Citations

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

Abstract Background Robotic left pancreatectomy (RLP) is increasingly adopted worldwide. Current guidelines suggest a learning curve of 21 cases, yet its impact on major morbidity and oncological quality remains uncertain. Methods A retrospective multicentre international study was undertaken across 10 centres in the UK, Spain, Germany, the USA, and Australia (2014–2025). Consecutive patients undergoing RLP were categorised into competency (first 21 cases per centre) or proficiency phase (>21). The primary outcome was major morbidity (Clavien–Dindo grade ≥ IIIa), and secondary outcome was the R1-margin rate. Mixed-effects logistic regression and risk-adjusted cumulative sum (RA-CUSUM) analyses were performed. Results 521 patients underwent RLP, including 200 (38.4%) in the competency phase and 321 (61.6%) in the proficiency phase. Median age was 63 years (IQR 54–73), and 56.4% were female. Rates of major morbidity were similar between phases (14.5% versus 14.0%, P = 0.981), as were R1 margin rates (21.6% versus 19.7%, P = 0.092). Independent predictors of major morbidity included male sex (OR 1.76, P = 0.037), preoperative pancreatitis (OR 2.23, P = 0.031), and multivisceral resection (OR 2.29, P = 0.034). Among patients with adenocarcinoma (n = 110), prolonged operative time (OR 1.39 per hour, P = 0.004) and nodal positivity (OR 2.62, P = 0.047) predicted R1 resection, while learning phase was not associated with margin status. RA-CUSUM demonstrated no excess morbidity over time in any centre. Conclusions In this first multicentre international analysis, the learning phase of RLP did not increase the risk of major morbidity or compromise oncological quality. These findings support the safe global adoption of RLP with appropriate training and case selection.

OBJECTIVE To assess whether initiating metformin at 25 weeks' gestation influences exclusive breastfeeding at 12 weeks postpartum in gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We performed a prespecified secondary analysis of the Effectiveness of Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Effects (EMERGE) trial, a multicenter, double-blind, placebo-controlled randomized study. A total of 535 pregnant women (510 with newly diagnosed GDM) were allocated 1:1 to metformin (titrated to 2.5 g/day) or placebo alongside usual care. Infant feeding was prospectively documented at birth and at 4 and 12 weeks postpartum. The primary outcome was exclusive breastfeeding at 12 weeks (intention to treat). Multivariable logistic regression adjusted for race, education, smoking, booking BMI, health care access markers, and diagnostic oral glucose tolerance test (OGTT) glucose levels. RESULTS Twelve-week feeding data were available for 476 pregnancies (236 in the metformin group and 240 in the placebo group). Exclusive breastfeeding at 12 weeks was 27% with metformin and 26% with placebo (absolute difference +1.3%; 95% CI –6.3 to 8.7; P = 0.75). The adjusted odds ratio (OR) for metformin versus placebo was 1.24 (95% CI 0.79–1.96; P = 0.36). Feeding patterns shifted from breastfeeding to formula temporally in both groups (P < 0.001), with no treatment-by-time interaction (P = 0.61). Non-Caucasian ethnicity independently predicted exclusive breastfeeding (adjusted OR 2.37; 95% CI 1.27–4.42). CONCLUSIONS Starting metformin treatment at 25 weeks in the GDM group was not associated with differences in exclusive breastfeeding at 12 weeks postpartum. Where metformin was discontinued at delivery, the results support compatibility of antenatal metformin with breastfeeding objectives. Breastfeeding outcomes were more linked to sociodemographic factors than metabolic ones, highlighting the need for culturally appropriate postpartum support.

Abstract Background Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with increased risks of adverse perinatal outcomes, and with long-term metabolic and cardiovascular consequences for both mother and child. The original EMERGE randomized controlled trial (RCT) evaluated the effectiveness of early metformin in addition to usual care in women with GDM on glycaemic control and perinatal outcomes. The EMERGE Mothers and Kids study is a longitudinal follow-up of the EMERGE trial participants, designed to investigate the long-term metabolic, cardiovascular, and neurodevelopmental outcomes in mothers and their offspring. Methods This is a prospective, observational cohort study of participants and their children from the EMERGE trial (NCT06327191). A single follow-up visit will be conducted up to 6 years after the index pregnancy. Maternal assessments include anthropometric data, glucose tolerance, and metabolic parameters. Child assessments include growth metrics, adiposity measured via skinfold thickness, and neurodevelopmental status assessed through validated questionnaires. Additional data on quality of life, mental health, breastfeeding, and health economics will also be collected. Discussion This study aims to provide insights into the long-term safety and efficacy of metformin use during pregnancy and its potential impact on the long term maternal and child health outcomes, contributing to evidence-based management of GDM. Trial registration: ClinicalTrials.gov; Identifier: NCT06327191

