The COVID-19 pandemic has resulted in significant disruptions to the daily routines of children, potentially altering trends in psychiatric diagnoses and medication utilization. This study investigates longitudinal changes in psychiatric diagnoses and the usage of psychotropic medications, thereby offering valuable insights into the developmental patterns of vulnerability among children and adolescents in the aftermath of the COVID-19 pandemic. This population-based, cross-sectional study utilized electronic medical records from Clalit Health Services (2016–2023). For each calendar year, data from approximately one million children and adolescents aged 5–18 years were analyzed. The study compared quarterly dispensing rates of antidepressants, antipsychotics, and psychostimulants, as well as the quarterly incidence of major psychiatric diagnoses, across pre-pandemic, pandemic, and post-pandemic periods. Poisson regression models, adjusted for seasonality, were employed to calculate counterfactual quarterly rates based on historical trends, thereby assessing the impact of the pandemic. During the pandemic, antidepressant dispensing exceeded expected levels, with the most pronounced increases observed among adolescents, particularly females (Relative Risk (RR) = 1.13). Conversely, psychostimulant dispensing initially declined (RR = 0.87) before rebounding following the pandemic. The use of antipsychotics exhibited modest and ongoing increases among young boys and adolescent girls, remaining elevated compared to pre-pandemic trends (RR 1.14–1.18). The incidence of diagnoses for Attention Deficit Hyperactivity Disorder (ADHD) increased across all demographic groups. Additionally, adolescent females experienced notable surges in anxiety (RR = 1.40), depression (RR = 1.49), and eating disorders (RR = 1.86). Many of these outcomes persisted at levels exceeding pre-pandemic forecasts during the post-pandemic period. The pandemic was associated with age- and sex-specific changes in paediatric mental health, with persistent increases in internalising disorders and antipsychotic use. These patterns, particularly pronounced among adolescents, suggest heightened developmental sensitivity to large-scale environmental stressors and underscore the need for targeted service planning and ongoing monitoring.

OBJECTIVE:Current recommendations for prescribing combined oral contraceptives (COCs) to people with epilepsy are often conflicting, particularly for weak inducers of cytochrome P450 3A4. We aimed to critically review the literature and compare the antiseizure medication (ASM)-induced changes in exposure to COC components. METHODS:In this systematic review and network meta-analysis (PROSPERO: CRD42024513792), in accordance with PRISMA 2015/2020, we searched PubMed, EMBASE, Cochrane, and FDA documents up to January 2026. Eligible studies were clinical trials assessing induction (≥ 5 days) of ethinylestradiol combined with progestins by ASMs. The areas under the concentration-time curve (AUC) of individual hormones with/without the ASM were indirectly compared. The point estimate was the standardized mean difference (SMD; significant when the 95% confidence interval does not encompass zero). Bias risk was assessed using the PKclin tool. RESULTS:The 17 studies (16 reports) involving 399 individuals and 15 ASMs were all conducted with COCs containing the two progestins least sensitive to enzyme induction and ≥ 30 μg ethinylestradiol. Nine ASMs were studied at doses 13-75% lower than the recommended maximum (median 50%). Brivaracetam (100 mg/day) reduced the exposure to ethinylestradiol more than 1000 mg/day levetiracetam (SMD -10; 95% confidence interval - 0.20-0). The effects of 300 mg/day lamotrigine on ethinylestradiol and levonorgestrel were greater than those of 400 mg/day lacosamide (0.18; 0.11-0.25, 0.28; 0.20-0.37). Low-dose (50 mg/day) and high-dose (200 mg/day) topiramate were comparable in their effects on ethinylestradiol and norethindrone, and the low dose did not differ from weak inducers in altering ethinylestradiol exposure. SIGNIFICANCE:Current recommendations may underestimate ASM effects on exposure to COC components, especially those in newer COCs. Greater caution is recommended with low-dose topiramate. For individuals treated with weak COC inducers without additional contraceptive means, COCs containing levonorgestrel or norethindrone might be preferable given their lower vulnerability to induction.

