Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare disease associated with immunodeficiency and immune dysregulation. Management may include sirolimus and immunoglobulin replacement therapy (IRT); neither is specifically approved for APDS in the USA. This systematic literature review evaluated the effectiveness and safety of sirolimus and IRT in patients with APDS. MEDLINE, Embase, and Cochrane Library databases were searched through July 2025, supplemented by grey literature and bibliographic searches. Eligible records reported treatment outcomes in patients with APDS receiving sirolimus and/or IRT. Quality assessment was performed; findings were narratively synthesized. Seventy-nine records (82 publications) were included: 69 case reports of 103 patients, 8 retrospective cohort studies, and 2 case series, describing 136 treatment regimens. No prospective studies were identified. Evidence was dominated by case reports (87.3
The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies has transformed the management of obesity, type 2 diabetes, heart failure, and chronic kidney disease by delivering substantial metabolic, cardiovascular, and renal benefits. However, their effects on skeletal muscle have become a growing area of interest. While SGLT2 inhibitors induce modest weight loss, their catabolic metabolic effects have prompted questions regarding skeletal muscle preservation, particularly in individuals with limited physiological reserve. Conversely, the profound weight loss achieved with incretin-based therapies has raised concerns about accompanying reductions in lean tissue and their potential functional consequences. In this narrative review, we critically evaluate the available evidence regarding the effects of these therapeutic classes on skeletal muscle, integrating findings from randomized controlled trials, observational studies, systematic reviews, and mechanistic investigations. We compare their distinct biological mechanisms; summarize clinical evidence on changes in muscle quantity, quality, strength, and physical performance; and discuss their implications for older adults; individuals with frailty, sarcopenia, or sarcopenic obesity; and patients with heart failure or chronic kidney disease. Overall, current evidence indicates that both SGLT2 inhibitors and incretin-based therapies preferentially reduce adipose tissue, whereas the accompanying reductions in lean tissue are generally proportional to the magnitude of weight loss. Importantly, reductions in lean tissue should not be equated with treatment-induced sarcopenia, as current evidence does not consistently demonstrate clinically meaningful impairment in muscle strength or physical performance. Nevertheless, the populations most susceptible to skeletal muscle dysfunction remain underrepresented in clinical trials. We discuss a phenotype-based approach that integrates skeletal muscle health into therapeutic decision-making and outline practical strategies—including resistance exercise, adequate protein intake, and individualized monitoring—to preserve muscle function during treatment. Future research should prioritize standardized functional outcomes and dedicated studies in vulnerable populations to enable precision cardiorenal-metabolic medicine.
As a result of a variety of pathophysiological mechanisms, type 2 diabetes displays notable clinical heterogeneity. However, large cohorts of newly diagnosed patients are still needed to validate systematic classification based on basic clinical indicators and its clinical significance. Patients with new-onset type 2 diabetes were divided into four pathophysiological subtypes based on HOMA-IR and HOMA-β. Each subtype’s clinical traits, metabolic profiles, and cross-sectional complication risk were assessed. A total of 21,340 patients who had just received a diagnosis of type 2 diabetes and were not receiving treatment were included. HOMA-IR and HOMA-β were computed. The overall medians were used as cut points to split patients into four groups: group 1, high resistance low secretion (HRLS); group 2, high resistance high secretion (HRHS); group 3, low resistance low secretion (LRLS); and group 4, low resistance high secretion (LRHS). The groups were compared in terms of prognosis, islet function, metabolic markers, and demographics. There were notable clinical and metabolic variations among the four groups. The HRLS group (n = 2743) had the highest risk of complications, the lowest disposition index, and the worst metabolic indicators. With the highest insulin levels and a moderate disposition index, the HRHS group (n = 7935) demonstrated typical metabolic syndrome. The LRLS group (n = 7927) demonstrated severe insulin secretory defects, as evidenced by their moderate disposition index, good sensitivity, and poor secretion. The LRHS group (n = 2735) had the highest disposition index and the least severe metabolic abnormalities. All intergroup comparisons had a p value < 0.001. Type 2 diabetes subtypes with different pathophysiological mechanisms and clinical prognoses can be effectively identified by simple classification based on HOMA-IR and HOMA-β, which offers a useful framework for precision medicine.
Elevated levels of circulating cytokines and immune cells are often observed in patients with coronavirus disease 2019 (COVID-19), some of which have been associated with disease severity and clinical outcomes across various medical interventions. We evaluated 50 biomarkers and immune cell types in blood from patients in a randomised controlled trial and hypothesised that baseline inflammatory cytokines and haematologic markers would be associated with COVID-19 severity and outcomes, and a composite biomarker score derived through statistical and machine learning capturing complementary immune pathways could provide stronger prognostic value than individual biomarkers. COMMUNITY was a phase 3, randomised, adaptive-platform study in adult patients hospitalised with COVID-19 with clinical severity grade 2–5 (8-point ordinal scale), enrolled November 24, 2020, to June 4, 2021. An exploratory biomarker analysis used clinical laboratory assessments and serum cytokine data collected from baseline up to day 29 (or discharge) from patients randomised to placebo or apremilast + standard of care (baseline only). Healthy volunteers and ambulatory patients with COVID-19 (not part of the study) were evaluated for comparison. Interleukin (IL)-6, IL-8, IL-10, and tumour necrosis factor alpha (TNFα) were higher at baseline in 378 hospitalised patients than healthy volunteers or ambulatory patients. These cytokines and several haematological markers (including neutrophil count and percentage) showed positive associations with clinical severity and were inversely associated with clinical outcomes. A composite score was derived from baseline IL-6 levels and percentage of neutrophils and showed a strong association with patient overall survival. With a tertile cutoff at which composite scores ≤ 72.1 indicate high-risk patients, the estimated hazard ratio of mortality from COVID-19 infection was 14.3 (95 https://clinicaltrials.gov/study/NCT04590586 ).
This study evaluated the cost-effectiveness of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) as a second-line treatment for patients with primary refractory or early relapsed transplant-eligible large B cell lymphoma (LBCL) from a US commercial third-party payer perspective. A partitioned survival model captured the event-free, post-event, and death states to estimate incremental cost-effectiveness ratios (ICERs) from cost and quality-adjusted life-years (QALYs) over a lifetime horizon. Mixture cure modeling was employed to extrapolate event-free survival (EFS) and overall survival (OS) beyond the trial follow-up period using data from the TRANSFORM and ZUMA-7 studies. The comparative treatment effect of liso-cel versus axi-cel was estimated using the Bucher method for indirect treatment comparisons, leveraging standard of care as a common comparator across both trials. Health state utility estimates and disutilities due to adverse events (AE) were derived from TRANSFORM EQ-5D-5L data and supplemented with published sources. The model incorporated costs associated with chimeric antigen receptor T cell therapy pre-treatment, treatment acquisition and administration (inpatient and outpatient), subsequent treatment, AE management, hospitalization after infusion, monitoring, and end-of-life care based on standard US sources. Liso-cel was projected to result in additional QALYs of 0.31, at a lower cost than axi-cel (incremental cost of − 9398). The cost of liso-cel was offset by lower costs associated with AE management (−11,109), chimeric antigen receptor T cell administration (− 15,074), and subsequent treatment (−2864). The main driver of results was the OS cure probability. Liso-cel as a second-line LBCL treatment was estimated to be cost-effective compared with axi-cel, as informed by pivotal trials, from a US commercial third-party payer perspective. Patients treated with liso-cel were estimated to gain slightly more QALYs at a lower cost. NCT03575351 (TRANSFORM), NCT03391466 (ZUMA-7).
