Real-world evidence (RWE) has emerged as an essential complement to randomized controlled trial data, providing insights into the effectiveness, safety, and tolerability of healthcare interventions in routine practice. The increasing digitalization of healthcare systems has enabled the generation of vast amounts of real-world data (RWD) from electronic medical records, claims databases, and digital health technologies. When appropriately analyzed, these data can inform clinical decision-making, regulatory evaluations, payer assessments, and healthcare resource optimization. Despite its growing importance, the generation of high-quality RWE presents significant methodological and operational challenges. Common challenges such as misclassification bias, confounding, incomplete longitudinal follow-up, poor data linkage, and risks of selective reporting. Addressing these challenges requires rigorous study designs, transparent methodologies, pre-specified and publicly registered protocols, and adherence to standard reporting guidelines. Advances in artificial intelligence (AI) and natural language processing hold promise for improving data accuracy, addressing time-varying confounding, scalability, efficiency, and enhancing study reproducibility. However, AI-driven approaches currently serve as supportive tools rather than autonomous solutions and require robust scientific oversight to ensure appropriate study design, causal reasoning, and clinical contextualization. This article highlights key principles, challenges, and emerging trends in RWE generation and dissemination, with a focus on the role of methodological rigor and expert scientific communication. Agencies and medical communication experts play a crucial role in ensuring that RWE generation aligns with stakeholder needs, regulatory frameworks, and scientific integrity. By leveraging innovative methodologies, robust protocols, transparent reporting, and stakeholder-focused dissemination strategies, RWE can reach its full potential in transforming patient care and driving evidence-based decision-making across healthcare systems. What is this article about?This article explores the use of real-world evidence (RWE) in healthcare. RWE is generated from data collected during routine patient care, such as electronic medical records, insurance claims, and digital health tools. RWE provides insights into how treatments perform in everyday clinical practice and complement traditional clinical trial data.What were the results?/What methodology/protocol is described?This article outlines how RWE is generated and analyzed using large healthcare databases and advanced analytics. Based on a targeted overview of RWE in healthcare, it discusses key challenges including data quality, accuracy, bias, incomplete follow-up, and need for transparent study-design and reporting. It also highlights the potential role of artificial intelligence in improving data extraction and study reliability while emphasizing the importance of human scientific oversight.What do the results mean?/Why is this important?Well-designed and clearly communicated RWE studies provide insights into treatment patterns, patient outcomes, and safety in real-world settings. These insights support better decision-making by healthcare professionals, regulators, and payers. By combining rigorous methods, emerging technologies, and expert scientific communication, RWE can improve patient care, guide policy decisions, and support efficient healthcare resource use.
The current nonoperative standard-of-care therapies for knee osteoarthritis (OA) include weight reduction, physical therapy, analgesics, optimization of biomechanics, and intra-articular injection of corticosteroids. Platelet rich plasma (PRP) is an orthobiologic intervention that is increasingly used in patients with knee OA, primarily due to its many key mediators that can potentially reduce joint inflammation thereby improving pain and enhancing overall joint function. The American Academy of Physical Medicine and Rehabilitation (AAPM&R) convened a technical expert panel (TEP) to summarize and assess the evidence for use of PRP in patients with knee OA and synthesize current knowledge into a summary document that can serve as a resource for clinicians. We address many of the questions and decision points that practitioners need to consider for responsible use of PRP in knee OA. To develop consensus-based practice recommendations to identify and address gaps in PRP applications in patients with knee OA. The AAPM&R orthobiologic TEP initiated development of this consensus guidance statement in March 2023. The TEP was responsible for formulating search terms and research questions and synthesizing evidence obtained from a structured literature review that was initially completed in April 2023 and subsequently updated to reflect studies published between May 2023 and June 2025. The recommended actions and best practices in this guidance reflect consensus being achieved by the expert physiatrists and supported by best available evidence, where available. These actions and practices were conceptualized in response to common questions this expert panel frequently encounter in the use and administration of PRP. The TEP was asked to consider the strengths and limitations of available evidence and augment with expert opinion focused on closing knowledge gaps guiding the delivery of PRP in patients with knee OA. As a result of the structured literature review and use of a modified Delphi process to achieve consensus on clinical guidance for PRP use in patients with knee OA, the AAPM&R TEP on use of PRP in knee OA arrived at five evidence-based clinical recommendations for PRP management and 11 consensus-based best practices supported by expert opinion and limited evidence. This consensus guidance addresses common questions about the use of PRP in patients with knee OA and provides actionable recommendations and best practices based on expert opinion supported by best available evidence. Despite their growing availability as point-of-care interventions, orthobiologic therapies remain an evolving area of practice. Robust, dose-dependent randomized controlled trials are needed to more clearly establish the clinical effects of PRP on patient outcomes. Clinical judgment should be exercised and management options tailored to individual patient needs, preferences, and risk profiles.