OBJECTIVES:Antiseizure medications (ASMs) can induce the activity of drug-metabolizing enzymes and drug transporters, including cytochrome P450 (CYP)2C9 and P-glycoprotein (P-gp). Our objective was to comparatively assess the effects of ASMs on exposure to clinical CYP2C9 and P-gp substrates. METHODS:This systematic review and network meta-analysis (NMA) was registered in PROSPERO (CRD42023473609) and performed following PRISMA 2020 guidelines. MEDLINE, EMBASE, and Cochrane Library were searched until October 22, 2025, with additional searches conducted in the FDA and EMA databases and ClinicalTrial.gov. Studies were included if they were prospective and the ASM was used as monotherapy for ≥5 days. The primary endpoint was the substrate area under the curve ratio (AUCR) with/without the ASM. Treatments were ranked by P-scores (range 0-1, higher values reflect stronger induction). The point estimate for indirect pairwise comparisons was the standardized mean difference (SMD). Bias risk was assessed using the PKclin tool. RESULTS:Twelve and six interventional pharmacokinetic studies with 227 and 97 participants were included in the CYP2C9 and P-gp NMAs, respectively. The ASM with the greatest CYP2C9 induction potential was carbamazepine (600 mg/day, P-score .78). The only statistically significant effect size estimate for CYP2C9 was obtained in the comparison between carbamazepine 600 mg/day and cenobamate 200 mg/day (SMD -.42; CI -.76, -.09). Carbamazepine (300 or 600 mg/day) was also the strongest P-gp inducer (P-scores, .79 and .55, respectively). The effects of its two doses did not differ, and 300 mg/day had a stronger effect on P-gp compared with the other ASMs. SIGNIFICANCE:Despite variability in populations, substrate drugs, and doses, our findings demonstrate that carbamazepine is an inducer at 300 mg/day, and that ASMs can rank differently as CYP2C9 versus P-gp inducers. Therefore, the safety of ASM polytherapy cannot be extrapolated from one pathway to another for treatment selection, for example, for post-stroke epilepsy.

To identify risk factors for opioid use and assess the effect of opioids on women with endometriosis. A retrospective cohort study. A tertiary medical center. Women with confirmed or suspected endometriosis aged 18–45 years. Recruited participants completed a questionnaire including baseline demographic and general health data, a Brief Pain Inventory (BPI-Heb) and a Visual Analogue Scale assessing Endometriosis associated pain symptoms. Women using opioids were compared to women not using opioids. Women treated with opioids further completed a Visual Analogue Scale quesionniare of pain symptoms after using opioids, a questionnaire assessing side effects, and the Opioid Risk Tool for the assessment of addiction risk. Ninety-eight patients were included in the study. Of them, 49 were opioid users, and 49 were non-opioid users. One unit increase in overall pain was associated with a 28

Nausea and vomiting in pregnancy (NVP) can substantially affect maternal well-being and quality of life. Cultural, social, and healthcare-system factors may influence healthcare-seeking behavior and management strategies. The primary objective of this study was to compare the proportion of Arab and non-Arab women who sought medical consultation for NVP. Secondary objectives were to assess differences in NVP duration and impact on quality of life, explore sources of advice and support, characterize recommendations for NVP management, and investigate reasons for not seeking medical consultation. This cross-sectional study was conducted in the maternity ward of Shamir (Assaf Harofeh) Medical Center between January and October 2018. Postpartum women who reported NVP during their most recent pregnancy were interviewed using a structured questionnaire available in Hebrew and Arabic. Group comparisons were performed using Chi-square, Fisher’s exact, t-tests, or Mann–Whitney U tests, as appropriate. Multivariable logistic regression was used to identify factors independently associated with seeking medical consultation. A total of 190 women were included (126 non-Arab and 64 Arab). Overall, 92 non-Arab women (73.0

IntroductionThis study aimed to evaluate the utilization of medical cannabis in a pediatric population and compare short-term persistence rates with those in adolescents and young adults.MethodsIn this retrospective, nationwide cohort study supplemented by data from an open-label study of children with ASD, patient cases under 12 years of age who received medical cannabis treatment between 2018 and 2022 were analyzed. The primary outcome assessed was treatment persistence within the first 3 months. Secondary outcomes included changes in THC ratios, amounts dispensed, and reasons for treatment discontinuation.ResultsThe patient population consisted of 1,341 children using medical cannabis for ASD (751), epilepsy (330), Tourette syndrome (165), and pediatric cancer (95). Out of 3,007 consecutive medical cannabis sessions, the adjusted hazard ratio for discontinuation in the first 3 months was 0.83 (95% CI [0.71–0.96], p = 0.01) for young adults compared to children. Approximately 60%–70% of children discontinued therapy within the first 6 months. Significant alterations in THC ratios or dispensed amounts were observed in most sessions within the initial 6 months. In the open-label study dataset, most treatment discontinuations were primarily attributed to adverse effects and a perceived lack of therapeutic efficacy.ConclusionOur findings suggest that short-term persistence of medical cannabis therapy is lower in children compared to adolescents and young adults. Moreover, many pediatric patients required adjustments to their THC ratios and showed a high frequency of treatment discontinuation. These observations underscore the importance of targeted strategies to improve medical cannabis treatment effectiveness and adherence in the pediatric population. Although MC may offer therapeutic benefits for pediatric patients, our findings emphasize the importance of careful patient selection and close medical follow-up to optimize clinical outcomes.

