EClinicalMedicine最新文献

Background: DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders.

Methods: In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023.

Findings: We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved.

Interpretation: dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders.

Funding: This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.

Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B).

Methods: The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout.

Findings: In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values.

Interpretation: Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD.

Funding: Sanofi.

Background: The World Health Organization recommends daily oral supplementation of iron for prevention of maternal anaemia. However, the adverse effects due to daily supplementation leads to poor compliance among pregnant women. Also, the mucosal block theory suggests that intermittent oral iron may be more efficient than daily iron with respect to optimum absorption. Our meta-analysis reviewed the existing clinical studies for the efficacy of daily versus intermittent oral iron supplementation.

Methods: In this systematic review and meta-analysis [PROSPERO ID:CRD42024498180], we searched PubMed, Google Scholar, Scopus, Science Direct and Cochrane database for studies published from 1st January 1970 to 31st December, 2023. Studies comparing daily and intermittent iron supplementation in pregnant women were included. The median intermittent iron dose was 120 mg/day and daily iron dose was 60 mg/day. The primary outcome was endpoint haemoglobin levels after iron supplementation. The data was analysed using the 'meta' and 'metafor' packages in RStudio using random effects model. The heterogeneity, publication bias, risk of bias and certainty of evidence were assessed using I2 statistics, funnel plots, Cochrane Risk of Bias 2 (ROB2) tool, and the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach respectively.

Findings: Of 4615 search results, 26 studies (n = 4365 participants) were included in this meta-analysis. There was no significant difference (p = 0.18) between the endpoint mean haemoglobin levels of the daily versus intermittent oral iron groups (standardized mean difference (SMD): 0.51, 95% CI: -0.23 to 1.24, I² = 97%, low certainty evidence) irrespective of baseline anaemic status. However, the endpoint ferritin levels were significantly higher in the daily supplementation group (SMD: 0.85, 95% CI: 0.15-1.54, p = 0.02, I² = 97%, low certainty evidence). The adjusted odds ratio for nausea, (adjusted odds ratio (OR) 3.56, 95% CI: 2.23-5.69, p < 0.001, I² = 9%, moderate certainty evidence), diarrhoea (adjusted OR 5.40, 95% CI: 1.90-15.33, p = 0.002, I² = 0%, low certainty evidence) and constipation (adjusted OR 1.95, 95% CI: 1.21-3.14, p = 0.006, I² = 0%, moderate certainty evidence) was significantly higher in daily oral iron supplementation group.

Interpretation: Intermittent oral iron supplementation with a median dose of 120 mg/day demonstrates comparable efficacy to daily oral iron supplementation median dose of 60 mg/day in increasing haemoglobin levels among pregnant women with a significant reduction in adverse events.

Funding: There was no funding for this study.

Background: The increased demand for induction of labour (IOL) at 39 weeks' gestation in normal-risk nulliparous patients creates significant logistical challenges for busy maternity units. A potential innovation is commencing induction by means of outpatient cervical ripening, using either a vaginal prostaglandin preparation (Propess) or an osmotic cervical dilator (Dilapan-S).

Methods: A Phase III, open label, single centre non-inferiority trial (EudraCT number 2019-004697-25) randomised healthy nulliparous women who chose elective IOL at 39 weeks to one of three methods of initial cervical ripening, specifically 12 h of Dilapan-S(D12), 24 h of Dilapan-S(D24), or 24 h of Propess(P24) between November 2020 and July 2023. After initial administration of the IOL agent in the hospital, participants returned home for 12 or 24 h, before readmission to complete delivery. The primary outcome was vaginal delivery achieved at any time, and this was compared in a non-inferiority analysis of Dilapan-S compared to Propess, within a 10% non-inferiority margin. Secondary outcomes included pairwise comparisons for each induction agent, and a range of logistical factors, such as time to delivery, the need for an additional cervical ripening agent, and length of hospital stay.