Chronic wounds impose a substantial and growing burden on healthcare systems worldwide, consuming significant resources while often delivering suboptimal patient outcomes. In parallel, value-based procurement (VBP) has gained increasing policy attention in medical devices as a multidisciplinary approach that links purchasing decisions to outcomes, service quality, and total cost of care rather than unit price alone. To examine how value-based procurement for medical devices is conceptualized, enabled, and implemented internationally, and to assess its relevance to wound care. We conducted an integrative review combining database searches with structured searching of authoritative policy and grey literature relevant to VBP for medical devices and wound care across 15 countries. Across jurisdictions, VBP in medical-device procurement moves beyond lowest-price purchasing towards multidimensional evaluation that may include clinical outcomes, patient-relevant outcomes, service and training, sustainability, and total or life-cycle cost. Legal frameworks enabling value-based award criteria were identified in all 15 countries examined, but operational maturity, institutional capacity, and documented implementation varied substantially. In wound care specifically, the evidence consistently indicates that major cost drivers are clinical time, healing duration, and complications rather than product acquisition cost alone. VBP appears to be an increasingly policy-enabled and selectively implemented procurement approach with clear relevance to wound care. However, operational maturity and empirical evaluation remain uneven across settings. Realizing its full potential will require better designed and reported wound-care studies, more standardized outcome measures, stronger real-world data infrastructure, and procurement processes capable of evaluating value across the full care pathway.
To evaluate the total cost of care, average monthly treatment cost, and cost per outcome of linvoseltamab versus teclistamab and elranatamab in triple-class-exposed relapsed/refractory multiple myeloma (RRMM) using matching-adjusted indirect comparisons (MAICs). Total cost per patient and cost per outcome were estimated over 1- and 2-year time horizons from a United States commercial payer perspective. Cost components included drug acquisition, administration, monitoring, adverse events, progression, and death. Dosing schedules were applied per prescribing information, aligning with pivotal trial-based MAIC-adjusted clinical inputs. Costs were sourced from databases and published literature. The 1- and 2-year cumulative costs were $387,773 and $488,088 with linvoseltamab versus $500,670 and $639,013 with teclistamab; costs per progression-free (PF) month were $40,904 and $29,036 versus $63,057 and $50,877; costs per overall response were $538,573 and $677,901 versus $794,714 and $1,014,307. The 1- and 2-year cumulative costs were $383,368 and $472,907 with linvoseltamab versus $416,359 and $475,918 with elranatamab, for adjusted median treatment durations of 11.3 versus 5.6 months; 1- and 2-year costs per PF month were $43,417 and $29,912 versus $50,529 and $33,304, while costs per overall response were $539,955 and $666,066 versus $682,556 and $780,193. Linvoseltamab had lower total costs and cost per outcome than teclistamab at 1- and 2-year timepoints. Linvoseltamab had comparable total costs to elranatamab despite longer treatment duration, and consistently lower costs per outcome. Within this exploratory MAIC model, linvoseltamab was associated with lower economic burden in heavily pretreated RRMM. These results should be interpreted considering study assumptions and limitations.