Exposure during pregnancy to secondhand smoke (SHS) is associated with a wide range of adverse fetal development effects and perinatal outcomes. This study aimed to measure SHS exposure in pregnant women using urinary cotinine measurements and to evaluate the association between paternal smoking and maternal urine cotinine and birth outcomes in a birth cohort of Israeli mothers and children. We measured cotinine in urine samples taken at birth from 96 non-smoking mothers participating in the EHF (Environmental Health Fund)-Assaf-Harofeh-Ichilov cohort. Half of the partners were smokers, based on the self-reported data. Logistic regression models were used to predict maternal urinary cotinine levels, and potential confounders were included in the model. We analyzed the association between maternal urinary cotinine levels and birth weight. In our study of 96 nonsmoking pregnant women, 94 https://clinicaltrials.gov/study/NCT03084445 .

AIM:GnRH agonists and dienogest are well established treatments for Endometriosis associated pain. Recently, oral GnRH antagonists were introduced and shown to be effective for endometriosis treatment. Yet, superiority of either of those drugs is not yet known. We aimed to compare the efficacy and side effect profile of GnRH analogues and dienogest for the treatment of endometriosis associated pain. METHODS:MEDLINE, Embase, and Cochrane were searched for randomized controlled trials evaluating the impact of dienogest and GnRH analogues on dysmenorrhea, dyspareunia and non-menstrual pelvic pain (NMPP). Adverse events studied included: headaches, hot flashes, amenorrhea, irregular vaginal bleeding and change in bone mineral density. Individual effect sizes were calculated with the pre-post differences for each treatment comparison as standardized mean differences (SMD). Network meta-analysis was conducted, incorporating direct and indirect comparisons of the different drugs. Risk Ratios (RR) and 95 % confidence intervals (CIs) for adverse events were calculated from the number of cases in the study arm, compared to the controls. RESULTS:A total of 8 studies including 3259 patients were identified. Both doses of GnRH antagonist, as well as dienogest were found superior to placebo for NMPP. The intervention hierarchy model revealed that high dose GnRH antagonist had the strongest effect in reducing NMPP (p = 0.07). Both doses of GnRH antagonist (p = 0.64 and p = 0.36) and dienogest (p = 0.31) were superior to placebo in reducing dyspareunia. In the hierarchy model, Leuprolide was found to have the most substantial effect (p = 0.24), while dienogest was beneficial compared to both doses of GnRH antagonist in reducing dyspareunia. High dose GnRH antagonist had the strongest effect in reducing dysmenorrhea (p = 0.05). The network meta-analysis has shown that dienogest had the best safety profile with the least adverse effects. CONCLUSIONS:Oral GnRH antagonist has shown to be the most effective in improving dysmenorrhea and NMPP, as compared to the other drugs. However, dienogest was found more beneficial in the treatment of dyspareunia. These finding may serve clinical practitioners in electing medical therapy.

Oral liquid medications (OLMs) for neonatal use are recommended to have an osmolality of ≤ 450 mOsm/kg to minimize gastrointestinal risks, specifically necrotizing enterocolitis. However, manufacturers and compounders rarely provide osmolality values. This study measured the osmolality of OLMs commonly used in neonatal and pediatric patients and identified OLMs that require further dilution before administration. OLMs used in neonatal and pediatric wards at Kaplan Medical Center, Israel, were included. Undiluted and 1:10 diluted samples were measured by an osmometer using freezing point depression. OLMs were categorized by formulation and product type, and statistical analysis assessed inter-group differences. Of 58 identified OLMs, 54 preparations were analyzed in this study. Median (interquartile range) osmolality was 2313 (1946) mOsm/kg. Among undiluted samples, six (11.1

