Vertex Pharmaceuticals

Time delays exist between inpatient blood glucose measurements, insulin administration and meal timing. The clinical impacts of time delay on insulin dosing and hypoglycaemia risk have not been fully evaluated. In this single-centre observational study, hospitalised individuals treated with insulin wore blinded Dexcom G6 Pro continuous glucose monitors (CGM) and received usual diabetes care. CGM values were matched by time to point-of-care (POC) blood glucose values and correctional insulin administration episodes. For each matched episode, time delay between POC measurement and correctional insulin administration and the difference between corresponding CGM values were calculated. Clinical impact of time delay was identified if insulin dosing would have changed with an updated glucose measurement. Across 243 participants, 2204 matched glucose-correctional insulin administration episodes were identified. Mean time delay (± SD) was 52.5 ± 37.4 min with mean absolute difference between CGM values of 1.0 ± 1.2 mmol/l. Had an updated CGM value at time of insulin administration been used, a different dose of correctional insulin may have been given in 28.4% of patient episodes. Time delay between inpatient POC glucose measurements and correctional insulin administration varies widely and may alter insulin dosing. Future studies are needed to investigate the role of CGM in optimising insulin dosing in the hospital.

This study analyzes real-world treatment patterns among patients newly initiating treatment for painful diabetic peripheral neuropathy using a contemporary dataset in the United States. A retrospective study using the MarketScan database [1/1/2016-06/30/2023] identified adults newly prescribed pain medication(s) used to treat neuropathic pain within 60 days of a diabetic peripheral neuropathy diagnosis. Patients with prior medication, conditions with similar treatment indications, cancer, or major surgery were excluded. Treatment patterns over a 12-month period and variable-length follow-up (four sequential treatment episodes) were captured, including treatment type, dosage, adherence, discontinuation (≥90-day gap), and switching. Among 22,955 patients identified, 98.5% initiated monotherapy treatment for painful diabetic peripheral neuropathy. The majority initiated treatment with gabapentinoids (gabapentin 59.0%; pregabalin 5.3%), followed by opioids (tramadol 15.1%, oxycodone 7.0%), and antidepressants (duloxetine 5.2%). Among patients initiating gabapentin, pregabalin, or duloxetine, most were prescribed daily doses below recommended levels (79% gabapentin, 91% pregabalin, 61% duloxetine) and the majority (81%-96%) did not increase their dose. Adherence was low. Over 50% discontinued their initial treatment within 3 months and approximately 75% discontinued in the 12-month follow-up period, with fewer than 25% switching to another medication. When evaluating treatment patterns across sequential treatment episodes, almost 65% discontinued all pain medications and did not receive subsequent treatment by the fourth treatment episode. High rates of treatment discontinuation and suboptimal adherence likely indicate challenges with tolerability and insufficient pain relief associated with current therapies for painful diabetic neuropathy. These findings emphasize the limitations of existing treatment options and highlight the unmet need for more effective and better-tolerated treatments for these patients.