Coronary artery disease (CAD) remains a leading global cause of mortality. The apelin/apelin receptor (APJ) system has emerged as a novel pathway implicated in cardiovascular regulation and disease progression. This pioneering case-control study, the first conducted in a Syrian population, investigated the association of the apelin receptor G212A polymorphism and plasma APJ levels with CAD susceptibility. The participants comprised 108 CAD patients confirmed by angiography and 114 healthy controls. Plasma APJ levels were quantified via enzyme-linked immunosorbent assay (ELISA), and the apelin receptor G212A genotype and allele frequencies were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The study was registered on ClinicalTrials.gov (Identifier: NCT05562687). Plasma APJ levels were significantly lower in CAD patients compared to controls (p < 0.005). Multivariable regression analysis further revealed that plasma APJ levels were independently associated with CAD and hypertension. While the heterozygous GA genotype and the A allele showed higher frequencies in CAD patients, no statistically significant association of the G212A polymorphism was observed between the patient and control groups (p > 0.05). Notably, the homozygous mutant AA genotype was not detected in any study participant. Our findings indicate significantly reduced plasma APJ levels in Syrian CAD patients, suggesting a diminished protective role of the apelin/APJ system in disease pathophysiology. Despite observed trends, the apelin receptor G212A polymorphism was not significantly associated with CAD risk in this specific cohort. This highlights the potential of plasma APJ as a biomarker and underscores the importance of population-specific genetic studies. This pioneering case-control study investigated the association of the apelin receptor (APJ) G212A polymorphism and plasma APJ levels with coronary artery disease (CAD) in a Syrian population. Recognizing the global burden of CAD and the emerging role of the apelin/APJ system in cardiovascular health, this research aimed to fill a critical gap in understanding population-specific genetic and biochemical markers. The study enrolled 108 angiographically confirmed CAD patients and 114 healthy controls, matched for age and gender. Comprehensive clinical data, plasma APJ levels (determined by ELISA), and APJ G212A genotype frequencies (analyzed via PCR-RFLP) were collected. Key findings revealed significantly lower plasma APJ levels in CAD patients compared to controls, with multivariable analysis confirming an independent association of reduced APJ levels with both CAD and hypertension. This suggests that a diminished apelin/APJ system activity may contribute to CAD pathophysiology. Conversely, the APJ G212A polymorphism did not show a statistically significant association with CAD susceptibility in this cohort, and the homozygous mutant AA genotype was notably absent. This highlights the importance of genetic studies in diverse populations, as genetic influences can vary by ethnicity. The research’s novelty lies in being the first to examine these specific associations within the Syrian population, providing unique insights into the local epidemiology of CAD and the potential role of the apelin/APJ system as a circulating biomarker. The findings underscore the need for further mechanistic investigations into how the apelin/APJ system is altered in cardiovascular disease and its clinical implications for risk assessment and therapeutic strategies.
The first iteration of Good Practice for Conference Abstracts and Presentations (GPCAP), published in 2019, set the baseline for general recommendations and expectations for scientific conference abstracts and presentations. While individual conference guidelines must be followed, these recommendations aim to provide principles and best practice for pharmaceutical company-sponsored research. The purpose of conferences is the prompt communication of new data for dissemination and discussion within the context of short deadlines and relevant audiences. These updated recommendations aim to provide support for all individuals with a vested interest in the communication of scientific data at conferences. To provide principles and best practice covering the preparation and presentation of pharmaceutical-supported conference material. Feedback from the previous iteration, interviews with experts, and general revisions have been incorporated into these updated recommendations, aligning with Good Publication Practice (GPP) 2022. New sections have been added to cover topics that have risen in prominence since the first iteration: patient engagement, accessibility, and inclusivity; artificial intelligence; and enhanced content. Other sections cover authorship, copyright, citations, and encores, and have been updated accordingly. Conferences remain the key arena for communication and discussion of scientific data in real time as new developments within the scientific field continue to evolve rapidly. These updated recommendations provide principle-based, practical, insights-driven recommendations and suggestions on how to submit and present company-sponsored research with high standards and a commitment to consistency, transparency, and integrity for the scientific community. The aim is to make conferences the best they can be for all interested parties, within the context of pharmaceutical company-sponsored research.
Long-acting injectable antipsychotics (LAIs) are underused, despite advantages in terms of patient outcomes. The Phase 3 RIsperidone Subcutaneous Extended-release (RISE) study evaluated the efficacy and safety of TV-46000, a subcutaneously administered long-acting formulation of risperidone, administered monthly (q1m) and once every 2 months (q2m), in patients with schizophrenia. During the relapse-prevention phase, TV-46000 significantly prolonged time to impending relapse versus placebo, with a safety profile comparable to other risperidone formulations. This post hoc study examined the number needed to treat (NNT) and the number needed to harm (NNH) using RISE data. NNT estimates versus placebo were calculated for patients who were free of impending relapse (ie, worsening symptom scores, psychiatric hospitalization, aggressive/violent behavior, suicidality), maintained stability, and achieved remission as well as all-cause discontinuation (an acceptability proxy). NNH estimates were calculated for safety and tolerability outcomes. TV-46000 NNT estimates (95% CI) versus placebo were 5 (4-7) for q1m and 7 (5-13) for q2m for avoidance of impending relapse, and 4 (3-6) and 6 (4-11) for maintenance of stability. Remission rates ranged from 16.6-23.5% and did not differ between TV-46000 and placebo (TV-46000 NNT estimates: q1m, 22; q2m, 15). For all groups, adverse event (AE)-related discontinuation rates were low (1.7-3.9%), and NNH estimates for TV-46000 q1m and q2m versus placebo were 190 and 45, respectively, and not statistically significant. For AEs common to many second-generation antipsychotics (eg, akathisia, restlessness, somnolence, sedation) and ≥7% weight increase from baseline, NNH estimates for TV-46000 versus placebo were ≥10 and not statistically significant, indicating favorable safety and tolerability. Robust, single-digit NNT estimates for avoiding impending relapse and maintaining symptomatic stability support TV-46000 q1m and q2m efficacy, and high NNH estimates for safety and tolerability endpoints suggest TV-46000 is well tolerated regardless of dosing frequency. These findings provide clinically intuitive data supporting a favorable benefit-risk profile of TV-46000 for relapse prevention.