INTRODUCTION:The COVID-19 pandemic caused unprecedented disruptions in healthcare delivery, and changes in medication utilization patterns. While previous studies examined specific therapeutic classes or populations, there is limited longitudinal evidence on medication trends among young adults throughout and beyond the pandemic. AIM:To analyze trends in medication dispensation before, during, and after the COVID-19 pandemic among young adults. METHODS:We conducted a population-based, retrospective cohort study including active-duty Israeli Defense Forces personnel between January 2017 and August 2023. Monthly dispensing rates per 1000 persons were analyzed using an interrupted time series (ITS) design, implemented via generalized linear models with log link and population offsets. Models included linear time trends, month fixed effects to account for seasonality, and negative binomial fallback for overdispersion. Pre-pandemic data (January 2017-March 2020) were used to estimate baseline trends, from which counterfactual predictions were generated for March 2020-August 2022. Goodness-of-fit was evaluated with RMSE and MAPE. RESULTS:Pre-pandemic trends varied across therapeutic groups. Adrenergic inhalants (IRR 1.008, 95% CI 1.004-1.011, p = 0.0001), antidiarrheals (IRR 1.005, 95% CI 1.001-1.008, p = 0.004), and ADHD medications (IRR 1.024, 95% CI 1.020-1.027, p < 0.001) exhibited significant upward slopes, whereas antibacterials, antidepressants and hormonal contraceptives showed no significant baseline trend. Seasonality was significant for all groups (p < 0.001). During the pandemic, cumulative differences revealed excesses for adrenergic inhalants (+93.98 per 1000), antidepressants (+87.03), and hormonal contraceptives (+679.21), alongside deficits for antibacterials (-201.99), antidiarrheals (-112.89), and ADHD medications (-294.69). CONCLUSIONS:Medication usage patterns can be classified into three classes: medications affected by the pandemic due to the inciting pathogen, disease symptoms, or pandemic social disruption; medications unaffected by the pandemic, affected by global disease trends; and medications with a trend change whose relation to the pandemic is unclear. These findings offer a novel framework for anticipating and managing medication needs in future pandemics.

There is a potential link between cannabis and mental disorders. Cannabis exposure involves in many cases negative mental emotions, which are unpleasant sensations or thoughts. Whereas mild cases of negative mental emotions inflict patient’s quality of life, more severe cases lead to therapy discontinuations, or even hospitalizations and death. This study characterizes cannabis users who experienced negative mental emotions after cannabis exposure. The Releaf App database was utilized to evaluate the association between personal and cannabis use characteristics on reporting a negative mental emotion during cannabis exposure. This global mobile lets individuals track real-time cannabis experience use with cannabinoid-based products, containing data points such as gender, age, reasons for use, product type, cannabis composition, and feelings and emotions experienced after cannabis use. Multivariable logistic regression models were constructed, adjusting for potential confounders such as gender and previous experience with cannabis use. The study population comprised 4,435 users, and 34,279 sessions were collected from various countries, mainly from North America, and included in the primary analysis. Reporting on negative mental emotions was associated with users in the age group of 18–30 years. Using cannabis for a mental purpose was associated with a small increase in reporting on negative mental emotions (OR = 1.10, 95

Background: Tramadol is primarily metabolized by the highly polymorphic CYP2D6 enzyme, leading to a large spectrum of adverse events and clinical response. Ample evidence pointed a reduced CYPD26 activity score in individuals harboring the CYP2D6*10/*10 genotype, nevertheless, there is scarce studies on the impact of CYP2D6*10/*10 genetic polymorphism on long-term tramadol's adverse effects. Aim: To test the correlation between CYP2D6*10/*10 expression and the risk for tramadol-associated adverse effects. Method: Using a database of Leumit Healthcare Services in Israel, we retrospectively assessed the occurrence of adverse events in patients who were prescribed tramadol. A binary logistic regression model was applied to model the relationship between CYP2D6*10/*10 genotype and the occurrence of adverse effects. Results: Data from four hundred ninety-three patients were included in this study. Only 25 (5.1%) patients were heterozygous for the CYP2D6*10 variant, while 56 patients (11%) were tested positive to the CYP2D6*10/*10 genotype. Compared to carriers of other variants, patients with the CYP2D6*10/*10 variant exhibited a higher occurrence of adverse events (odds ratio [OR] = 6.14, 95% confidence interval 3.18-11.83); the odds ratio for central nervous system adverse events and gastrointestinal adverse events were 5.13 (95% CI 2.84-9.28), and 3.25 (95% CI 1.78-5.93), respectively. Conclusion: Among the different CYP2D6 genotypes, CYP2D6*10/*10 genotype carries the higher risk of tramadol related adverse events. Appreciating the frequency of this specific allele it seems prudent to pharmacogenetically screen patients considered for long term tramadol treatment for better tolerability and efficacy outcomes.

