4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold.

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb ) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m2. Compared with placebo, the use of semaglutide was associated with substantial decreases in long-term relative (WMD -12.1%, 95% CI -13.5 to -10.7) and absolute body weight (WMD -12.3 kg, 95% CI -13.6 to -11.0). At the longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared with 2.2% with placebo (RR 15.08, 95% CI 9.31 to 24.43). The risk of gastrointestinal adverse events was higher in participants who took semaglutide than placebo (RR 1:47, 95% CI 1.28 to 1.68); however, the majority of these events were transient and mild-to-moderate in severity and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss in patients with overweight/obesity and without diabetes.

Efficacy and Safety of E-Cigarette Use for Smoking Cessation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: People who smoke conventional cigarettes are increasingly turning to electronic cigarettes (e-cigarettes) as a pathway to quitting. However, the efficacy and safety of e-cigarettes for smoking cessation remains controversial. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), identified through a systematic search of the MEDLINE, EMBASE, and Cochrane CENTRAL databases. Inclusion was restricted to RCTs with a follow-up duration ≥6 months. The primary endpoint was the most rigorous criterion of biochemically validated abstinence at maximum follow-up, and the primary comparison was nicotine e-cigarettes versus any conventional (ie, non-e-cigarette) smoking cessation therapy. The Cochrane Risk of Bias Tool was used to assess bias. Count data were pooled across trials using random-effects models with inverse variance weighting to estimate relative risks (RRs) and corresponding 95% confidence intervals (CIs). We registered the study protocol with the Open Science Framework Registries (osf.io/26fkq). RESULTS: A total of 5 RCTs (n = 3253) were included. Compared with conventional smoking cessation therapies, the use of nicotine e-cigarettes was associated with an increase in abstinence, defined by the most rigorous criterion of abstinence reported (RR 1.77; 95% CI, 1.29-2.44). Nicotine e-cigarettes also increased abstinence (defined by the most rigorous criterion) compared with non-nicotine e-cigarettes (RR 1.56; 95% CI, 1.13-2.15). The incidence of death or serious adverse events was low across all trials at maximum follow-up. CONCLUSIONS: Among individuals attempting to quit smoking, nicotine e-cigarettes are more efficacious than conventional nicotine replacement or behavioral smoking cessation therapies, and may prove beneficial in reducing smoking-related health risks.

Cardiovascular Pathophysiology, Epidemiology, and Treatment Considerations of Coronavirus Disease 2019 (COVID-19): A Review.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly evolving, with important cardiovascular considerations. The presence of underlying cardiovascular risk factors and established cardiovascular disease (CVD) may affect the severity and clinical management of patients with COVID-19. We conducted a review of the literature to summarize the cardiovascular pathophysiology, risk factors, clinical presentations, and treatment considerations of COVID-19 patients with underlying CVD. Angiotensin-converting enzyme 2 (ACE2) has been identified as a functional receptor for the SARS-CoV-2 virus, and it is associated with the cardiovascular system. Hypertension, diabetes, and CVD are the most common comorbidities in COVID-19 patients, and these factors have been associated with the progression and severity of COVID-19. However, elderly populations, who develop more-severe COVID-19 complications, are naturally exposed to these comorbidities, underscoring the possible confounding of age. Observational data support international cardiovascular societies' recommendations to not discontinue ACE inhibitor/angiotensin-receptor blocker therapy in patients with guideline indications for fear of the increased risk of SARS-CoV-2 infection, severe disease, or death. In addition to the cardiotoxicity of experimental antivirals and potential interactions of experimental therapies with cardiovascular drugs, several strategies for cardiovascular protection have been recommended in COVID-19 patients with underlying CVD. Troponin elevation is associated with increased risk of in-hospital mortality and adverse outcomes in patients with COVID-19. Cardiovascular care teams should have a high index of suspicion for fulminant myocarditis-like presentations being SARS-CoV-2 positive, and remain vigilant for cardiovascular complications in COVID-19 patients.