The intertwined global epidemics of chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) pose an increasing challenge in chronic disease management, constituting a clinically significant bidirectional threat. This review integrates current evidence to propose a pathological interactive axis underlying this comorbidity, driven by shared risk factors such as smoking, obesity, and physical inactivity, and mediated through interconnected inflammatory signaling (e.g. IL-6/NF-κB and NLRP3/IL-1β), metabolic dysregulation, and oxidative stress. Within this framework, pulmonary inflammation in COPD may exacerbate systemic metabolic abnormalities, whereas chronic hyperglycemia and insulin resistance in T2DM may, in turn, aggravate lung injury, sustaining a self-perpetuating cycle of multi-organ dysfunction. Against this background, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a pharmacological class of interest due to their pleiotropic metabolic and anti-inflammatory properties. Experimental and indirect clinical evidence suggests that SGLT2i may modulate key inflammatory and oxidative stress pathways, including macrophage polarization, AMPK/NF-κB/NLRP3 signaling, mitochondrial protection, and Nrf2-SIRT1 activation. In addition, SGLT2i-associated improvements in body weight, metabolic efficiency, and cardiopulmonary loading may indirectly influence pulmonary-metabolic interactions. However, evidence for direct benefits on COPD-specific clinical outcomes remains limited and largely hypothesis-generating. Despite these mechanistic insights, substantial gaps remain regarding cross-organ molecular interactions, the role of hypoxia, and translational limitations of current models. Future research should prioritize dedicated randomized controlled trials, advanced single-cell and spatial omics approaches, and integrated digital health strategies to refine individualized SGLT2i-based interventions and advance multi-organ protective therapies in this complex patient population.
This consensus statement from multidisciplinary experts and consumers across Australia provides comprehensive recommendations on the prevention and management of frailty in community-dwelling older adults. The study uses a modified Delphi design. Phase I involved iterative discussion among six frailty care working groups, based on current evidence and expert opinion, to draft the statements. Phase II involved validation of each statement across two Delphi rounds conducted to determine level of agreement. A lifelong approach to health promotion for frailty prevention should focus on raising awareness, annual screening (65+ years) and personalised counselling around accessible health behaviours to manage chronic comorbidities. An individualised, balanced, protein-rich diet is likely to be effective in delaying the onset of frailty. Protein-energy malnutrition and nutritional deficiencies should be identified and treated. A nutrition care plan that considers the relaxation of dietary restrictions aligned with goals of care should be planned for older adults with severe frailty. Progressive, individualised and ongoing exercise should be a combination of aerobic and resistance exercise, and balance and functional training tailored to frailty level and supervised by professionals. Social prescribing for older adults should be co-designed with a link worker to support meaningful, accessible and culturally appropriate activities that foster social engagement, with plans customised to the individual's frailty level. A comprehensive, multidisciplinary medication review tailored to the older adult's health status, preferences and frailty degree helps optimise medication use, minimise harm and support functional independence across all stages of frailty. Older adults with severe frailty need a regularly reviewed, personalised care plan, which involves carers in decision-making, supports advance care planning and ensures high-quality end-of-life care. The consensus statements introduce an integrated, evidence-informed and consumer-focused framework to guide healthcare professionals in delivering personalised and effective care for community-dwelling older adults living with or at risk of frailty.