OBJECTIVE:To evaluate the association between cannabis use during pregnancy and the risk for long-term neuropsychiatric pathology in the offspring. DATA SOURCES:MEDLINE, EMBASE, and Cochrane library databases were systematically searched until January 22, 2024, with no language or date restrictions. STUDY ELIGIBILITY CRITERIA:Studies were eligible for inclusion if they reported quantitative data on any long-term neuropsychiatric outcome in offspring whose mothers used cannabis during pregnancy for medical or recreational use, by any route and at any trimester, in comparison to offspring of women who abstained from cannabis use during pregnancy. All observational study designs were included in the analysis. STUDY APPRAISAL AND SYNTHESIS METHODS:A systematic review and meta-analysis were performed according to the PRISMA and MOOSE guidelines. The data was extracted independently by 2 reviewers. The following offspring outcomes were of interest: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, anxiety, psychotic disorders, as well as cannabis and other substance use. Odds ratios (OR) and 95% confidence intervals (CI) were pooled for each neuropsychiatric outcome in the offspring of women exposed to cannabis during pregnancy compared with nonexposed. Data were pooled using random-effects models. RESULTS:Eighteen eligible observational studies were included in the systematic review, and 17 were included in the final quantitative analysis, representing 534,445 participants. After adjusting for confounders, the pooled OR for ADHD was 1.13 (95% CI 1.01-1.26); for ASD, the pooled OR was 1.04 (95% CI 0.74-1.46); for psychotic symptoms, the pooled OR was 1.29 (95% CI 0.97-1.72); for anxiety, the pooled OR was 1.34 (95% CI 0.79-2.29); for depression, the pooled OR was 0.72 (95% CI 0.11-4.57); and for offspring's cannabis use, the pooled OR was 1.20 (95% CI 1.01-1.42). CONCLUSION:Prenatal cannabis exposure is not associated with an increased risk of ASD, psychotic symptoms, anxiety, or depression in offspring. However, it may slightly elevate the risk of ADHD and predispose offspring to cannabis consumption. Despite these findings, caution is warranted regarding cannabis use during pregnancy. Further research is imperative, especially given the increasing potency of cannabis in recent years.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. In 203 patients, 55

Background-Various antidepressant agents are metabolized by the CYP2C19 enzyme, including Citalopram and Escitalopram. Variation in CYP2C19 expression might give rise to different plasma concentrations of the active metabolites, potentially affecting both drugs' efficacy and tolerability. Aim-The aim of this study was to evaluate differences in the Escitalopram and Citalopram efficacy and tolerability between different CYP2C19 genotype-based metabolizing categories in outpatients suffering from major depressive disorder (MDD). Methods-In a retrospective, longitudinal cohort study of electronic medical-record data, 283 patients with MDD who were prescribed Escitalopram or Citalopram with the available CYP2C19-genotyping test were enrolled. The primary efficacy end point was adverse drug reactions recorded in the medical files. A proportional-odds, multilevel-regression model for longitudinal ordinal data was used to estimate the relation between the CYP2C19 genotype and adverse drug reactions, adjusting for potential confounding variables and other explanatory variables. Latent-class analysis (LCA) was utilized to detect the presence of clinically significant subgroups and their relation to an individual's metabolizing status for CYP2D6/CYP2C19. Results-With poor CYP2C19 metabolizers as a reference, for each unit difference in the activity score of the CYP2C19 phenotype, the odds ratio for drug intolerability was lowered by 0.73 (95% credible intervals: 0.56-0.89), adjusting for significant covariates. In addition, applying LCA, we identified two qualitatively different subgroups: the first group (61.85%) exhibited multiple side effects, low compliance, and frequent treatment changes, whereas the second group (38.15%) demonstrated fewer side effects, good adherence, and fewer treatment changes. The CYP2C19 phenotype was substantially associated with the group membership. Conclusions-We found a positive association between the CYP2C19 activity scores, as inferred from the genotype, and both the efficacy of and tolerability to both Es/Citalopram. LCA enabled valuable insights into the underlying structure of the population; the CYP2C19 phenotype has a predictive value that discriminates between low-adherence, low-drug-tolerance, and low-response patients and high-adherence, high-drug-tolerance, and high-response patients. Personalized medicine based on CYP2C19 genotyping could evolve as a promising new avenue towards mitigating Escitalopram and Citalopram therapy and the associated side effects and enhancing treatment success.

