Is trofinetide a future treatment for Rett syndrome? A comprehensive systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Rett syndrome (RTT) is a rare, life-threatening, genetic neurodevelopmental disorder. Treatment in RTT encounters many challenges. Trofinetide, a modified amino-terminal tripeptide of insulin-like growth factor 1, has demonstrated clinically promising results in RTT. In this study, trofinetide efficacy and safety in RTT are systematically reviewed and meta-analyzed. METHODS: A systematic search of five electronic databases was conducted until January 2024. Review Manager 5.4 software was used for the analysis. The analysis was based on a weighted mean difference and standard error with a confidence interval (CI) of 95%, and a statistically significant P-value was considered if it was < 0.05. The study was registered on PROSPERO with registration number CRD42024499849. Quality of evidence was assessed using GRADE. RESULTS: Three randomized controlled trials (RCTs) with 276 patients were included in the analysis. Trofinetide improved both caregiver outcomes and clinical scales by improving the Rett Syndrome Behavior Questionnaire (RSBQ) (mean difference (MD): - 3.46 points, 95% CI: - 5.63 to - 1.27, P = 0.0002) and Clinical Global Impression Scale-Improvement (CGI-I) (MD: - 0.35, 95% CI: - 0.51 to - 0.18, P < 0.0001), respectively. However, trofinetide neither improved the Caregiver Top 3 Concerns Visual Analog Scale nor the Rett Motor Behavioral Assessment. Regarding safety, trofinetide was significantly associated with vomiting compared to placebo (odds ratio (OR): 3.17, 95% CI: 1.57 to 6.43, P = 0.001). After solving heterogeneity, results showed a statistically significant incidence of diarrhea in the trofinetide (200 mg) group compared to placebo (OR: 18.51, 95% CI: 9.30 to 36.84, P ≤ 0.00001). CONCLUSIONS: Trofinetide demonstrated statistically significant improvements in CGI-I and RSBQ in pediatrics and adult patients with Rett. Side effects are limited to vomiting and diarrhea. Although diarrhea yielded an insignificant result in our analysis, it emerged as a cause for treatment discontinuation in the participating trials, and a statistically significant risk for diarrhea emerged when excluding the study using a lower dose of the drug, hence causing heterogeneity, in the meta-analysis. Given the diverse genetic landscape of RTT, future RCTs investigating correlations between RTT genotype and phenotypic improvements by trofinetide will be beneficial. RCTs encompassing male patients with larger and longer cohorts are recommended.

Factors influencing stress and resilience among Egyptian medical students: a multi-centric cross-sectional study.

BACKGROUND: Psychological stress is a common psychological comorbidity among medical students and worsens their quality of life. Psychological resilience is thought to have a protective role against stress. However, evidence regarding the prevalence of stress and resilience alongside their associated factors is scarce, especially in the Middle East. This is the first multicenter, cross-sectional study to investigate resilience and stress among Egyptian medical students. METHODS: The current cross-sectional study was conducted on 2465 university students in seven public universities in Egypt. The universities were selected using the simple randomization method. The data was collected using a self-administered questionnaire consisting of four parts: demographic data, socioeconomic tool represented in the Family Affluence Scale (FAS), the Kessler Psychological Distress Scale (K10), and the Brief Resilience Scale (BRS). Data was analyzed in SPSS version 26 software. RESULTS: The majority of the students were stressed (86.5%), most of whom had severe stress (48.9%). Most of the students had low resilience (49.9%), while only 3.2% had high resilience. In the logistic regression analysis, being a female, living alone, spending long hours on social media, and thinking of suicide or leaving medicine were associated with being stressed and having low resilience. Medical students with low resilience were significantly more liable to stress [Adjusted odds ratio (AOR) = 3.667, confidence interval (CI): 2.709-4.965, P = 0.000], and vice versa [AOR = 3.709, CI: 2.746-5.009, P = 0.000]. Interestingly, high socioeconomic status showed a significant association with high resilience (P = 0.004); nonetheless, it was not associated with stress (P = 0.993). Academic grades were not associated with both the level of stress and resilience. Aging, being in clinical or academic stages, smoking, having a chronic disease, and being financially-supported are neither associated with stress nor resilience. CONCLUSIONS: The present study revealed that Egyptian medical students had low resilience and high stress, with a significant relationship between both of them. Further investigations via longitudinal study design to understand the resilience-stress relationship are recommended. Developing and implementing resilience-improving strategies in medical schools is highly recommended to decrease the prevalence of stress and its subsequent burdens.