Invasive mold infections (IMIs) remain a leading cause of morbidity and mortality in susceptible pediatric populations. Numerous challenges exist in diagnosis and management, with limited pediatric clinical trial data. The pediatric specific epidemiology of IMIs, current diagnostic and management approaches, and recommendations are presented. The potential role of isavuconazole, a newer triazole antifungal, is evaluated. Treatments for IMIs in pediatric patients include mold-active triazoles, such as voriconazole and posaconazole, and liposomal amphotericin B. Isavuconazole has recently been approved for clinical use and will be a valuable addition to the antifungal armamentarium. Several agents with novel mechanisms of action are under development which show promise for the treatment of rare mold infections. Management principles in pediatric patients include prompt initiation of antifungal therapy, species identification, and susceptibility testing, clinical evaluation of other infection sites, timely source control (e.g. surgery), control of conditions predisposing patients to IMIs, and administration of supportive therapies. The pharmacology, tolerability, and safety of the newer triazole isavuconazole has been established for the treatment of pediatric patients with IMIs with supportive efficacy data. However, further larger-cohort studies are warranted to define its role relative to the existing mold-active triazoles and liposomal amphotericin B.
To describe the clinical characteristics, treatment approaches, and disease burden among older people with obesity disease (PwOD) in Japan. Secondary data from the Japanese cohort of the real-world, cross-sectional Adelphi Obesity Disease Specific Programme survey (July-December 2022) were analyzed. Physician's and PwOD's self-reported responses, including quality of life based on the Short Form Health Survey Version 2.0 (SF-36v2.0) and activity impairment from the Work Productivity and Activity Impairment (WPAI) questionnaire, were described by age group (<65 years, ≥65 years, and ≥75 years). Lower SF-36v2.0 scores (<45) and higher percentages in the WPAI questionnaire indicate greater impairment. Physicians (n = 101) provided data for 442 PwOD; 61 PwOD completed self-reported questionnaires. Older PwOD mainly consulted internal medicine physicians (≥65 years [45%] and ≥75 years [70%]). Common weight loss approaches across groups were: diets recommended and supervised by a healthcare provider (HCP)/dietitian/nutritionist/health coach; PwOD's own diet and exercise regime; and prescription obesity management medications. Physicians prioritized non-older PwOD for weight loss surgery or new weight loss drugs. In older PwOD, mean SF-36v2.0 physical component and bodily pain scores, and activity impairment were 34.5 (SD 12.8), 41.5 (SD 7.6), and 33.3% (SD 29.6%), respectively. Major weight loss goals in older PwOD were reducing joint pain and exercising regularly. Older Japanese PwOD faced physical impairments and were generally treated with lifestyle interventions by internal medicine physicians rather than specialists such as endocrinologists/diabetologists. HCPs should recognize obesity disease and obesity-related health disorders and provide appropriate medical care tailored to the specific needs of older PwOD.
Atypical antipsychotics are common adjunctive therapies for major depressive disorder (MDD) with inadequate antidepressant (ADT) response. In 2025, lumateperone was approved in the US as adjunctive treatment for adults with MDD, and comparative evidence is lacking. This network meta-analysis compared the efficacy and safety of lumateperone with those of other approved atypical antipsychotics for MDD. Registrational randomized clinical trials as documented in US product labeling (RCTs; N = 10; aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine XR) were used to build a star-shaped, 11-treatment-dose node network anchored on placebo + ADT. Outcomes available for ≥ 9 RCTs were considered. Efficacy outcomes comprised change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS), MADRS response and remission, and change from baseline in Clinical Global Impression-Severity (CGI-S) scale. Safety outcomes included weight change from baseline, akathisia, and somnolence. A fixed-effect Bayesian approach was applied. Pairwise treatment effects were compared; a probability of superiority > 85% (< 15%) indicated favored (unfavored) treatment. Network-wide treatment ranking was estimated using Surface Under the Cumulative Ranking (SUCRA) curves. Based on MADRS change from baseline, all atypical antipsychotics were favored versus placebo + ADT, with mean difference from placebo highest for lumateperone 42 mg/day (- 4.70). Other efficacy endpoints showed a consistent pattern, with active treatments favored over placebo + ADT across most nodes for response (10/11), remission (6/11), and CGI-S change (10/11). SUCRA ranking placed lumateperone as the treatment with the highest likelihood of being most efficacious across