Risk Of Serious Adverse Events Research Articles

Comparative Safety of Ultrasound Enhancing Agents: A Systematic Review and Bayesian Network Meta-Analysis: Comparative Safety Evaluation of Optison.

Ultrasound enhancing agents (UEAs), including Optison, Definity, and Lumason, enhance the diagnostic performance of echocardiography, particularly in patients with suboptimal acoustic windows. However, there remains a paucity of comparative safety assessments among the Food and Drug Administration (FDA)-approved UEAs. A PRISMA-guided systematic literature review performed in August 2023 searched Medline, Embase, Cochrane Library, and grey literature. Randomized and non-randomized comparative evidence on safety of contrast enhanced procedures were included. A feasibility assessment ensured homogeneity across studies by comparing patient characteristics and outcomes. Bayesian hierarchical network meta-regression was employed to indirectly compare published safety outcomes across different UEAs. In addition, adverse events (AEs) between 2019-2023 for each UEA were retrieved from the FDA Adverse Events Reporting System (FAERS), and comparative safety outcomes were derived using annual UEA administration in the US. Screening of 4146 records rendered 19 studies for inclusion in the indirect comparison analysis after feasibility assessment. Optison demonstrated favorable safety in direct comparisons with Definity and Lumason across the majority of investigated AEs. Network meta-regression results on serious adverse events (SAEs) within 30 minutes revealed odds ratios (ORs) of 0.59 (95% confidence interval: 0.27-1.23) and 0.63 (0.29-1.33) for Optison vs. Lumason and Definity, respectively, indicating a decreased risk of SAEs for Optison vs. Lumason and Definity, further supported by statistically significant ORs within FAERS: 0.01 (0-0.02), P<0.001 and 0.15 (0.05-0.48), P=0.001, for Optison vs. Lumason and Definity, respectively. In conclusion, our results restate the favorable comparative safety profile of Optison, providing new evidence to inform clinical decision-making.

Abstract 4137804: Associations between falls and other serious adverse events and antihypertensive medication in individuals with dementia: An observational cohort study

Background: The balance of benefits and risks associated with lowering blood pressure levels in individuals with dementia remains controversial with a lack of evidence for possible harms associated with antihypertensive treatment (AHT). Objectives: We examined the association between AHT and serious adverse events (SAEs) in individuals with dementia compared to those without. Methods: This was a retrospective analysis using nationally representative, UK general practice population between 1998 and 2018, using data from electronic health records (Clinical Practice Research Datalink, GOLD). Individuals included were age ≥40 years and not previously prescribed AHT. Diagnosis of dementia was based on standardised clinical codes. The primary outcome was the first hospitalisation or death from a fall within 10 years of the follow-up period. Secondary outcomes were first hospitalisation or death from hypotension, syncope, and fracture. Cox regression analyses, adjusted for propensity score were used to assess the risk of SAEs. Results: In a population of 1,219,732 individuals, 23,510 had dementia. Antihypertensive medications were newly prescribed in 4,062/23,510 (17.3%) individuals with dementia and 142,385/1,196,222 (11.9%) individuals without dementia in the 12 months exposure period. In individuals with dementia, AHTs were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.15, 95% confidence interval [CI] 1.08, 1.22), hypotension (aHR 1.51, 95%CI 1.29, 1.78), syncope (aHR 1.34, 95%CI 1.11, 1.61), but not fracture (aHR 1.05, 95%CI 0.96, 1.15). In individuals without dementia, the association between AHT and SAEs was similar, with an increased risk of hospitalisation or death from falls (aHR 1.07, 95%CI 1.05, 1.10). However, absolute risk of falls with AHT per 10,000 individuals per year was significantly higher in individuals with dementia (47, 95%CI 26, 70) compared to those without (14, 95%CI 10, 18). The absolute risks of hypotension and syncope with AHT were also higher in the individuals with dementia compared to those without. Conclusions: AHT was associated with increased risk of SAEs in individuals with and without dementia, however, the absolute risk of harm from falls was more than double in individuals with dementia. Clinicians, patients, and their carers should consider these risks before starting new antihypertensive medications, particularly in the context of dementia, although they remain small.

On target dosing: erythropoietin exposure in neonates with hypoxic-ischemic encephalopathy in the HEAL trial.

The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia demonstrated no neurodevelopmental benefit but was associated with a higher rate of serious adverse events (SAEs). Understanding if targeted Epo plasma exposures were achieved in the HEAL trial and if SAEs were associated with higher exposures would help future therapeutic programs of Epo as a candidate neuroprotective treatment. Ancillary study of a subset of HEAL neonates who received Epo (1000 U/kg IV on days 1, 2, 3, 4, and 7) and had plasma drug concentrations measured. Within a Bayesian pharmacokinetic framework, the area under the curve during the first 48 h (AUC48h) and 7 days (AUC7d) of treatment was estimated. The % of neonates who achieved animal model neuroprotective targets of AUC48h >140,000 mU*h/ml and AUC7d >420,000 mU*h/ml was calculated. The relationship between AUC7d and SAEs after study drug was evaluated using logistic regression. Among n = 89 neonates, variation in Epo exposure was low, and over 95% of neonates achieved the target AUC48h and AUC7d. No meaningful relationship was seen between AUC7d and risk of SAE. The Epo dosing strategy in the HEAL trial consistently achieved target plasma exposures. Higher exposures were not associated with SAEs. In the HEAL randomized, placebo-controlled trial of high-dose erythropoietin (Epo) for neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia, the Epo dosing strategy achieved animal model neuroprotective plasma exposure targets in >95% of neonates. This understanding further strengthens the HEAL trial's primary conclusion that Epo provides no additional benefit in neonates with HIE also receiving therapeutic hypothermia. While Epo treatment was associated with a higher rate of serious adverse events (SAEs) compared to placebo in the primary HEAL trial, higher plasma exposures of Epo were not associated with the risk of SAEs.