Background Motor speech disorders are early, common, and functionally limiting features of atypical parkinsonian disorders (APDs) such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA). These impairments are underrecognized and undertreated in neurology clinics. Objectives This review aims to characterize speech impairment in APDs, offer practical guidance for clinical evaluation, highlight the role of Speech‐Language pathologists (SLPs) in diagnosis and management, and outline current and emerging management strategies. Methods A narrative review was conducted by the Diagnosis and Treatment Working Group of CurePSP's Centers of Care, integrating literature and clinical experience to summarize evaluation, diagnosis, and treatment of motor speech disorders in APDs. Results Speech changes in APDs are often mixed dysarthrias with hypokinetic, spastic, and/or ataxic components, and may include apraxia of speech; these are frequently more severe and progress quicker than in Parkinson's disease. These features can assist in differential diagnosis and should prompt early referral to SLPs. Despite the high prevalence of speech and voice changes, comprehensive assessment of motor speech disorders is uncommon in neurology clinics. Current evidence regarding the efficacy of interventions is mixed. Digital acoustic analysis and neuromodulation offer promising directions for diagnosis and treatment. Conclusions Early, collaborative management of motor speech impairment elevates care in APDs. Neurologists and SLPs must work together to improve recognition, diagnosis, and care. Future research should focus on objective biomarkers and personalized therapies to support communication, autonomy, and quality of life for individuals living with APDs.

Blood iron levels are related to many health conditions, affecting hundreds of millions of individuals worldwide. To aid in the prevention and treatment of iron-related disorders, previous research has developed a low-cost, accurate, point-of-care method for measuring iron from a single finger-prick blood sample. This study builds upon that work by introducing an improved imaging method that accurately reads sensor images irrespective of variations in environmental illumination and camera quality. Smartphone cameras were used as analytical tools, demonstrating an average coefficient of variation of 5.13% across different phone models, and absorbance results were found to be improved by 8.80% compared to the method in a previous study. The proposed method successfully enhances iron detection accuracy under diverse lighting conditions, paving the way for smartphone-based sensing of other colorimetric reactions involving various analytes.

Abstract Aims To investigate the cost‐effectiveness of early initiation of metformin and usual care for gestational diabetes mellitus (GDM). Methods Economic evaluation from a healthcare perspective, based on the EMERGE randomised controlled trial. In total, 535 women with GDM were randomised to placebo in addition to usual care or metformin in addition to usual care. Economic outcomes included incremental healthcare costs and quality adjusted life years ( QALYs ) and expected cost‐effectiveness at cost‐effectiveness threshold values of €20,000, €45,000 and €100,000 per QALY gained. Uncertainty was explored using parametric, non‐parametric, deterministic and probabilistic methods and heterogeneity using subgroup analysis. Results On average, relative to the placebo arm, the early metformin arm was associated with non‐statistically significant mean increases of €193.07 (95% CI : −€789.88, €1176.01; p = 0.700) and 0.002 QALYs (95% CI : −0.009, 0.013; p = 0.771). In terms of expected cost‐effectiveness at threshold values of €20,000, €45,000 and €100,000 per QALY gained, the probability of the early metformin arm being more cost‐effective was estimated at 0.423, 0.452 and 0.524. Exploratory subgroup analyses provided more favourable but not definitive evidence in favour of the early metformin arm for cohorts with previous GDM and previous caesarean section. Conclusions We do not find definitive evidence that early initiation of metformin in addition to usual care for GDM was more cost‐effective than usual care alone. The clinical and economic evidence may be considered equivocal, but worthy of further examination.

