Green Lane Hospital

The discovery of RNA interference in 1998 opened avenues for the manipulation of gene expression, leading to the development of small interfering RNA (siRNA) drugs. Patisiran, the first FDA-approved siRNA medication, targets hereditary transthyretin amyloidosis with polyneuropathy. Givosiran, lumasiran and nedosiran further expand siRNA applications in treating rare genetic diseases, demonstrating positive outcomes. In cardiology, inclisiran, approved for hypercholesterolaemia, showcases sustained reductions in LDL cholesterol levels. However, ongoing research aims to establish its impact on cardiovascular outcomes. Lipoprotein(a), an independent risk factor for atherosclerotic cardiovascular disease, has become a focus of siRNA therapies, precipitating the development of specific siRNA drugs like olpasiran, zerlasiran and lepodisiran, with promising reductions in lipoprotein(a) levels. Research to assess the effectiveness of these medications in reducing events is currently under way. Zodasiran and plozasiran address potential risk factors for cardiovascular diseases, targeting triglyceride-rich lipoproteins. Zilebesiran, which targets hepatic angiotensinogen mRNA, has demonstrated a dose-related reduction in serum angiotensinogen levels, thereby lowering blood pressure in patients with systemic arterial hypertension. The evolving siRNA methodology presents a promising future in cardiology, with ongoing studies assessing its effectiveness in various conditions. In the future, larger studies will provide insights into improvements in cardiovascular outcomes, long-term safety and broader applications in the general population. This review highlights the historical timeline of the development of siRNA-based drugs, their clinical indications, potential side-effects and future perspectives.

BackgroundResearch on medicines access and use is heterogeneous and can be challenging for decision-makers to interpret. Pharmaceutical policy is an additional component for study and is the foundation for the promotion of access and use of medicines. This systematic review summarizes findings from the literature on medicines policy, access and use over the past two decades in Mexico and identifies research gaps that should be addressed.MethodsA systematic review of the literature published between 2000 and 2022 was conducted to identify publications on medicines policy, access and use in Mexico. The study followed PRISMA Statement guidelines 2020. A narrative review including content analysis was conducted.ResultsA total of 5057 articles were reviewed, of which 77 fit the inclusion criteria. Studies described the lack of an explicit national policy, a misalignment between the legal framework and reinforcement incentives, deficient policy documentation at the national level, and the absence of necessary medicines regulation and transparency. In terms of access to medicines, challenges related to supply, selection, acquisition, distribution and expenditure were noted. Regarding medicine use, key study findings included a lack of adherence to standard treatment guidelines, dispensing, lack of reliable information on medicines, lack of treatment adherence and harmful self-medication.ConclusionThe appropriate use of medicines and adequate access to them are priority topics for the formulation of Mexican pharmaceutical policy. It is critical that further research includes longitudinal studies of medicine access and use, and the consideration of studying the private sector as well as new methodological approaches. Many reported challenges related to access to and use of medicines have persisted across decades, suggesting a lack of effective research-to-practice knowledge transfer and policy implementation.This article is part of the Hospital pharmacy, rational use of medicines and patient safety in Latin America Special Issue: https://www.drugsincontext.com/special_issues/hospital-pharmacy-rational-use-of-medicines-and-patient-safety-in-latin-america/

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%±14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Abstract Applying digestate, the residue from anaerobic digestion, to soil as a replacement for inorganic fertiliser is of growing interest in agriculture. However, the impacts of different fractions of digestate on the soil carbon (C) cycle remain unclear and provide the focus for the research reported here. We examined the effects of applying whole digestate (WD) and solid digestate (SD) on carbon dioxide (CO 2 C) efflux, the concentrations of dissolved organic carbon (DOC), microbial biomass C (C micro ) and phospholipid fatty acids, alongside carbon use efficiency (CUE). A 21‐day laboratory microcosm incubation was used to investigate the impacts of digestate when applied to two grassland soils of high versus low initial nutrient content. Application rates for SD and WD were based on recommended nitrogen (N) inputs to grassland soils for these organic materials. Compared to control treatments, cumulative CO 2 C efflux and the concentration of DOC increased significantly after WD and SD application, although only within the low nutrient soil. Both C micro and the fungal‐to‐bacterial ratio increased significantly following SD application, regardless of the initial soil nutrient content. These observations are likely to reflect the larger input of C, alongside the dominance of more strongly lignified compounds, associated with SD compared to WD to achieve a constant N application rate. Our results also indicate that the two digestate fractions generated significantly different CUE. The application of SD led to increases in C micro and positive values of CUE, whereas decreases in C micro and negative values of CUE were observed following WD application. These findings emphasize the need to carefully plan the management of digestate in agricultural production systems, to minimize negative impacts on C storage within soils whilst maximizing the agronomic value derived from digestate. Highlights Past research has not fully elucidated the impacts of digestate fractions on the soil C cycle. Soil nutrient status + digestate fraction shown to impact microbial community and CO 2 C efflux. Solid digestate fraction has positive impacts on microbial biomass and carbon use efficiency.