Findings: Of the 327 women randomised at 38 weeks, 271 (83%) completed the induction intervention. The D24 and P24 groups showed similarly high rates of vaginal delivery, 75% and 76% respectively. D12 had a lower vaginal delivery rate of 64% and consequently the overall comparison of Dilapan-S to Propess did not demonstrate non-inferiority (difference = -6%, 95% CI = -17%, 5%) because the lower 95% CI exceeded the -10% threshold of non-inferiority. The majority of participants across all groups were delivered by any means within 72 h of starting the induction process, inclusive of time spent at home (89% of the D24 group, 98% of the D12 group, 95% of the P24 group). There were no differences in rates of adverse events between groups.

Interpretation: There were similarly high vaginal delivery rates for D24 and P24, with at least 75% of patients successfully delivering vaginally following outpatient cervical ripening, with no significant adverse maternal or neonatal outcomes.

Funding: The Rotunda Foundation, Medicem Technology s.r.o.

Background: In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations.

Methods: Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors.

Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences -0.07 (95% CI -0.13, -0.02), -0.09 (-0.15, -0.02), -0.08 (95% CI -0.14, -0.02), and -0.08 (-0.13, -0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05).

Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve.

Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

Background: Eribulin prolongs overall survival (OS) of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), particularly in later chemotherapy (ChT) treatment. However, the health-related quality of life (HRQoL) and efficacy of first or second-line therapy in eribulin-treated patients remain unknown. Using eribulin in the first- or second-line may demonstrate the non-inferiority of HRQoL compared to S-1, an oral 5-fluorouracil derivative, while maintaining OS.

Methods: This randomised, controlled, open-label, phase III trial was conducted at 50 hospitals in Japan. Patients were enrolled from June 2016 and October 2019. Patients with HER2-negative MBC once under or no previous ChT were randomly assigned (1:1) to receive eribulin or S-1. HRQoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) every six weeks until week 24 and every nine weeks until week 42. The primary endpoint was the deterioration defined as more than 10 points worsening of the general health score of QLQ-C30 or death within one year after randomisation. The secondary endpoints included OS. (Trial ID: UMIN000021398).

Findings: Three hundred and two patients were enrolled, with 152 and 148 assigned to the eribulin and S-1 groups, respectively. The questionnaire compliance rate was 85.6%. Risk difference of global health status deterioration through one year was -0.66% (95% CI: -12.47-11.16; non-inferiority P = 0.077) for eribulin compared to S-1 groups. Median time to first deterioration for global health status score was 5.64 (95% CI: 3.51-8.00) and 5.28 months (95% CI: 3.28-7.80) in the eribulin and S-1 groups, respectively. The median OS was 34.7 and 27.8 months, (HR: 0.72, 95% CI: 0.54-0.96; P = 0.026); the median progression-free survival was 7.57 and 6.75 months in the eribulin and S-1 groups, (HR: 0.88, 95% CI: 0.67-1.16; P = 0.35), respectively. No new adverse events occurred.

Interpretation: The time of the first clinical deterioration was similar between the two groups and OS significantly increased in eribulin-treated patients.

Funding: This study was funded by CSPOR-BC and Eisai CO., Ltd.

Background: Understanding the chronic obstructive pulmonary disease (COPD) care cascade is crucial for identifying where and when to intervene to improve COPD outcomes. We aimed to determine the proportion of patients with COPD seeking care in China's health system who are lost at each stage of the COPD care cascade and how the patterns of loss vary across geographical regions and population groups.

Methods: From November 3, 2018, to April 22, 2021, we used individual-level patient data from the national Chinese 'Happy Breathing' Programme, which aims to identify patients with COPD and provide appropriate care. COPD was defined as a post-bronchodilator ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) <0.70. We calculated the proportions of individuals who, at enrolment into the 'Happy Breathing' Programme, (i) had ever undergone a pulmonary function test, (ii) had been diagnosed with COPD in the past, (iii) were currently on treatment for COPD, and (iv) had achieved control of their COPD. We examined the association between reaching each stage of the care cascade and individual patient characteristics as well as regional-level economic development and available resources in the health system using multilevel regression.