La pandémie de la maladie à coronavirus 2019 (COVID-19) causée par le coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2) évolue rapidement, et des considérations cardiovasculaires importantes y sont rattachées. La présence de facteurs de risque cardiovasculaire sous-jacents ou d'une maladie cardiovasculaire (MCV) établie peut influer la gravité de la COVID-19 et la prise en charge des patients qui en sont atteints. Nous avons effectué une revue de la littérature afin de résumé la physiopathologie cardiovasculaire, les facteurs de risque, les manifestations cliniques et les traitements à considérer pour les patients atteints de la COVID-19 et présentant une MCV sous-jacente. L'enzyme de conversion de l'angiotensine 2 (ECA2), qui intervient dans le système cardiovasculaire, a été identifiée comme étant un récepteur fonctionnel du SRAS-CoV-2. L'hypertension, le diabète et la MCV sont les affections concomitantes les plus fréquentes chez les patients atteints de la COVID-19, et ces facteurs ont été associés à l'évolution et à la gravité de la COVID-19. Les personnes âgées, chez qui les complications de la COVID-19 sont plus graves, sont cependant naturellement plus exposées à ces affections, ce qui fait ressortir l'âge comme étant un facteur de confusion possible. Les données d'observation soutiennent les recommandations des organismes internationaux s'intéressant à la santé cardiovasculaire, qui sont de ne pas cesser le traitement d'inhibiteur d'enzyme de conversion de l'angiotensine ou d'antagoniste des récepteurs de l'angiotensine lorsque ces traitements sont indiqués selon les lignes directrices, par crainte d'accroître le risque de maladie grave ou de décès pour les patients atteints par le SRAS-CoV-2. Compte tenu des effets cardiotoxiques des antiviraux expérimentaux et des interactions possibles entre les traitements expérimentaux et les médicaments utilisés pour traiter les MCV, plusieurs stratégies de protection cardiovasculaire ont été recommandées pour le traitement des patients atteints de la COVID-19 présentant une MCV sous-jacente. L'élévation de la troponine est associée à un risque accru de mortalité hospitalière et à des résultats défavorables pour les patients atteints de la COVID-19. Les équipes de soins cardiovasculaires doivent toujours garder à l'esprit qu'un patient présentant des symptômes évocateurs d'une myocardite fulminante pourrait être infecté par le SRAS-CoV-2 et surveiller les complications cardiovasculaires chez les patients atteints de la COVID-19.

Diagnostic performance of 18F-DCFPyL positron emission tomography/computed tomography for biochemically recurrent prostate cancer and change-of-management analysis.

INTRODUCTION: Conventional imaging (CI) performs poorly to identify sites of disease in biochemically recurrent prostate cancer. 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) is most studied but has a very short half-life. This study reports the diagnostic performance of the novel prostate-specific membrane antigen (PSMA) radiotracer 18F-DCFPyL using real-life data and tumor board simulation to estimate the impact of 18F-DCFPyL PET on patient management. METHODS: Ninety-three 18F-DCFPyL PET/CT scans performed for patients previously treated for prostate cancer with a rising prostate-specific antigen (PSA) were retrospectively compared to contemporary CI and clinical imaging and PSA followups. A chart review was performed to document prior imaging, pathology results, serial serum PSA measurements, and other pertinent clinical data. Clinical utility of 18F-DCFPyL PET was measured using a simulated tumor board formed by three physicians with extensive prostate cancer experience deciding on management with and without knowledge of PET/CT results. RESULTS: At median PSA 2.27 (interquartile rage [IQR] 5.27], 82% of 18F-DCFPyL PET/CT demonstrated at least one site of disease: non-regional lymph nodes (37% of scans), regional lymph node metastases (28%), local recurrence (27%), and bone metastases (20%), with higher PET positivity at higher PSA. Compared to 18F-DCFPyL PET/CT, CI showed overall poor performance, with accuracy below 20% for all extent of disease. PET/CT changed management in 44% of cases. The most frequent scenario was a radical change from initiating androgen deprivation therapy (ADT) to stereotactic body radiotherapy (SBRT) of oligo-lesional disease. In univariate and multivariate analysis, no patient characteristic could predict change of management by PET/CT results. CONCLUSIONS: 18F-DCFPyL significantly outperforms CI in recurring prostate cancer and is likely to impact management.