ObjectivePatients undergoing single-ventricle palliation have experienced significant improvement in survival in the recent era. However, a substantial proportion of these patients undergo reoperations. We performed a review of the Australia and New Zealand (ANZ) Fontan Registry to determine the overall reintervention and reoperative burden in these patients.MethodsA retrospective longitudinal cohort study was performed using data from patients who underwent a Fontan operation between 1975 and 2016 from the ANZ Fontan Registry. The data obtained included Fontan operation, reinterventions and most recent follow-up status. We examined the type and timing of reinterventions and survival.ResultsOf the 1428 patients identified, 435 (30%) underwent at least one reintervention after the Fontan operation: 110 patients underwent early reintervention and 413 underwent late reinterventions. Excluding Fontan conversion and transplantation, 220 patients underwent at least one interventional procedure and 209 patients underwent at least one reoperation. Fenestration closure and pacemaker-related procedures were the most common catheter and surgical interventions, respectively. The cumulative incidence of reintervention following Fontan was 23%, 37% and 55% at 10, 20 and 30 years, respectively. Survival and freedom from failure were worse in patients requiring later reintervention after Fontan surgery (51% vs 83% and 42% vs 69%, respectively at 30 years, p<0.001). This difference persisted after excluding pacemaker-related procedures (p<0.001). Operative mortality for non-pacemaker late reoperations after Fontan was 6%.ConclusionsA substantial proportion of Fontan patients require further intervention to maintain effective single-ventricle circulation. Patients undergoing reoperation after Fontan have higher rates of mortality and failure, despite intervention.

KEY POINTS ■ Coronary heart disease (CHD) is the leading cause of death among women and men. ■ Many gender differences in anatomical and physiological aspects of CHD have been described,but mechanisms remain poorly understood. ■ While most women will present with typical chest discomfort and accompanying symptoms, cli-nicians should be alert to atypical symptom constellations among women (and men), interpret symptoms in the context of the overall risk profile, and follow up with appropriate diagnostic testing.

Imaging is essential in the diagnosis, management, surgical planning and eventual outcome in patients with anorectal malformation (ARM). This article outlines the imaging that may be required and the information needed by the surgeon to attain the best possible surgical outcome. ARM encompasses a wide spectrum of congenital malformations relating to the distal rectum and anus as well as the urinary and or gynaecological systems. The malformations range from a relatively simple perineal fistula with the potential for an excellent functional outcome, to complex cloacal malformation that requires specialist care and intervention. Approximately half of these children will have associated abnormalies. In the first 24–48 hours of life, imaging is used to determine if any associated anomalies are severe enough to preclude an operation, and what operation will be required so that the child can grow as normally as possible. If a colostomy is done, pre-definitive repair imaging in the form of a high-pressure distal colostogram determines the surgical approach required to repair the malformation. In more complicated cases of cloacal malformation, advanced imaging in the form of MRI or 3D fluoroscopy is valuable. In the South African setting, 2D fluoroscopy with the surgeon present is adequate to help in planning for the surgical management. Communication between the radiologist and paediatric surgeon is essential to ensure that such patients have the best possible outcome.

Regular exercise, physical fitness and sedentary behaviours are each known to be associated with cardiovascular and total mortality. This review evaluates recent research on these associations and its implications for guidelines on physical activity. In several large cohort studies, modest levels of exercise, much less than recommended in current guidelines, were associated with lower mortality. Avoiding prolonged sitting has also been associated with lower mortality risk. Most research suggests graded decreases in long-term mortality with an increase in usual physical activity and fitness. However, at very high exercise levels, these benefits may be attenuated, particularly in patients with known coronary heart disease. In sedentary persons, a modest increase in physical activity and avoiding prolonged sitting are likely to have important health benefits. Further research is needed to determine the most effective strategies for increasing physical activity.