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When are observational studies as credible as randomised trials?

Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF).

Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05–1.08]), MI (OR per 1-SD increase: 1.74 [1.21–2.51]), HF (OR per 1-SD increase: 1.28 [1.10–1.48]), and AF (OR per 1-SD increase: 1.20 [1.08–1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225–1.587]), MI (beta: 0.045 [0.023–0.067]), HF (beta: 0.105 [0.066–0.143]) and AF (beta: 0.021 [0.012–0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models.

We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD.

Mettre à jour les recommandations sur la corticothérapie prénatale dans la période de prématurité tardive.

Personnes enceintes à risque d’accouchement prématuré entre 34 SA + 0 j et 36 SA + 6 j.

Administrer ou non un traitement unique de corticothérapie prénatale entre 34 SA + 0 j et 36 SA + 6 j.

Morbidité néonatale (détresse respiratoire, hypoglycémie), troubles neurodéveloppementaux à long terme et autres issues indésirables à long terme (retard de croissance, trouble cardiométabolique, problèmes respiratoires).

La corticothérapie prénatale administrée entre 34 SA + 0 j et 36 SA + 6 j diminue le risque de morbidité respiratoire néonatale, mais augmente le risque d’hypoglycémie néonatale. Les effets à long terme de la corticothérapie prénatale administrée entre 34 SA + 0 j et 36 SA + 6 j demeurent incertains.

Pour obtenir des données probantes sur les effets néonataux de l’administration d’une corticothérapie prénatale en période de prématurité tardive, les auteurs ont résumé les données de l’analyse Cochrane de 2020 sur la corticothérapie prénatale et ont combiné ces données à celles des essais randomisés répertoriés par une recherche dans la base de données Ovid MEDLINE pour les articles publiés entre le 1^er janvier 2020 et le 11 mai 2022. Compte tenu du manque de données probantes directes concernant les effets de la corticothérapie prénatale en période de prématurité tardive sur le devenir neurodéveloppemental, les auteurs ont résumé les données concernant les effets de la corticothérapie prénatale sur le devenir neurodéveloppemental dans tous les âges gestationnels en utilisant les sources suivantes : (1) l’analyse Cochrane de 2020 et (2) les données probantes obtenues à partir de recherches dans les bases de données Ovid MEDLINE, Embase et Cochrane Central Register of Controlled Trials (CENTRAL) de leur création au 15 janvier 2022. Aucune restriction n’a été appliquée en ce qui concerne la date ou la langue de publication. Compte tenu du manque de données probantes directes concernant les effets de la corticothérapie prénatale en cas de prématuré sur les issues à long terme, les auteurs ont résumé les données concernant les effets de la corticothérapie prénatale sur les autres issues à long terme dans tous les âges gestationnels en combinant les données de l’analyse Cochrane de 2020 et celles tirées des études observationnelles abordant les effets à long terme de la corticothérapie prénatale sur la croissance, le devenir cardiométabolique et le devenir respiratoire, études répertoriées dans Ovid MEDLINE et publiées de sa création au 22 octobre 2021. Les auteurs ont examiné la bibliographie des études et revues systématiques retenues afin d’obtenir des références supplémentaires. Voir l’annexe A pour connaître les termes de recherche et consulter les résumés.

Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l’annexe B en ligne (tableau B1 pour les définitions et tableau B2 pour l’interprétation des recommandations fortes et conditionnelles [faibles]).

Fournisseurs de soins de maternité, notamment les sages-femmes, les médecins de famille et les obstétriciens.

• 1.

  Les données probantes indiquent que la corticothérapie prénatale en cas de prématurité est associée à une réduction de la morbidité et de la mortalité périnatales. Le rapport risques-bénéfices absolus de la corticothérapie prénatale change en période de prématurité tardive comparativement aux âges gestationnels plus précoces (moyenne).

• 2.

  La corticothérapie prénatale en période de prématurité tardive, c’est-à-dire administrée entre 34 SA + 0 j et 36 SA + 6 j, diminue le risque de morbidité respiratoire néonatale, mais augmente le risque d’hypoglycémie néonatale (élevée).

• 3.

  Chez une personne enceinte atteinte d’un diabète sucré préexistant, l’administration d’une corticothérapie prénatale en période de prématurité tardive peut aggraver l’hypoglycémie néonatale (faible).

• 4.

  Les effets de la corticothérapie prénatale en période de prématurité tardive demeurent incertains en ce qui concerne le devenir neurodéveloppemental et les autres issues é long terme (faible).

• 5.

  D’autres recherches sont nécessaires pour déterminer la dose optimale pour la corticothérapie prénatale (moyenne).

• 1.

  Il demeure fortement recommandé d’administrer la corticothérapie prénatale jusqu’à 33 SA + 6 j lorsque l’accouchement est attendu dans les 7 jours (forte, élevée).

• 2.

  L’âge gestationnel jusqu’où la corticothérapie prénatale est fortement recommandée passe de 34 SA + 6 j à 33 SA + 6 j (conditionnelle, faible).

• 3.

  Chez les personnes enceintes à risque d’accouchement prématuré entre 34 SA + 0 j et 36 SA + 6 j, il est recommandé d’envisager la corticothérapie prénatale en fonction de la discussion avec la patiente sur les risques et bénéfices absolus spécifiques à la semaine d’âge gestationnel (forte, moyenne).