Meta-Analysis of Complete versus Culprit-Only Revascularization in Patients with ST-Segment Elevation Myocardial Infarction and Multivessel Coronary Disease.

Approximately half of patients with ST-segment elevation myocardial infarction (STEMI) present with noninfarct related multivessel coronary artery disease (CAD) during primary percutaneous coronary intervention (PCI). However, questions remain concerning whether patients with STEMI and multivessel CAD should routinely undergo complete revascularization. Our objective was to compare the risks of major cardiovascular outcomes and procedural complications in patients with STEMI and multivessel CAD randomized to complete revascularization versus culprit-only PCI. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing complete revascularization to culprit-only PCI. RCTs were identified via a systematic search of MEDLINE, Embase, and Cochrane CENTRAL. Count data were pooled using DerSimonian and Laird random-effects models with inverse variance weighting to obtain relative risks (RRs) and 95% confidence intervals (CIs). A total of 9 RCTs (n = 6,751) were included, with mean/median follow-up times ranging from 6 to 36 months. Compared with culprit-only PCI, complete revascularization was associated with a substantial reduction in major adverse cardiovascular events (13.1% vs 22.1%; RR: 0.54; 95%CI: 0.43 to 0.66), repeat myocardial infarction (4.9% vs 6.8%; RR: 0.64; 95%CI: 0.48 to 0.84), and repeat revascularization (3.7% vs 12.3%; RR: 0.33; 95%CI: 0.25 to 0.44). Complete revascularization may have beneficial effects on all-cause and cardiovascular mortality, but 95%CIs were wide. Findings for stroke, major bleeding, and contrast-induced acute kidney injury were inconclusive. In conclusion, complete coronary artery revascularization appears to confer benefit over culprit-only PCI in patients with STEMI and multivessel CAD, and should be considered a first-line strategy in these patients.

Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients.

Current guidelines recommend transcatheter aortic valve implantation (TAVI) for patients with severe aortic stenosis at elevated surgical risk, but not for patients at low surgical risk. Our objective is to compare major clinical outcomes and procedural complications with TAVI versus surgical aortic valve replacement in patients with severe aortic stenosis at low surgical risk. We conducted a systematic review and meta-analysis of randomized controlled trials, identified through a systematic search of the MEDLINE, Embase, and Cochrane databases. Count data were pooled across trials using random-effects models with inverse variance weighting to obtain relative risks (RRs) and corresponding 95% confidence intervals (CIs). Three randomized controlled trials (n = 2,629) were included. At 30 days, TAVI was associated with a substantial reduction in all-cause mortality (RR: 0.45, 95%CI: 0.20 to 0.99), atrial fibrillation (RR: 0.27, 95%CI: 0.17 to 0.41), life threatening/disabling bleeding (RR: 0.29, 95%CI: 0.12 to 0.69), and acute kidney injury (RR: 0.28, 95%CI: 0.14 to 0.57). The reduction in atrial fibrillation persisted at 12 months (RR: 0.32, 95%CI: 0.21 to 0.49). However, TAVI patients had an increased risk of permanent pacemaker implantation at both 30 days (RR: 3.13, 95%CI: 1.36 to 7.21) and 12 months (RR: 2.99, 95%CI: 1.19 to 7.51). Due to the low absolute numbers of events, results were inconclusive at 30 days and 12 months for cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction. In conclusion, while some outcomes remained inconclusive, these data suggest that TAVI should be considered as a first-line therapy for the treatment of severe aortic stenosis in low surgical risk patients.