David L. Neil

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

Background: Oral corticosteroids (OCS) are commonly used to treat asthma but increase the risks for multiple morbidities; reducing OCS exposure may benefit patients. We analysed independent risk factors and longitudinal changes in OCS usage among patients with asthma to predict future risks of OCS-related adverse outcomes. Methods: Optimum Patient Care Research Database United Kingdom primary care electronic medical records (EMR) from January 1990 to June 2021 were used to select adults (18– 93 years) with asthma who had follow-up data from ≥ 2 years before to ≥ 3 years after an index visit for active symptoms; this date was defined by the largest pre-visit to post-visit change in mean annual OCS use. OCS usage during every follow-up year was categorised as none, low (mean < 2 prescriptions/year), or high (mean ≥ 2 prescriptions/year). Pre-index to post-index changes between usage categories were calculated. Risk modelling selected cohorts without 17 morbidities (documented pre-index) reported to be associated with OCS exposure, including type 2 diabetes, osteoporosis, hypertension, and pneumonia. Cox regression analyses selected published risk factors associated with each condition and available in EMR for inclusion in proportional hazards models. Results: The pre-index to post-index OCS usage category remained unchanged in 38.6% of patients, increased in 39.2%, and decreased in 22.2%, with 20.7% having no further OCS prescriptions. In models, the risks of all adverse outcomes increased with projected categoric OCS use; for example, hazard ratios for a one-category increment (none to low, low to high) were 1.55 (1.42– 1.69) for type 2 diabetes, 1.56 (1.36– 1.78) for post-menopausal osteoporosis, 1.05 (1.00– 1.10) for hypertension, and 1.67 (1.52– 1.83) for pneumonia (all p < 0.001). Conclusion: OCS exposure in this primary care asthma population usually continued longitudinally. Our models predict increased risk of multiple morbidities with higher projected OCS exposure. These findings support early initiation of strategies to minimise OCS use in asthma.

Background: Frailty is the pre‐eminent exigency of aging. Although frailty‐related impairments are preventable, and multidomain interventions appear more effective than unimodal ones, the optimal components remain uncertain.Methods: We devised multidomain interventions against physical and cognitive decline among prefrail/frail community‐dwelling ≥65‐year‐olds and evaluated these in complementary cluster‐randomized trials of efficacy and participant empowerment. The Efficacy Study compared ~3‐monthly telephone consultations vs. 16, 2 h sessions/year comprising communally partaken physical and cognitive training plus nutrition and disease education; the Empowerment Study compared the standard Efficacy Study multidomain intervention (Sessions 1–10) vs. an enhanced version redesigned to empower and motivate individual participants. Changes from baseline in physical, functional, and cognitive performance were measured after 6 and 12 months in the Efficacy Study and after 6 months in the Empowerment Study, with post‐intervention follow‐up at 9 months. Primary outcomes are as follows: Cardiovascular Health Study frailty score; gait speed; handgrip strength; and Montreal Cognitive Assessment (MoCA). Secondary outcomes are as follows: instrumental activities of daily living; metabolic equivalent of task (MET); depressed mood (Geriatric Depression Scale‐5 ≥2); and malnutrition (Mini‐Nutritional Assessment short‐form ≤11). Intervention effects were analyzed using a generalized linear mixed model.Results: Efficacy Study participants (n = 1082, 40 clusters) were 75.1 ± 6.3 years old, 68.7% women, and 64.7% prefrail/frail; analytic clusters: 19 intervention (410/549 completed) vs. 21 control (375/533 completed). Empowerment Study participants (n = 440, 14 clusters) were 75.9 ± 7.1 years old, 83.6% women, and 56.7% prefrail/frail; analytic clusters: seven intervention (209/230 completed) vs. seven control (189/210 completed). The standard and enhanced multidomain interventions both reduced frailty and significantly improved aspects of physical, functional, and cognitive performance, especially among ≥75‐year‐olds. Standard multidomain intervention decreased depression [odds ratio 0.56, 95% confidence interval (CI) 0.32, 0.99] and malnutrition (odds ratio 0.45, 95% CI 0.26, 0.78) by 12 months and improved concentration at Months 6 (0.23, 95% CI 0.04, 0.42) and 12 (0.46, 95% CI 0.22, 0.70). Participant empowerment augmented activity (4.67 MET/h, 95% CI 1.64, 7.69) and gait speed (0.06 m/s, 95% CI 0.00, 0.11) at 6 months, with sustained improvements in delayed recall (0.63, 95% CI 0.20, 1.06) and MoCA performance (1.29, 95% CI 0.54, 2.03), and less prevalent malnutrition (odds ratio 0.39, 95% CI 0.18, 0.84), 3 months after the intervention ceased.Conclusions: Pragmatic multidomain intervention can diminish physical frailty, malnutrition, and depression and enhance cognitive performance among community‐dwelling elders, especially ≥75‐year‐olds; this might supplement healthy aging policies, probably more effectively if participants are empowered.