endpoints. Treatments differed in their safety profiles. Lumateperone was the only node with no weight gain relative to placebo and ranked first for weight-related safety outcomes. Lumateperone also ranked better than average for akathisia risk but below average for somnolence risk. Lumateperone represents an effective adjunctive therapy for adult MDD, with no weight change. Major depressive disorder is relatively common, and many adult patients do not experience sufficient improvement with antidepressant therapy alone. When this occurs, clinicians may prescribe an atypical antipsychotic to be taken with antidepressants. In 2025, lumateperone was approved in the US as an add-on treatment for adults with major depressive disorder. This network meta-analysis compared the efficacy and safety of lumateperone with those of other atypical antipsychotics approved for add-on treatment of major depressive disorder across clinical trials done by each company to obtain approval by the United States Food and Drug Administration. Ten trials compared placebo with different dosages of aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine extended release (for a total of 12 options evaluated) when used together with antidepressant medication. The analysis focused on consistently used measures of depression severity and improvement, including changes in depression rating scale scores, rates of clinical response, and remission of symptoms. Safety outcomes such as weight change, akathisia (inner restlessness), and somnolence were also assessed. Across all measures of symptom improvement, most atypical antipsychotics were more efficacious than placebo. Lumateperone showed the highest likelihood of being the most effective treatment for all efficacy outcomes. Safety differed across treatments, with lumateperone uniquely showing no weight gain versus placebo and ranking better than average for akathisia (inner restlessness) and below average for somnolence. Overall, these results suggest that lumateperone represents an effective treatment used alongside antidepressants for adults with major depressive disorder, with no weight change.
to investigate whether drug resistance is differentially reported for integrase strand-transfer inhibitors (INSTIs) in a global pharmacovigilance database. A disproportionality analysis was conducted to assess resistance to the five available INSTIs using VigiBase, the WHO global database of individual case safety reports (ICSRs). ICSRs were identified through Medical Dictionary for Regulatory Activities - MedDRA preferred terms (PTs) drug resistance, drug resistance mutation, genotype drug resistance test/test positive, multiple-drug resistance and pathogen resistance between October 2007 and September 2024. Descriptive analyses were employed to characterize individual cases according to sociodemographic and reporting-related variables. Disproportionality signals for at least one resistance-related MedDRA PTs compared with all other drugs in the database were expressed as reporting odds ratios (ROR) and information component (IC), with 95% confidence intervals (CI). 35,406,826 deduplicated ICSRs were identified; 22,825 comprised reports of drug resistance and 1,084 involved exposure to INSTIs. Cases of HIV resistance were predominantly males. Most reports were regarded as serious and originated from Europe and the Americas. Disproportionality signals for drug resistance were observed for all first-generation (ROR= 52.5; CI 95% = 47.6-57.9; IC = 5.56; 95% CI = 5.4-5.7 - raltegravir) and second-generation INSTIs (ROR = 55.9; CI 95% = 50.8-61.5; IC = 5.65; 95% CI = 5.5-5.8 - dolutegravir). HIV drug resistance to all INSTIs as well significant disproportionate safety signals were identified. These findings should be interpreted with caution given the inherent limitations of spontaneous reporting. Resistance monitoring in clinical settings is relevant. Resistance to integrase strand-transfer inhibitors (INSTIs) is a growing concern, as these medicines have been widely used in HIV treatment and HIV prevention, the so-called pre-exposure prophylaxis and post-exposure prophylaxis. In this study, we assessed reports of suspected drug resistance to the five approved INSTIs - bictegravir, cabotegravir, dolutegravir, elvitegravir and raltegravir, using a global database of spontaneous reports of adverse events of the World Health Organization. The study was conducted from October 2007 to September 2024. Among more than 35 million reports in the database, 1,084 involved suspected resistance to INSTIs. We used a statistical method commonly applied in drug safety monitoring to identify whether resistance was reported more frequently for INSTIs compared to other medicines in the database. Our results showed that reports of drug resistance were disproportionately higher for all INSTIs. These findings highlight the importance of continuous drug resistance monitoring in routine clinical care, especially as HIV treatment and prevention strategies increasingly rely on INSTI-based regimens.
