Vertex Pharmaceuticals

Understanding the pathways through which diet affects human metabolism is a central task in nutritional epidemiology. This article proposes novel methodology to identify food items associated with blood metabolites in 2 cohorts of healthcare professionals. We analyze 244 metabolites characterized by statistical complexities that include skewness, left-censoring, and structural missingness. Though existing methods can address such factors in low-dimensional settings, they cannot exploit the nutritional or statistical relationships among the 30 considered food intake variables, and they are unsuitable for performing high-dimensional inference. To address these challenges, we develop a novel Bayesian variable selection framework for metabolite response variables based on a skew-normal censored mixture model, while exploiting substantive information on the considered food items via a Markov random field prior. Applying this methodology to the cohort data identifies multiple metabolite-diet associations that are consistent with previous research as well as several potentially novel associations that were not detected using standard methods. The proposed approach is implemented in the R package multimetab, facilitating its use in high-dimensional metabolomic analyses.

Suzetrigine is a non-opioid, highly selective NaV1.8 pain-signal inhibitor of the voltage-gated sodium channel NaV1.8, with no addiction potential approved in the US for moderate-to-severe acute pain in January 2025. In this phase 4, single-arm study, suzetrigine was administered as part of multimodal therapy (MMT;100-mg preoperatively, then 50-mg q12h) for ≤14days. Patients underwent aesthetic/reconstructive surgeries wherein opioids are commonly used ≥72h postoperatively. Investigators determined MMT, with acetaminophen and/or ibuprofen recommended. The primary endpoint was proportion of patients reporting good/very good/excellent on a patient global assessment (PGA) for pain control at end of treatment. Opioid-rescue and safety were also evaluated. Patients (N=99) underwent various procedures, the most common being aesthetic and reconstructive breast procedures (33.3% and 13.1%, respectively), abdominoplasty with liposuction (28.3%), and turbinoplasty (13.1%). Most patients (90.7%) rated suzetrigine as part of MMT as good/very good/excellent on a PGA for pain control at end of treatment, which was consistently high across surgeries. Most patients (90.9%) did not require opioid-rescue; those who did received 2.4 tablets (mean) after surgery (mean:2.0days). Most common MMT was suzetrigine with only acetaminophen and/or ibuprofen (78.8%), while 12.1% used suzetrigine alone. Suzetrigine was safe and well-tolerated. Adverse events were consistent with postoperative settings. Suzetrigine demonstrated highly effective pain management and enabled opioid-free recovery for most patients (90.9%) when initiated preoperatively and as part of MMT in aesthetic and reconstructive surgeries wherein opioids are commonly used postoperatively; in contrast, in studies of mixed cosmetic procedures in the literature, <10% did not require opioids.

β-thalassemia is a globally distributed hereditary red blood cell disorder. Up to now, clinical management of transfusion-dependent β-thalassemia (TDT) patients is still based on chronic transfusion combined with iron chelation therapy. Allogeneic hematopoietic cell transplantation potentially provides a cure, but few patients have an HLA-identical sibling, and optimal results are reported in patients ≤ 14 years. The European Hematology Association (EHA), through the EHA Scientific Working Group on Red Cells/Iron and the European Bone Marrow Transplantation (EBMT) group, has updated a 2021 EHA decision-making algorithm on evidence and expert consensus with the aim of identifying which patients with TDT could benefit from gene therapy (GT). Indeed, it is important to establish the patient setting for whom it is a priority, particularly in the early phase of real-world use outside experimental trials. Moreover, actual price, limited availability, and resource disposal constitute a further indication of a rational and progressive approach to this innovative treatment. In this expert consensus document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. This expert opinion provides dynamic, updatable, priority-based guidance for physicians taking care of TDT patients.