The highly variable human minisatellites MS32 (D1S8), MS31A (D7S21), and CEB1 (D2S90) all show recombination-based repeat instability restricted to the germline. Mutation usually results in polar interallelic conversion or occasionally in crossovers, which, at MS32 at least, extend into DNA flanking the repeat array, defining a localized recombination hotspot and suggesting that cis-acting elements in flanking DNA can influence repeat instability. Therefore, comparative sequence analysis was performed to search for common flanking elements associated with these unstable loci. All three minisatellites are located in GC-rich DNA abundant in dispersed and tandem repetitive elements. There were no significant sequence similarities between different loci upstream of the unstable end of the repeat array. Only one of the three loci showed clear evidence for putative coding sequences near the minisatellite. No consistent patterns of thermal stability or DNA secondary structure were shared by DNA flanking these loci. This work extends previous data on the genomic environment of minisatellites. In addition, this work suggests that recombinational activity is not controlled by primary or secondary characteristics of the DNA sequence flanking the repeat array and is not obviously associated with gene promoters as seen in yeast.[The sequence data described in this paper have been submitted to the GenBank data library under accession nos. AF048727(CEB1), AF048728 (MS31A), and AF048729 (MS32).]

Little is known about the role of meiotic recombination processes such as unequal crossover in driving instability at tandem repeat DNA. Methods have therefore been developed to detect meiotic crossovers within two different GC‐rich minisatellite repeat arrays in humans, both in families and in sperm DNA. Both loci normally mutate in the germline by complex conversion‐like transfer of repeats between alleles. Analysis shows that inter‐allelic unequal crossovers also occur at both loci, although at low frequency, to yield simple recombinant repeat arrays with exchange of flanking markers. Equal crossovers between aligned alleles, resulting in recombinant alleles but without change in repeat copy number, also occur in sperm at a similar frequency to unequal crossovers. Both crossover and conversion show polarity in the repeat array and are co‐suppressed in an allele showing unusual germline stability. This provides evidence that minisatellite conversion and crossover arise by a common mechanism, perhaps by alternative processing of a meiotic recombination initiation complex, and implies that minisatellite instability is a by‐product of meiotic recombination in repeat DNA. While minisatellite recombination is infrequent, crossover rates indicate that the unstable end of a human minisatellite can act as a recombination warm‐spot, even between sequence‐heterologous alleles.

Minisatellites provide not only the basis for DNA fingerprinting and DNA profiling but also extremely informative systems for analysing processes of tandem repeat turnover in the human genome. Minisatellite instability appears to involve distinct mutation processes in somatic and germline cells; in the germline, mutation is frequently dominated by inter‐allelic conversion‐like events most likely occurring at meiosis and apparently regulated by cis‐acting mutation initiator elements. Attempts to define these initiators in transgenic mice have so far been thwarted by what appears to be a major human/mouse barrier to the inter‐species transfer of repeat instability. Minisatellites not only show high frequency spontaneous mutation in the germline, but also appear to be very sensitive to mutation induction by ionizing radiation, both in experimentally irradiated mice and in human populations exposed following the Chernobyl disaster; the mechanisms of mutation induction by radiation remain enigmatic.