The skin acts as a reflection of systemic endocrine activity, revealing the complex interaction among hormonal, metabolic and immune mechanisms. This narrative review synthesizes current evidence on the molecular and clinical connections between endocrine disorders and dermatologic findings. Endocrine diseases such as diabetes mellitus (DM), thyroid disorders (TD), polycystic ovary syndrome (PCOS), Cushing syndrome (CS) and acromegaly show characteristic skin features that often appear before systemic diagnosis. Dysregulation of insulin-like growth factor-1 (IGF-1) and PI3K/Akt/mTOR pathways, cytokine signaling and epigenetic modulation contribute to these manifestations and represent promising therapeutic targets. Emerging biomarkers including skin derived microRNAs, fibroblast growth factor signaling and advanced glycation end products may support early detection, prognosis and therapeutic monitoring. Integrating dermatologic evaluation into endocrine screening can reduce diagnostic delay, improve patient outcomes and strengthen collaboration between dermatology and endocrinology. Future studies should validate standardized diagnostic algorithms and biomarker-based approaches for personalized care.
We describe major changes in the nitrous oxide market fueling recreational use with a focus on prevalence, desired effects, adverse events, treatments, and public health interventions. Nitrous oxide is currently sold with easy and discreet access for children and young adults in formulations that attract them. Over 13 million people in the United States have ever used nitrous oxide recreationally and inhalants are mostly used by pre-teen to early 20-year-olds. Poison control center calls have increased 1,300% from 2003 to 2024 and deaths have risen 6-fold from 2010 to 2023. There are many acute adverse events ranging from frostbite to asphyxia. Adverse effects from chronic use are related to cobalt oxidation which impairs vitamin B12 functioning. The resulting dysfunction of methionine synthase induces methionine deficiency frequently causing paresthesia, ataxia, unsteady gait, and cognitive issues. Less commonly, paralysis, bladder and erectile dysfunction, macrocytic anemia and thromboembolism can occur. The European Federation of Clinical Chemistry and Laboratory Medicine guidance specifies diagnostic parameters, supportive care, and replenishment of vitamin B12 levels with intramuscular cyanocobalamin. There may be a role for routine direct methionine replenishment, but it is not universally recommended. Routine folic acid supplementation is controversial and should likely be reserved for those with low serum folate concentrations. Clinicians need to be aware of this growing trend to detect adverse events from chronic nitrous oxide use and treat them before they become permanent. Clinicians can provide or advocate for public health information and regulations to prevent adverse events from occurring.
Amphotericin B deoxycholate (AmBD), an effective and inexpensive antifungal agent, has significant adverse effects. Studies demonstrating the use of protective measures to prevent or reduce different adverse effects of AmBD are scarce in patients with hematological disorders. Therefore, we aimed to evaluate the adverse effect profile of AmBD administered with a standardized infusion protocol among hematologic patients. This prospective observational study was conducted at a tertiary care center of India among 150 hospitalized patients of all ages with different hematological disorders who had received AmBD administered with standardized infusion protocol consisting of premedication use, intravenous hydration and salt loading, and electrolyte supplementation. The clinical characteristics were recorded. Renal function parameters and serum electrolyte levels were measured at regular interval. AmBD-associated infusion-related adverse events (IRAEs), electrolyte imbalances and nephrotoxicity were assessed. AmBD-associated IRAEs, hypokalemia, hypomagnesemia, and nephrotoxicity were observed in 48 (32%), 90 (60%), 123 (82%), and 42 (28%) patients, respectively. In majority of patients, these adverse effects were reversible. AmBD was stopped due to severe IRAEs in 8 (5.3%), hypokalemia in 4 (2.7%), and nephrotoxicity in 6 (4%) patients. Baseline invasive fungal infection (IFI) and AmBD dose >1 mg/kg were risk factors for developing nephrotoxicity. We have demonstrated that the AmBD use in hematologic patients is associated with a relatively lower and the reversible IRAEs and nephrotoxicity along with manageable electrolyte imbalances, if it is administered with standardized infusion protocol. Therefore, AmBD should be considered as an inexpensive antifungal agent for IFIs among hematologic patients in resource-constrained settings.
