Although several risk single nucleotide polymorphisms (SNPs) have been found to play an important role in etiology of irritable bowel syndrome (IBS), the findings are inconsistent. A descriptive correlational design was used to analyze the baseline data of a randomized controlled trial including participants with IBS and healthy controls (HC). Pain severity and interference, anxiety, sleep, and fatigue were measured using the Brief Pain Inventory (BPI) and patient-reported outcomes measurement information system (PROMIS). Fisher’s exact test and multivariate linear regression were used to investigate the associations between IBS risk alleles and IBS symptoms. Participants were predominantly female, white, and had an average age of 21.13 ± 2.42 years. Polymorphisms within TNFSF15 (rs4263839), SLC6A4 5-HTTLPR, HTR3A (rs1062613), and OXTR (rs2254298) were associated with IBS risk, and TNFSF15 (rs4263839), COMT (rs6269), SLC6A4 5-HTTLPR polymorphisms were associated with pain severity. TNFSF15 (rs4263839) and COMT (rs4680; rs4633) genotypes were associated with sleep disturbance, and the ADRA1D SNP rs1556832 was associated with fatigue in both IBS and HC groups. Genotypic differences were associated with IBS risk and symptoms including abdominal pain, sleep disturbance, and fatigue. Further investigation is warranted to reveal the mechanisms by which these genetic variations influence the dynamic nature of IBS symptoms over time.

Conducting phase I trials is particularly challenging when dealing with late-onset dose-limiting toxicity (DLT) or when patient accrual is rapid relative to the DLT assessment window. In such cases, a new cohort may be ready for enrollment before the DLT assessments are complete for the current cohort, complicating dose assignment decisions. The time-to-event Bayesian optimal interval (TITE-BOIN) design was developed to address this issue by enabling real-time dose assignment for new cohorts, even when some enrolled patients’ DLT data are still pending. This design has been increasingly adopted in practice. Upon reviewing trial protocols utilizing TITE-BOIN, we observed considerable variation in dosing decision criteria, ranging from no requirements to requiring that at least two thirds of enrolled patients’ DLT data should be available before enrolling the next cohort. This raises a critical question: How can safety comparable with the fully staggered design be ensured? This article addresses this question by evaluating how the percentage of pending patients and the duration of their follow-up affect the operating characteristics of the TITE-BOIN design. Based on these evaluations, we generally recommend suspending accrual to allow for longer safety follow-up if fewer than 51% of patients at the current dose have their DLT data ascertained or if TITE-BOIN recommends dose escalation and the shortest follow-up time for pending patients at the current dose is less than 25% of the DLT assessment window. The rules should be further calibrated to suit specific trial considerations. Equipped with these rules, TITE-BOIN achieves similar accuracy in identifying the MTD and comparable safety to the fully staggered approach while substantially reducing trial duration and increasing patient access by enabling real-time dose decisions when some patients’ DLT data are still pending.

Caffeine has beneficial effects on firefighter job performance reducing fatigue and improving psychomotor vigilance. However, excessive caffeine intake may raise blood pressure (BP) following a bout of acute exercise among adults with elevated BP. The influence of caffeine intake on the ambulatory BP (ABP) response to vigorous physical exertion among firefighters has not been studied. In this sub-study we conducted secondary statistical analyses from a larger clinical trial (NCT04514354) that included examining the influence of habitual caffeine intake, and cardiometabolic biomarkers shown to influence BP, on the ABP response following a bout of sudden vigorous exertion over 19 h among firefighters. Previously, we found high amounts of calcium and sodium intake raised BP following a bout of acute exercise among adults with elevated BP. Thus, other secondary aims were to examine the influence of habitual calcium and sodium intake, and cardiometabolic biomarkers have shown to influence BP, on the ABP response following sudden vigorous exertion over 19 h among firefighters. Firefighters (n = 15) completed a Food-Frequency Questionnaire assessing habitual dietary intake over the past year. They randomly completed a maximal graded exercise stress test (GEST) and non-exercise CONTROL on separate non-workdays leaving the laboratory wearing an ABP monitor for 19 h. Prior to and immediately after the GEST, fasting venous blood was collected to measure lipid-lipoproteins, c-reactive protein, and blood glucose. Height and weight were taken to calculate body mass index. Repeated measures ANCOVA tested if the ABP response differed after GEST vs. CONTROL. Linear mixed models examined the relationships among caffeine, calcium, sodium, cardiometabolic biomarkers, and the ABP response following GEST vs. CONTROL. Firefighters were middle-aged (40.2 ± 9.5 year), overweight (29.0 ± 3.9 kg/m²) men with elevated BP (124.1 ± 10.3/79.6 ± 11.5 mmHg) who consumed 542.0 ± 348.9 mg of caffeine/day, about ~50% more than the dietary reference intake. Unexpectedly, systolic ABP was higher by 18.0 ± 6.7 mmHg and diastolic ABP by 9.1 ± 5.4 mmHg (ps < 0.01) over 19 h following GEST vs. CONTROL. We found 24% of the variance in the adverse ABP response to maximal physical exertion was explained by caffeine intake, and when combined with c-reactive protein, non-high-density lipoprotein-cholesterol, body mass index, blood glucose, and resting heart rate, up to 74% of the variability in the ABP response was explained. Additionally, we found calcium (ps < 0.001) and sodium (p < 0.0001) intake each explained up to 24% of the ABP response. Further investigation is needed in a larger, more diverse sample of firefighters to better establish how caffeine contributes to the adverse BP response to strenuous physical exertion.