Findings: Among the 29,201 patients with COPD in the 'Happy Breathing' Programme, 41.0% (95% confidence interval [CI]: 40.4-41.6%) had ever been tested for COPD, 17.6% (95% CI: 17.1-18.0%) had previously been diagnosed with COPD, 8.5% (95% CI: 8.2-8.8%) were currently on treatment for COPD, 4.6% (95% CI: 4.3-4.8%) of patients had mild or no exacerbations in the prior year, and 3.9% (95% CI: 3.7-4.2%) of patients had suffered no exacerbations in the prior year. On average, patients living in the cities of Beijing, Wuhan, and Yinchuan had progressed further along the COPD care cascade than patients living in Daqing and Luoyang. Using multilevel regression, we found that young age, rural residence, and low regional per-capita GDP were significantly associated with larger losses at each stage of the COPD care cascade.

Interpretation: Substantial proportions of patients with COPD are lost at each stage of the COPD care cascade in the Chinese health system. The largest losses occur during the initial stages of the cascade, when diagnosis first occurs. New policies and interventions are required to boost COPD care, especially screening and diagnosis, in the Chinese health system to reduce this large disease burden.

Funding: This work was supported by Major Programme of National Natural Science Foundation of China (82090011), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-049), and Horizon Europe (HORIZON-MSCA-2021-SE-01; project number 101086139-PoPMeD-SuSDeV). TB was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt professorship award.

SARS-CoV-2 infection during pregestational and early pregnancy periods has an unclear impact on fetal development. Although vertical transmission is rare, potential effects on the developing fetal brain are plausible. However, robust evidence linking maternal SARS-CoV-2 infection to congenital anomalies is limited due to inadequate tracking of infection history and methodological flaws in published studies. This is further complicated by limitations, such as restricted testing access and undiagnosed infections, particularly in low- and middle-income countries. Most data focus on hospitalized women near term, lacking information on first- and second-trimester infections. Thus, an accurate assessment of the impact of COVID-19 on congenital anomalies is essential. It should however be emphasised that we have robust evidence that vaccination against COVID-19 before or during early pregnancy is not associated with malformations, ruling out any role of COVID-19 vaccines in these increased rates of congenital abnormalities. This viewpoint discusses findings from surveillance registries, highlights study limitations, and offers research recommendations to inform clinical guidelines and public health strategies, aiming to mitigate the effects of viral infections on early neurodevelopment.

Background: Pregnant women with hepatitis C virus (HCV) infection represent a special population in which treatment access remains limited despite its increasing prevalence. A reliable estimate of the burden and clinical outcomes of pregnant women with HCV infection is crucial for HCV elimination. We aimed to determine the prevalence, maternal-to-child transmission (MTCT), maternal and fetal complication rates, and direct acting antivirals (DAA) treatment outcomes of chronic HCV infection in pregnant women.

Methods: We searched PubMed, EMBASE, Scopus, Web of Science from inception until March 1, 2024, for studies reporting on the prevalence, MTCT, complications of HCV infection, and treatment outcomes of DAA in pregnant women. Study quality was assessed using the Newcastle-Ottawa Scale. We performed subgroup analysis based on 9 variables to explore the source of heterogeneity in HCV prevalence. The PROSPERO registration number is CRD42024500023.

Findings: From a total of 311,905,738 pregnant women from 333 studies, the pooled global seroprevalence of HCV in pregnant women was 2.6% (95% CI: 2.0-3.2, I ² = 100%) which increased in patients with intravenous drug use and HIV. Majority of the HCV cases in pregnant women (75%) are diagnosed through universal screening. The pooled MTCT rate was 9.0% (95% CI: 6.6-11.7, I ² = 79%), which was higher with HIV co-infection (OR: 3.1, 95% CI: 2.1-4.6, I ² = 10%), but was not influenced by the mode of delivery or breastfeeding. Pregnant women with HCV infection had more maternal complications, including intrahepatic cholestasis, preterm delivery, and antepartum hemorrhage. Neonates of mothers with HCV had higher odds of being small for gestational age. The pooled rate of sustained virologic response (SVR12) among the 74 women treated with DAA during pregnancy was 98.4%, with no serious adverse events reported.

Interpretation: HCV prevalence in pregnant women varies by geographic region and patient population, while MTCT occurs in almost one in ten viremic mothers. The incidence of both maternal and neonatal complications is significantly higher in patients with HCV infection. Limited data suggest that DAA are safe in pregnant women with HCV infection.

Funding: None.