation), and calculated multivariable adjusted risk ratios (RR), stratified by motivation score.We obtained motivation scores for 230 smokers. Follow-up was 94% (217/230) at 1-year and 68% (156/230) at 5-year. Among participants with low motivation to quit, 19% of smokers in the reactive phase had quit at 1 year compared to 50% of smokers in the proactive phase (multivariable adjusted RR = 2.85, 95%CI:0.91–8.91). Among highly motivated smokers, rates did not differ between phases: 48% vs. 49% (multivariable adjusted RR = 1.02, 95%CI:0.75–1.39, p-value for interaction between motivation-to-quit categories = 0.10). At 5-year follow-up, the point estimates were similar.While our study has limitations inherent to the study design and sample size, we found that a proactive approach to offer systematic smoking cessation counseling for smokers with ACS reporting low motivation to quit was associated with higher smoking cessation rates at 1 year.

Abstract Background Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes. Methods The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA). Results Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL

Background Trimethylamine N‐oxide (TMAO) may have prothrombotic properties. We examined the association of TMAO quartiles with major adverse cardiovascular events (MACE) and the effect of TMAO on the efficacy of ticagrelor. Methods and Results PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin ‐ Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow‐up 33 months). Baseline plasma concentrations of TMAO were measured in a nested case‐control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (MACE) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [eGFR]. Odds ratios (OR) were used for the association between TMAO quartiles and MACE, adjusting for baseline clinical characteristics (age, sex, eGFR, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs‐TnT [high‐sensitivity troponin T], hs‐CRP [high‐sensitivity C‐reactive protein], NT‐proBNP [N‐terminal‐pro‐B‐type natriuretic peptide]). Higher TMAO quartiles were associated with risk of MACE (OR for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06–1.93, P trend=0.015). The association was driven by cardiovascular death (OR 2.25, 95% CI, 1.28–3.96, P trend=0.003) and stroke (OR 2.68, 95% CI, 1.39–5.17, P trend

Objective. To obtain a real-world perspective of the optimal timing of angiography performed within 24 hours of admission with non-ST elevation myocardial infarction (NSTEMI). Background. Current guidelines recommend angiography within 24 hours of hospitalisation with NSTEMI. The recent VERDICT trial found that angiography within 12 hours of admission with NSTEMI was associated with improved cardiovascular outcomes among high-risk patients. We compared the outcomes of real-world NSTEMI patients undergoing angiography within 12 hours of admission with those of patients undergoing angiography 12 to 24 hours after admission. Methods. NSTEMI patients without life-threatening features who received angiography within 24 hours of admission were obtained from the SPUM-ACS registry, a cohort of consecutive patients admitted with acute coronary syndromes to four university hospitals in Switzerland. Cox models assessed for an association between door-to-catheter time and one-year major adverse cardiovascular events (MACE: cardiovascular mortality, myocardial infarction, and stroke). Results. Of 2672 NSTEMI patients, 1832 met the inclusion criteria. Among them, 1464 patients underwent angiography within 12 hours (12 h group) compared with 368 patients between 12 and 24 hours (12–24 h group). Multiple logistic regression identified out-of-hours admission as the only factor associated with delayed angiography. After 2 : 1 propensity score matching, 736 patients from the 12 h group and 368 patients from the 12–24 h group demonstrated no significant difference in rates of one-year MACE (7.7% vs. 7.3%, HR: 1.050, 95% CI 0.637–1.733, p=0.847). Stratification by GRACE score (>140 vs. ≤140) found no significant reduction in MACE among high-risk patients in the 12 h group (p for interaction = 0.601). Conclusions. In an unselected real-world cohort of NSTEMI patients, angiography within 12 hours of admission was not associated with improved one-year cardiovascular outcomes when compared with angiography 12 and 24 hours after admission, even among high-risk patients.

BACKGROUND The role of income in cardiovascular disease prevention after an acute coronary syndrome (ACS) remains unclear. We aimed to assess the association between income and control of cardiovascular risk factors one year after an ACS in a country with universal health insurance. METHODS Between 2013 and 2014, we studied 255 consecutive patients with ACS in an observational study in a university hospital in Switzerland in which self-reported household income was assessed. We classified patients into two categories based on the median income in Switzerland: higher than CHF 6000 (€ 5300) or less than or equal to CHF 6000 (€ 5300) per month. One year after discharge, patients were evaluated for the achievement of lipid and blood pressure targets, smoking cessation and drug adherence. Multivariate odds ratios (OR) were adjusted for age, sex, education, living status and working status. RESULTS Overall, 52.2% (n = 133) of patients with ACS were in the low-income category and 47.8% (n = 122) were in the high-income category. One year after discharge, high-income patients had higher rates of smoking cessation (64.2 vs 30.1%, multivariate-adjusted odds ratio (OR) 3.82, 95% confidence interval (CI) 1.58–9.24) and blood pressure target achievement (78.6 vs 60.2%, multivariate-adjusted OR 2.19, 95% CI 1.09–4.41) compared to those in the low-income category. There were no differences regarding adherence to drugs or lipid control between the two income groups. CONCLUSION A high household income was associated with a higher rate of smoking cessation and better control of blood pressure one year after ACS, independently of education, living status and working status.