Liver disease remains a major cause of non-AIDS-related morbidity and mortality in people living with HIV (PLWH). Calcium homeostasis is involved in multiple hepatic processes, but the clinical relationship between serum calcium and liver injury in PLWH remains unclear. We conducted a retrospective longitudinal cohort study incorporating repetitive measurements and proteomic analysis. Associations between serum calcium and liver disorders were assessed using logistic regression, Cox regression, and piecewise linear regression models. Among 2,726 patients with 10,621 blood samples over median 2.9-year follow-up, U-shaped relationships were observed between serum calcium and liver dysfunction/injury incidence, with a threshold corresponding to approximately 2.26 mmol/L (Ca × 2 = 4.52). In repetitive measurement analysis, serum calcium showed negative and positive associations with liver outcomes within Ca × 2 < 4.52 and ≥4.52 ranges, respectively (p < 0.05). In longitudinal analysis, patients with baseline Ca × 2 ≥ 4.52 had significantly increased adjusted risks of liver dysfunction (2.02, 95% CI: 1.33-3.07) and liver injury (4.61, 95% CI: 1.86-11.45) compared to Ca × 2 < 4.52. Each baseline Ca × 2 increase independently associated with 2.36-fold increased liver dysfunction risk (p < 0.05). Unadjusted models and Kaplan-Meier analysis showed consistent results. Proteomic analysis identified F5, GDI2, and LDHA significantly associated with both serum calcium and liver function, enriched in coagulation and glycolysis pathways. Elevated serum calcium at combined antiretroviral therapy (cART) initiation strongly correlates with subsequent liver disorders in PLWH with Ca × 2 ≥ 4.52, potentially involving dysregulated coagulation and glycolysis pathways. These reference levels can guide assessment of calcium intake strategies in PLWH.
This study focused on the correlations of lipoprotein-associated phospholipase A2 (Lp-PLA2) and angiotensin II (Ang II) levels with the severity of coronary artery stenosis (CAS) in elderly patients with suspected coronary heart disease (CHD). This retrospective case-control study was conducted on 228 elderly patients suspected of CHD. Their clinical data were collected. Patients were grouped by CHD diagnosis and by CAS severity. Correlation analyses were performed between Lp-PLA2, Ang II, lipid profiles, and the atherogenic index of plasma (AIP). Influencing factors for moderate-to-severe CAS in elderly patients were identified by univariate/multivariate logistic regression models. Receiver operating characteristic curves were used to analyze diagnostic performance for the severity of CAS in elderly patients. Lp-PLA2 and Ang II levels were notably elevated in patients with CHD and were positively associated with the severity of CAS. Lp-PLA2 level correlated with lipid levels. Both Lp-PLA2 and Ang II were correlated with AIP. Elevated levels of Lp-PLA2 and Ang II were independent risk factors for moderate-to-severe CAS in elderly patients. Both Lp-PLA2 and Ang II demonstrated certain diagnostic value for identifying moderate-to-severe CAS in this population. The combination of Lp-PLA2 and Ang II demonstrated diagnostic performance comparable to AIP and superior to either marker alone for identifying moderate-to-severe CAS. Lp-PLA2 and Ang II are closely associated with AIP in elderly patients with CHD, are independent risk factors for moderate-to-severe CAS, and may serve as valuable biomarkers for diagnosis and risk stratification.
Oral anticoagulants (OACs), including vitamin K antagonists and direct-acting OACs, are commonly used for the prevention and treatment of thrombosis. OAC-treated patients may require urgent anticoagulation reversal in circumstances of life-threatening bleeding or emergent surgery. Despite the availability of Food and Drug Administration-approved OAC reversal agents, published treatment guidelines, and institutional protocols, use of OAC reversal products and dosing vary considerably and off-label use is common. We review key factors influencing current clinical practice and examine barriers to the successful implementation of anticoagulation protocols, including discrepancies in the definition of major bleeding, dosing considerations, variability in laboratory testing practices, inconsistent study endpoints, formulary considerations, and the use of OAC reversal agents in special populations. We provide our expert opinion on best practices for oral anticoagulant reversal and an anticoagulation reversal protocol that could be implemented by healthcare institutions to standardize and optimize clinical practice.
Delayed onset and/or protracted labor progression is a relatively common obstetrical condition. The hypothesis that low molecular weight heparins may induce positive effects on uterine tissues in promoting and shortening delivery time was advanced in the last few years through several retrospective studies in pregnant women treated for thrombotic disorders. Tafoxiparin, a depolymerized form of heparin with a molecular structure created to eliminate the anticoagulant effects of heparins, is under investigation as a potential tool to promote labor activation and progression. The authors conducted a critical review on current pharmacological and clinical evidence of tafoxiparin effects on labor. To date, available results may indicate potential benefits of using tafoxiparin for cervical ripening and labor augmentation, but several aspects need further clarifications and investigations. Clinical evidence is still weak to generalize the results of the trials and support the introduction of the drug into daily medical practice because few studies specifically focussing on this topic were published until now. In addition, many queries are left to be explored with future research, including optimal timing and doses, better route of administration, patient and physician acceptability, target pregnant populations, and cost-effectiveness aspects.