• 4.

  La corticothérapie prénatale n'est généralement pas recommandée entre 34 SA + 0 j et 36 SA + 6 j en cas de diabète préexistant. Dans la discussion sur les risques et bénéfices de la corticothérapie prénatale, il y a lieu de prendre en compte l'augmentation du risque d'hypoglycémie dans de telles grossesses (conditionnelle, faible). Compte tenu du peu de données probantes disponibles sur l'effet de la CTP en période de prématurité tardive chez les patientes ayant un diabète préexistant, le présent document — conformément à ce qu'on peut lire dans d'autres lignes directrices récentes2 — ne recommande généralement pas la CTP en période de prématurité tardive chez les patientes ayant un diabète préexistant en raison du risque d'aggravation de l'hypoglycémie.

To update recommendations for administration of antenatal corticosteroids in the late preterm period.

Pregnant individuals at risk of preterm birth from 34⁰ to 36⁶ weeks gestation.

Administration or non-administration of a single course of antenatal corticosteroids at 34⁰ to 36⁶ weeks gestation.

Neonatal morbidity (respiratory distress, hypoglycemia), long-term neurodevelopment, and other long-term outcomes (growth, cardiac/metabolic, respiratory).

Administration of antenatal corticosteroids from 34⁰ to 36⁶ weeks gestation decreases the risk of neonatal respiratory distress but increases the risk of neonatal hypoglycemia. The long-term impacts of antenatal corticosteroid administration from 34⁰ to 36⁶ weeks gestation are uncertain.

For evidence on the neonatal effects of antenatal corticosteroid administration at late preterm gestation, we summarized evidence from the 2020 Cochrane review of antenatal corticosteroids and combined this with evidence from published randomized trials identified by searching Ovid MEDLINE from January 1, 2020, to May 11, 2022. Given the absence of direct evidence on the impact of late preterm antenatal corticosteroid administration on neurodevelopmental outcomes, we summarized evidence on the impact of antenatal corticosteroids across gestational ages on neurodevelopmental outcomes using the following sources: (1) the 2020 Cochrane review; and (2) evidence obtained by searching Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to January 5, 2022. We did not apply date or language restrictions. Given the absence of direct evidence on the impact of late preterm antenatal corticosteroid administration on other long-term outcomes, we summarized evidence on the impact of antenatal corticosteroids across gestational ages on other long-term outcomes by combining findings from the 2020 Cochrane review with evidence obtained by searching Ovid MEDLINE for observational studies related to long-term cardiometabolic, respiratory, and growth effects of antenatal corticosteroids from inception to October 22, 2021. We reviewed reference lists of included studies and relevant systematic reviews for additional references. See Appendix A for search terms and summaries.

The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix B (Tables B1 for definitions and B2 for interpretations of strong and conditional [weak] recommendations).

Maternity care providers, including midwives, family physicians, and obstetricians.

• 1.

  Evidence suggests that antenatal corticosteroid administration at preterm gestation is associated with reduced perinatal morbidity and mortality. The balance of absolute benefits and harms of antenatal corticosteroid administration changes at late preterm gestation compared with earlier gestational ages (moderate).

• 2.

  Late preterm antenatal corticosteroid administration (i.e., at 34⁰ to 36⁶ weeks gestation) decreases the risk of neonatal respiratory morbidity but increases the risk of neonatal hypoglycemia (high).

• 3.

  Late preterm antenatal corticosteroid administration in pregnant individuals with pre-gestational diabetes mellitus may worsen neonatal hypoglycemia (low).

• 4.

  The impact of late preterm antenatal corticosteroids on neurodevelopment and other long-term outcomes remains uncertain (low).

• 5.

  Further research is needed to determine the optimal dose of antenatal corticosteroids (moderate).

• 1.

  We continue to strongly recommend antenatal corticosteroid administration up to 33⁶ weeks gestation when delivery is expected within 7 days (strong, high).

• 2.

  We have changed the upper gestational age boundary to which we strongly recommend antenatal corticosteroid administration from 34⁶ to 33⁶ weeks gestation (conditional, low).

• 3.

  For pregnant individuals at risk of delivery between 34⁰ and 36⁶ weeks gestation, we recommend considering antenatal corticosteroids based on discussion with patients about absolute harms and benefits specific to the gestational week (strong, moderate).

• 4.

  Between 34⁰ and 36⁶ weeks gestation, we do not recommend antenatal corticosteroids for pregnancies with pre-gestational diabetes in most cases. The greater risk of hypoglycemia in these pregnancies should be considered as part of the discussion on harms and benefits of antenatal corticosteroids (conditional, low).

Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kidney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF.

Retrospective cohort study.

Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diagnosis of nonvalvular AF during 2011-2018.

Initiation of DOAC or VKA treatment.

Primary outcomes were CKD progression (composite of >30% estimated glomerular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism.

Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estimation of per-protocol effects.

We included 32,699 patients (56% initiated DOAC) who were observed for a median of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60 mL/min/1.73 m². The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.98) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.89) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation.

Missing information on time in therapeutic range and treatment dosages.

Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death.

The literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents.

Cases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC).

The PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC₀₂₅ = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC₀₂₅ = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases.

Despite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.