BackgroundStructured secondary cardiovascular prevention programs (SSCP) following acute coronary syndromes (ACS) may reduce major adverse cardiovascular events (MACE) through better adherence to post-ACS recommendations.MethodsThrough a prospective multicenter cohort study, we compared the outcomes of two sequential post-ACS patient cohorts, the initial one receiving standard care (SC) followed by one receiving additional interventions (SSCP) aimed at improving patient education as well as healthcare provider and hospital systems. The primary endpoint was MACE at one year. Secondary endpoints included adherence to recommended therapies, attendance to cardiac rehabilitation (CR) and successful achievement of cardiovascular risk factor (CVRF) targets.ResultsIn total, 2498 post-ACS patients from 4 Swiss university hospitals were included: 1210 vs 1288 in the SC and SSCP groups, respectively. The SSCP group demonstrated a significant increase in attendance to CR programs (RR 1.08, 95%CI 1.02-1.14, P = 0.006), despite not achieving the primary MACE endpoint (HR 0.97, 95%CI 0.77-1.22, P = 0.79). After age-stratification, significant reductions in cardiac death, MI and stroke events (HR 0.53, 95%CI 0.30-0.93, P for interaction = 0.016) were observed for SSCP patients ≤ 65 years old. The SSCP group also scored significantly better for the LDL cholesterol target (RR 1.07, 95%CI 1.02-1.13, P = 0.012), systolic blood pressure target (RR 1.06, 95%CI 1.01-1.13, P = 0.029) and physical activity (RR 1.10, 95%CI 1.01-1.20, P = 0.021).ConclusionsThe implementation of an SSCP post ACS was associated with an improvement in the control of CVRF and attendance to CR programs, and was also associated with significant reductions in cardiac death, MI and stroke at one year for patients ≤65years old.

Understanding the cellular and molecular basis of selective vulnerability has been challenging, especially for motor neuron diseases. Developing drugs that improve the health of neurons that display selective vulnerability relies on in vivo cell-based models and quantitative readout measures that translate to patient outcome. We initially developed and characterized UCHL1-eGFP mice, in which motor neurons are labeled with eGFP that is stable and long-lasting. By crossing UCHL1-eGFP to amyotrophic lateral sclerosis (ALS) disease models, we generated ALS mouse models with fluorescently labeled motor neurons. Their examination over time began to reveal the cellular basis of selective vulnerability even within the related motor neuron pools. Accumulation of misfolded SOD1 protein both in the corticospinal and spinal motor neurons over time correlated with the timing and extent of degeneration. This further proved simultaneous degeneration of both upper and lower motor neurons, and the requirement to consider both upper and lower motor neuron populations in drug discovery efforts. Demonstration of the direct correlation between misfolded SOD1 accumulation and motor neuron degeneration in both cortex and spinal cord is important for building cell-based assays in vivo. Our report sets the stage for shifting focus from mice to diseased neurons for drug discovery efforts, especially for motor neuron diseases.

BackgroundEarly withdrawal of recommended antiplatelet treatment with clopidogrel adversely affects prognosis following percutaneous coronary interventions. Optimal antiplatelet treatment is essential following ST‐segment elevation myocardial infarction (STEMI) given the increased risk of thrombotic complications. This study assessed the frequency, predictors, and clinical impact of early prasugrel cessation in patients with STEMI undergoing primary percutaneous coronary interventions. Methods and ResultsWe pooled patients with STEMI discharged on prasugrel in 2 prospective registries (Bern PCI Registry [NCT02241291] and SPUM‐ACS (Inflammation and Acute Coronary Syndromes) [NCT01000701]) and 1 STEMI trial (COMFORTABLE‐AMI (Comparison of Biomatrix Versus Gazelle in ST‐Elevation Myocardial Infarction) [NCT00962416]). Prasugrel treatment status at 1 year was categorized as no cessation; crossover to another P2Y12‐inhibitor; physician‐recommended discontinuation; and disruption because of bleeding, side effects, or patient noncompliance. In time‐dependent analyses, we assessed the impact of prasugrel cessation on the primary end point, a composite of cardiac death, myocardial infarction, and stroke. Of all 1830 included patients (17% women, mean age 59 years), 83% were treated with new‐generation drug‐eluting stents. At 1 year, any prasugrel cessation had occurred in 13.8% of patients including crossover (7.2%), discontinuation (3.7%), and disruption (2.9%). Independent predictors of any prasugrel cessation included female sex, age, and history of cerebrovascular event. The primary end point occurred in 5.2% of patients and was more frequent following disruption (hazard ratio 3.04, 95% confidence interval,1.34–6.91; P=0.008), without significant impact of crossover or discontinuation. Consistent findings were observed for all‐cause death, myocardial infarction, and stent thrombosis following prasugrel disruption. ConclusionsIn this contemporary study of patients with STEMI, early prasugrel cessation was not uncommon and primarily involved change to another P2Y12‐inhibitor. Disruption was the only type of early prasugrel cessation associated with statistically significant excess in ischemic risk within 1 year following primary percutaneous coronary interventions.