BACKGROUND:Therapeutic options for intermediate- or high-risk pulmonary embolism (PE) include anticoagulation, systemic thrombolysis and catheter-directed thrombolysis (CDT); however, the role of CDT remains controversial. We sought to compare the efficacy and safety of CDT with other therapeutic options using network meta-analysis. METHODS:We searched PubMed (MEDLINE), Embase, ClinicalTrials.gov and Cochrane Library from inception to Oct. 18, 2022. We included randomized controlled trials and observational studies that compared therapeutic options for PE, including anticoagulation, systemic thrombolysis and CDT among patients with intermediate- or high-risk PE. The efficacy outcome was in-hospital death. Safety outcomes included major bleeding, intracerebral hemorrhage and minor bleeding. RESULTS:We included data from 44 studies, representing 20 006 patients. Compared with systemic thrombolysis, CDT was associated with a decreased risk of death (odd ratio [OR] 0.43, 95% confidence interval [CI] 0.32-0.57), intracerebral hemorrhage (OR 0.44, 95% CI 0.29-0.64), major bleeding (OR 0.61, 95% CI 0.53-0.70) and blood transfusion (OR 0.46, 95% CI 0.28-0.77). However, no difference in minor bleeding was observed between the 2 therapeutic options (OR 1.11, 95% CI 0.66-1.87). Compared with anticoagulation, CDT was also associated with decreased risk of death (OR 0.36, 95% CI 0.25-0.52), with no increased risk of intracerebral hemorrhage (OR 1.33, 95% CI 0.63-2.79) or major bleeding (OR 1.24, 95% CI 0.88-1.75). INTERPRETATION:With moderate certainty of evidence, the risk of death and major bleeding complications was lower with CDT than with systemic thrombolysis. Compared with anticoagulation, CDT was associated with a probable lower risk of death and a similar risk of intracerebral hemorrhage, with moderate certainty of evidence. Although these findings are largely based on observational data, CDT may be considered as a first-line therapy in patients with intermediate- or high-risk PE. PROTOCOL REGISTRATION:PROSPERO - CRD42020182163.

OBJECTIVE:Antiseizure medications (ASMs) are commonly categorized as enzyme-inducers and non-enzyme-inducers based on their propensity to enhance the metabolism of concomitantly administered drugs. This systematic review and network meta-analysis aimed to rank ASMs as cytochrome P450 3A (CYP3A)-inducers based on a comparative assessment of ASM-induced reduction in the concentrations of sensitive substrate drugs. METHODS:The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42022335846), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) standards were followed. We searched MEDLINE, Embase, and Cochrane until March 14, 2023 without an initial date restriction. Data were additionally obtained via the US Food and Drug Administration database. Studies had to be prospective, with ASM monotherapy for ≥5 days. The primary parameter was the magnitude of change in the area under the concentration-time curve of CYP3A substrates following treatment with the ASM. The standardized mean difference (SMD) was used as the point estimate for the indirect comparisons between ASMs using the pairwise method. Bias risk was assessed using the PKclin tool. RESULTS:We identified 14 open-label, fixed-sequence studies with 370 participants. The effect size of 600 mg/day carbamazepine did not differ from those of 300 mg/day phenytoin (SMD = -.06, 95% confidence interval [CI] = -.18 to .07) and 200 mg/day cenobamate (SMD = -.11, 95% CI = -.26 to .04). Carbamazepine at 600 mg/day was the strongest CYP3A-inducer (P-score = .88), followed by carbamazepine 400 mg/day (.83), phenytoin 300 mg/day (.79), and cenobamate 200 mg/day (.73). Eslicarbazepine (800 mg/day) ranked higher than cenobamate 100 mg/day and oxcarbazepine 900 mg/day (.60, .39, and .37, respectively). SIGNIFICANCE:Despite the limited number of studies, our network meta-analysis emphasizes that the magnitude of ASM effects on CYP3A substrate metabolism is a dose-dependent continuum. When possible, ASM classification as inducers should apply cutoff values tailored to the outcome. Prescribers should monitor plasma concentrations or clinical effects of CYP3A substrates and consider selecting concomitant medications accordingly.