On May 5, 2021, and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval, respectively, for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval (AA) was granted based on the overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, P = 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months [95% confidence interval (CI), 17.8–22.1] and 16.8 months (95% CI, 14.9–18.7) in the pembrolizumab and placebo arms, respectively [hazard ratio (HR), 0.80 (95% CI, 0.67–0.94); P = 0.004]. However, in exploratory subgroup analyses, treatment benefit seemed to be driven by the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 population [85% of patients, with an OS HR of 0.79 (95% CI, 0.66–0.95)], whereas in the PD-L1 CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement [HR, 1.10 (95% CI, 0.72–1.68)]. These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a “one-trial” approach allowing AA based on the response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a first-line metastatic setting, following FDA’s Project FrontRunner approach.

Introduction: Exclusive breastfeeding (EBF) outcomes can vary by concomitant emotions, ongoing pain, and breastfeeding self-efficacy. The purpose of this study is to examine the association of ongoing pain with breastfeeding, concomitant emotions and breastfeeding self-efficacy scores (BSES) with EBF outcomes at 6 weeks postpartum. Design: A secondary analysis of a randomized pilot trial of a home-based breastfeeding pain self-management (BSM) intervention for 56 mothers (26 BSM, 30 Control). The BSM intervention provided self-management strategies for breastfeeding and breastfeeding pain. Effect modification of EBF and associated symptoms of depression, anxiety, sleep, well-being pain severity scores, BSES, and group assignment was assessed using the likelihood ratio test. Results: EBF at 6 weeks controlling for demographic covariates, the group, pain severity, anxiety and sleep were significant predictors. Mothers with every one point increase in their pain severity score and sleep score, had a decrease of 9% (OR = .91, 95%CI = [.79, .98]) and 25% (OR = .75, 95% CI = [.52, .95]) respectively and with a one point increase in the anxiety score, a 58% (OR = 1.58, 95% CI = [1.13, 2.72]) increase in the odds of EBF at week 6. Conclusion: Examinations of EBF at 6 weeks should include evaluation of mothers’ ongoing pain and emotional distress, as mothers continue breastfeeding even at personal cost. Early identification and validation of breastfeeding challenges, ongoing pain, and emotional distress are needed to bolster mothers’ confidence in their breastfeeding skills, thus supporting their EBF goals. Quick points: Unresolved pain during breastfeeding may affect breastfeeding self-efficacy, maternal self-efficacy and bonding The effect of maternal emotion on breast and nipple pain and breastfeeding outcomes is not consistently evaluated during breastfeeding Mothers who received breastfeeding pain self-management strategies reported higher breastfeeding self-efficacy scores and lower pain and anxiety scores Providing breastfeeding pain self-management is a pathway to increase breastfeeding self-efficacy and exclusive breastfeeding Empowering women with the skills needed to self-manage anxiety and pain by providing real-time support in the first weeks after birth support mother to reach their breastfeeding goals