In the ASPEN trial, brensocatib, a dipeptidyl peptidase 1 inhibitor, significantly reduced the burden of pulmonary exacerbations versus placebo in participants with bronchiectasis. A prespecified subgroup analysis evaluated the efficacy and safety of brensocatib in participants of Asian race with bronchiectasis from ASPEN. Participants with confirmed bronchiectasis and a history of exacerbations in the 12 months before screening [adults (18-85 years), ≥ 2; adolescents (12- < 18 years), ≥ 1] received once-daily brensocatib (10 or 25 mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Efficacy endpoints included annualized exacerbation rate, time to first exacerbation, and change at 52 weeks in post-bronchodilator (BD) forced expiratory volume (FEV) in 1 s (post-BD FEV1) and Quality of Life-Bronchiectasis Respiratory Symptom Score (QOL-B RSS). Safety was monitored from enrollment through the end of study. Overall, 191 participants were of Asian race (n = 63, brensocatib 10 mg; n = 64, brensocatib 25 mg; n = 64, placebo). Brensocatib 10 mg and brensocatib 25 mg significantly reduced the annualized exacerbation risk (both by ~ 60%; p = 0.0005 and p = 0.0012, respectively) and prolonged the time to first exacerbation (hazard reduced by ~ 55%; p = 0.0039 and 0.0082, respectively) versus placebo. Brensocatib 25 mg significantly reduced post-BD FEV1 decline [least squares mean difference (95% CI): 69 (24-114) mL, p = 0.0029] and improved QOL-B RSS score [7.49 (2.48-12.50) points, p = 0.0034] versus placebo. The frequency of treatment-emergent adverse events was similar across treatment groups and consistent with the overall ASPEN results. In participants of Asian race, brensocatib 10 mg and 25 mg reduced the burden of pulmonary exacerbations, and the 25-mg dose reduced lung function decline and improved patient-reported symptoms versus placebo. The efficacy and safety of brensocatib in participants of Asian race were largely consistent with the overall ASPEN population, with select outcomes showing numerically greater benefit, although ASPEN was not powered to detect treatment differences in prespecified subgroup analyses. NCT04594369. Bronchiectasis is a long-term inflammatory lung disease that usually worsens over time. Brensocatib is a new medicine developed to treat bronchiectasis. In a clinical trial called ASPEN, people with bronchiectasis took brensocatib at doses of 10 mg or 25 mg or a placebo, for 52 weeks. In ASPEN, brensocatib reduced the number of exacerbations versus placebo. In this study, researchers wanted to know the effect of brensocatib in people of Asian race with bronchiectasis who took part in ASPEN. A total of 191 people of Asian race were assessed: 63 took brensocatib 10 mg, 64 took brensocatib 25 mg, and 64 took a placebo. During the study, both doses of brensocatib reduced the risk of people having an exacerbation by about 60% versus placebo and prolonged the time to their first exacerbation, reducing the chance of exacerbating by about 55%. Compared with placebo, the 25-mg dose reduced the decline in lung function caused by bronchiectasis and improved bronchiectasis symptoms as reported by the people themselves. The occurrence of side effects was similar among the people who took brensocatib and those who took placebo and was similar to the overall ASPEN clinical trial. In summary, brensocatib reduced the burden of exacerbations and improved lung function and the symptoms of bronchiectasis in people of Asian race from ASPEN, although the number of people was small. Generally, the benefits of brensocatib in people of Asian race were similar to those in the overall ASPEN clinical trial, and some benefits were numerically larger.

Acute chest syndrome (ACS) is a leading cause of morbidity in pediatric sickle cell disease (SCD). The Clinical Respiratory Score (CRS) is used prospectively at the bedside for ACS, whereas the NHLBI Clinical Severity Index (CSI) classifies ACS severity retrospectively. We evaluated the diagnostic performance of peak CRS to identify severe ACS. We conducted a retrospective cohort study of patients with ACS (one admission each) aged 3-21 years at a tertiary children's hospital (2015-2021). Peak CRS was abstracted from bedside documentation; CSI (1 = mild, 2 = moderate, 3 = severe) was assigned from the chart. The primary analysis estimated sensitivity, specificity, positive/negative predictive values (PPV/NPV), and accuracy of peak CRS ≥ 4 for identifying CSI = 3, with exact 95% confidence intervals. We prespecified a CRS 0-1 subgroup to assess NPV and de-escalation outcomes [respiratory support, transfusion, length of stay (LOS)]. Among 213 patients, peak CRS ≥ 4 predicted CSI = 3 with sensitivity 1.00 (95% CI 0.863-1.000), specificity 0.888 (0.835-0.926), PPV 0.543 (0.402-0.678), NPV 1.000 (0.978-1.000), and accuracy 0.901 (0.854-0.935). No severe events occurred with CRS < 4 (95% upper bound ~1.8%). In CRS 0-1 (n = 74), none had severe ACS (95% upper bound ~4.1%) nor required significant respiratory support; 75.7% were not transfused; and median LOS was 2.3 days (IQR 1.4-3.1). Peak CRS ≥ 4 identifies a high-risk cohort for severe ACS; CRS 0-1 identifies a low-risk cohort requiring minimal intervention. CRS offers a bidirectional bedside tool to guide escalation and de-escalation of care; prospective validation is warranted.

Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

Cystic fibrosis-related diabetes (CFRD) is a common and serious complication of cystic fibrosis (CF) that leads to worse clinical outcomes. Sleep disturbance is prevalent in CF and may represent a modifiable contributor to dysglycemia in CFRD, however concurrent real-world assessments of sleep and glycemia are limited. This was a fully remote, 10-day observational study to evaluate the feasibility of at-home phenotyping of sleep and glycemia in adults with CFRD. Participants were recruited nationwide and completed continuous glucose monitoring, wrist actigraphy, validated surveys, and at-home fingerstick hemoglobin A1c collection. Feasibility was assessed with study completion and enrollment rates. Descriptive analyses characterized sleep and glycemic measures, and exploratory analyses assessed their relationship. Thirty patients (43.7 ± 12.3 years; 83.3% female; 93.3% White) were enrolled, yielding 100% completion and 96.8% enrollment. Broadly, 76.7% of participants reported poor overall sleep quality; in terms of sleep disorders, 46.7% endorsed clinically significant insomnia symptoms, 30% were at high risk for obstructive sleep apnea, and 16.7% met criteria for definite restless legs syndrome. Time in range (TIR) did not differ across sleep categories. Actigraphy estimates indicated median (Q1, Q3) sleep duration of 7.5 h (6.5, 8.1) and sleep efficiency of 87.5% (83.9, 89.3). Among the actigraphy measures, longer sleep onset latency was significantly correlated with lower TIR. This study demonstrates the feasibility of fully remote physiological phenotyping in CF research and highlights sleep patterns as a potential contributor to metabolic health in CFRD.