Cystic fibrosis (CF) is an inherited multi-organ disorder. People with CF (pwCF) experience recurrent and chronic lung infections and a progressive loss of lung function. PwCF with poor and rapidly declining lung function may be considered for lung transplantation (LTx), which may improve their quality of life and survival. Nontuberculous mycobacteria (NTM) can cause pulmonary disease in pwCF, and NTM infection is a poor prognostic factor in LTx. Guidelines recommend NTM infection should not automatically preclude LTx. It is important to evaluate the evidence base for LTx in pwCF and NTM pulmonary disease. To evaluate clinical outcomes in pwCF and with NTM infection (NTM infection alone or with NTM pulmonary disease) who undergo LTx by comparing: 1. pwCF with current NTM lung infection who undergo LTx versus those with NTM infection who do not undergo LTX; 2. pwCF with current NTM lung infection who undergo LTx versus those without NTM undergoing LTx. We searched the Cochrane Cystic Fibrosis Trials Register, CENTRAL, MEDLINE, Embase, and PubMed as well as two ongoing trials registries. We checked references. The latest search date was 17 February 2026. We considered non-randomised studies of pwCF (any age) with or without NTM lung infection or disease being considered for LTx as well as studies of pwCF and NTM who either did or did not undergo LTx. Our critical outcomes were mortality, disseminated NTM infection post-LTx, time to chronic lung allograft dysfunction (CLAD), and quality of life at any time points reported. We additionally planned to report lung function, hospitalisations for pulmonary exacerbations, and nutritional parameters in the review. We assessed the risk of bias in three studies using ROBINS-I and in one study using the Joanna Briggs Institute checklist for case series. We could only report results narratively. We used GRADE to assess the certainty of the evidence. We included four single-centre retrospective studies (388 adults). Sample sizes ranged from nine to 177 participants. Mycobacteria abscessus was the most common NTM species identified, and all studies reported infection with other pathogens. All studies compared pwCF and NTM infection to pwCF without NTM infection, all undergoing LTx. Each study reported mortality and disseminated NTM infection post-LTx; two studies recorded CLAD. No study reported quality of life, specific lung function measures (although one study commented briefly on lung function in general), hospitalisations for pulmonary exacerbations, or nutritional parameters. We analysed all NTM infections together for practical reasons and were not able to undertake a planned subgroup analysis by subspecies, but acknowledge that the prognosis and clinical trajectory of pwCF infected with different NTM may not be similar. We downgraded the certainty of the evidence due to non-randomised study design and serious risk of bias across all studies. We assessed all identified evidence as of very low certainty, such that lung transplant may have little to no effect on any of the outcomes listed below, but the evidence is very uncertain. Mortality Two studies (18 participants with NTM) reported similar survival data between NTM-positive LTx recipients and matched controls without NTM. Another study (9 participants) reported that two of five participants NTM-positive at LTx died within a few months post-LTx, whilst one of four NTM-negative participants died three years post-LTx due to chronic rejection. One study (177 participants) found that pwCF who had positive NTM cultures pre-LTx had a longer median survival duration than those who had negative cultures. This study additionally reported on survival of participants with post-LTx NTM infection, finding that the five participants who had post-LTx NTM disease had a longer mean survival duration than the 141 participants without post-LTx NTM disease. Disseminated NTM infection post-LTx In the largest study, of the 18 pwCF with NTM at the time of LTx, seven had at least one positive NTM culture, and four developed NTM disease post-LTx. Conversely, 79 of the 89 pwCF without NTM remained so post-LTx; 10 participants recorded a positive NTM culture, but none developed NTM disease. For the 39 participants without a baseline NTM culture, three participants recorded positive NTM cultures post-LTx, and one developed NTM disease. Of the remaining small studies, one reported that NTM was isolated in four of 13 participants at LTx and in three of these post-LTx. A second study reported that one out of five pwCF had NTM infection post-LTx (all were positive at LTx). The third study reported that five out of nine participants had NTM disease at LTx, and two of these five remained NTM-positive post-LTx. CLAD Two studies assessed CLAD. One study reported that none of the five NTM-positive LTx recipients developed CLAD, stating that the risk of CLAD appeared to be similar between the NTM and the comparator group. The second study stated that three out of nine LTx recipients with NTM disease developed chronic rejection or graft dysfunction. There are no randomised trials to guide clinicians and patients or their families when making decisions regarding LTx in pwCF with NTM. The available data come from observational studies and registry data, often with few people with NTM reported. It has not been possible to pool the available data in meta-analysis, and we are very uncertain of the effect of NTM on pwCF undergoing LTx on the risk of developing NTM disease post-LTx, survival after LTx, and the development of CLAD. The studies were small and at times contradictory. In the era of highly effective modulator treatments, as some centres do not offer LTx to people with a history of NTM, there is an urgent need for more data to guide decision-making. This review is part of a suite of reviews on NTM funded jointly by the CF Foundation and the CF Trust. Protocol registration (2024): www.crd.york.ac.uk/PROSPERO/view/562682.

Genetic risk for coronary artery disease (CAD) can be estimated using polygenic risk scores (PRS), but greater clarity is needed on how PRS might inform clinical risk assessment and prevention. We assessed the risk for CAD jointly conferred by LDL-C and CAD PRS relative to established treatment thresholds. This study followed 257,158 UK Biobank (UKBB) participants and 67,668 from the All of Us Research Program (AoU), a longitudinal U.S. cohort, without prior CAD, stroke, or diabetes. In UKBB, Cox proportional hazards models estimated CAD hazard ratios for each LDL-C × CAD PRS stratum relative to individuals with LDL-C < 100 mg/dL. The severe hypercholesterolemia (LDL-C ≥ 190 mg/dL) group, the guideline-designated threshold for statin initiation, served as a benchmark against which groups were compared. Parallel analyses were performed in AoU cross-sectionally. Over a median (IQR) follow-up of 13.5 (12.8-14.2) years, 13,886 (5.4%) participants developed CAD in UKBB. Higher CAD PRS was associated with CAD risk that was comparable to, or in some strata exceeding, that associated with LDL-C ≥ 190 mg/dL by pairwise Wald tests at progressively lower LDL-C concentrations in both cohorts. Individuals with high genetic risk and moderate LDL-C elevations, representing 14.8% of the study population, have CAD risk comparable to or greater than that of SH. Consideration of dynamic LDL-C thresholds among those with high CAD PRS may identify individuals with risk sufficiently high to warrant preventive therapy.

Use of adeno-associated virus (AAV)-mediated transfer of functional microdystrophins to address Duchenne muscular dystrophy (DMD) has been established. RGX-202, an AAV8 vector encoding a novel, optimized human microdystrophin with an extended C-terminal domain, expressed under the Spc5-12 muscle-specific promoter, was evaluated for tolerability and efficacy in dystrophin-deficient mdx mouse in 12- and 26-week studies at vector doses ranging from 3 × 1013 to 5 × 1014 gc/kg. A single intravenous administration of RGX-202 was well tolerated and led to robust, dose-dependent expression of microdystrophin in skeletal and cardiac muscles at 12 weeks, which persisted to 26 weeks post-administration. Increased microdystrophin was associated with recruitment of the dystrophin-associated protein complex to the sarcolemma, particularly at doses ≥1 × 1014 gc/kg. Histologic and magnetic resonance imaging examinations revealed marked and sustained suppression of dystrophic pathology in all RGX-202-treated mice. Functionally, gains were observed in the in vitro specific force of extensor digitorum longus muscle, in vivo grip strength, and the rescue of treadmill and gait deficits. These findings provide preclinical evidence for the therapeutic efficacy of RGX-202 at a minimum effective dose (MED) of 1 × 1014 gc/kg in the murine DMD model. This MED served as the starting dose for the RGX-202 clinical study (NCT05693142), which has currently completed phase III enrollment.