Abstract Metformin is well‐established as a treatment for type 2 diabetes in non‐pregnant individuals. The low cost, acceptability and broad tolerability of metformin have also made it an attractive option for research into the treatment of other conditions associated with insulin resistance. Despite almost 50 years of clinical experience with the use of metformin to treat diabetes in pregnancy, many questions remain regarding its precise effectiveness in different maternal subgroups, as well as potential short‐term and long‐term effects on the offspring. In this narrative review, we present the current evidence for the use of metformin during pregnancy in various maternal subgroups, including women living with overweight and obesity, women at risk of gestational diabetes, women diagnosed with gestational diabetes and women with pregestational diabetes, including type 2 diabetes. Our specific focus is on the impact of metformin on short‐term maternal, fetal and neonatal outcomes. We also consider the evidence for other emerging indications for metformin in pregnancy, such as the prevention and management of pre‐eclampsia. Plain Language Summary This article looks at research on how metformin use in pregnancy affects mothers and newborns in the short term. Doctors have prescribed metformin since the 1970s for the treatment of diabetes in pregnancy. Despite years of use, there are still questions about how safe and effective metformin is for mothers and their children. Metformin taken during pregnancy moves through the placenta into the foetus's bloodstream. The short‐term and long‐term effects of metformin on offspring need careful attention. The studies that have looked at the link between metformin use and birth defects have not found any strong link between taking metformin in pregnancy and birth defects, however close attention will continue to be paid in this area. Some large studies have examined the use of metformin in pregnant women who do not have diabetes, but who do live with overweight or obesity. The studies are difficult to compare. Some, but not all, of these studies have shown less weight gain for the mother if metformin is taken by these women during pregnancy. Other large studies have looked at whether metformin can prevent gestational diabetes. The results are mostly disappointing. They suggest that metformin does not stop gestational diabetes from developing. However, the participants in these studies were mostly from white backgrounds and metformin may help prevent gestational diabetes in women of different ethnic backgrounds. However, more research is needed. Metformin has been widely studied as an alternative to insulin for the treatment of gestational diabetes. Because different countries diagnose and treat GDM differently, this makes comparing study results difficult. Women with gestational diabetes seem to gain less weight during pregnancy if they use metformin rather than insulin. Using metformin instead of insulin may result in lower average birth weights for babies from these pregnancies. Also, the use of metformin may lead to fewer babies being born abnormally large. Similarly, large trials have examined the use of metformin in pregnant women who are living with type 2 diabetes. These studies show that metformin can lower a mother's insulin needs. It can also help control weight gain and reduce the risk of having a large baby. One study found that metformin use in women living with Type 2 diabetes might increase the risk of having smaller babies. This was especially true if the mother had high blood pressure or kidney disease. This finding requires further investigation. Metformin might help prevent pre‐eclampsia, but this is still unclear. Research is ongoing into a potential role for metformin in the treatment of pre‐eclampsia. In conclusion, metformin has been studied in many groups of pregnant women. Women with gestational diabetes or type 2 diabetes may see benefits like less weight gain and better blood sugar/glucose control. Current evidence suggests that metformin shouldn't be used if there are foetal growth issues. It is also not recommended for mothers with high blood pressure or kidney disease. Future studies might find specific groups of pregnant women who would benefit the most from metformin.

Abstract Aim Women with gestational diabetes mellitus (GDM) display adverse lifetime cardiometabolic health. We examined whether early metformin in GDM could impact cardiometabolic risk factors postpartum. Methods EMERGE, a double-blind, placebo-controlled trial, randomized pregnancies 1:1 to placebo or metformin at GDM diagnosis and followed participants from randomization until 12 ± 4 weeks postpartum. In total, 478 pregnancies were available for postpartum maternal assessment, 237 and 241 assigned to metformin and placebo respectively. Weight (kg), body mass index (BMI) (kg/m2), waist circumference (cm), and blood pressure (mmHg) were measured, infant feeding method documented, and blood specimens drawn for a 75-gram oral glucose tolerance test, fasting insulin, C-peptide, and lipid analysis. Results Despite similar weight and BMI at trial randomization, participants receiving metformin had significantly lower weight (79.5 ± 15.9 vs 82.6 ± 16.9 kg; P = .04) and BMI (29.3 [5.6] vs 30.5 [5.4]; P = .018) at the postpartum visit. However, no difference in weight change from randomization to 12 weeks postpartum was observed between metformin and placebo groups. Overall, 29% (n = 139) of the cohort met criteria for prediabetes or diabetes, with no positive impact with metformin. There were also no differences in measurements of insulin resistance, blood pressure, or lipids between groups. Conclusion Early metformin use in GDM did not impact important cardiometabolic parameters in the early postpartum period despite significant benefits in weight gain and insulin use in pregnancy.