Corticosteroids in Pediatric Bacterial Meningitis: A Meta-Analysis of Randomized Controlled Trials Comparing Dexamethasone and Adjunctive Therapies

Introduction: Bacterial meningitis remains a significant cause of morbidity and mortality in children. Adjunctive corticosteroid therapy, particularly dexamethasone, has shown promise in reducing inflammation and improving outcomes. This meta-analysis aimed to evaluate the efficacy and safety of dexamethasone compared to placebo or other adjunctive therapies in pediatric bacterial meningitis. Methods: A systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted from January 2013 to October 2024. Randomized controlled trials (RCTs) comparing dexamethasone with placebo or other adjunctive therapies in children with bacterial meningitis were included. Primary outcomes were hearing loss, neurological sequelae, and mortality. Secondary outcomes included adverse events. Data were pooled using a random-effects model, and the risk ratio (RR) with 95% confidence intervals (CI) was calculated. Results: Six RCTs met the inclusion criteria, comprising 2,840 children. Dexamethasone was associated with a significant reduction in hearing loss (RR 0.57, 95% CI 0.45-0.71, p=0.005) and neurological sequelae (RR 0.66, 95% CI 0.56-0.78, p=0.006) compared to placebo. No significant difference in mortality was observed (RR 0.78, 95% CI 0.49-1.27, p=0.32). The incidence of adverse events, including gastrointestinal bleeding and hyperglycemia, was similar between the dexamethasone and placebo groups. Conclusion: Adjunctive dexamethasone therapy in pediatric bacterial meningitis significantly reduces hearing loss and neurological sequelae without increasing mortality or the risk of serious adverse events.

Risk of new vertebral compression fractures and serious adverse effects after vertebroplasty: a systematic, critical review and meta-analysis of randomized controlled trials.

Osteoporotic vertebral fractures (OVFs) significantly impact morbidity, mortality, functionality, and quality of life. Vertebroplasty, a widely utilized treatment for OVFs, has its efficacy and safety debated due to varying outcomes reported across clinical trials and meta-analyses. This study aims to critically review and conduct a meta-analysis of randomized controlled trials (RCTs) focusing on the safety of vertebroplasty, specifically its association with serious adverse effects and the development of new vertebral fractures, while exploring potential confounders. We conducted a systematic review and meta-analysis by searching PubMed, Web of Science, and EMBASE. The search was updated to February 23, 2024. We included published RCTs comparing vertebroplasty to conservative treatment (CT) or placebo/active control, focusing on new fractures and serious adverse effects. The primary outcomes were "incidence of new fractures" and "serious adverse effects". We applied the Dersimonian-Laird method with a random effects model to estimate risk ratios (RRs) of the primary outcomes, using the I2 statistic to assess heterogeneity among studies. Sensitivity analyses were conducted when significant heterogeneity was detected. Subgroup analyses were performed based on the characteristics of the control groups, risk of bias based on The Cochrane Risk of Bias Tool 2, time from fracture onset, and multicentric versus single-center trials. In total, 14 RCTs encompassing 1,413 patients were analyzed. High and unclear risk of bias were observed in 15 and 25 items, respectively. No significant difference was observed in the incidence of new vertebral fractures between vertebroplasty and the control groups [RR =1.05, 95% confidence interval (CI): 0.71-1.56; I2=55%; P<0.01]. However, vertebroplasty was associated with a significantly lower incidence of serious adverse effects (RR =0.53, 95% CI: 0.31-0.91; I2=0%; P=0.93). Subgroup analyses revealed no significant differences based on control types, risk of bias, or number of institutions involved. Notably, early vertebroplasty (within 6 weeks of symptom onset) showed a protective effect against new vertebral fractures (RR =0.60, 95% CI: 0.38-0.92; I2=0%; P=0.53). The sensitivity analysis showed that one study influenced the observed heterogeneity but did not significantly modify the pooled estimate. Vertebroplasty is not associated with an increased risk of developing new vertebral fractures and may reduce the risk of serious adverse effects compared to placebo or CT. Early intervention post-fracture appears beneficial. However, the limited number and quality of RCTs call for further high-quality studies.

Usefulness of a dedicated laser-cut metal stent with an anchoring hook and thin delivery system for endoscopic ultrasound-guided hepaticogastrostomy in malignant biliary obstruction: a prospective multicenter trial (with video).

Background and AimsEUS-guided hepaticogastrostomy (EUS-HGS) carries a risk of serious adverse events (AEs). A newly designed, partially covered laser-cut stent with antimigration anchoring hooks and a thin tapered tip (7.2F), called a Hook stent, has been developed to prevent serious AEs associated with EUS-HGS. The present prospective multicenter clinical trial evaluated the efficacy and safety of the Hook stent for EUS-HGS after failure of ERCP in patients with unresectable malignant biliary obstruction. MethodsThe primary endpoint was the rate of clinical success, and the secondary endpoints were the rates of technical success, AEs, recurrent biliary obstruction (RBO), procedure success without using a tract dilation device, re-intervention for RBO, time to RBO (TRBO) and overall survival (OS). ResultsA total of 38 patients underwent EUS-HGS using the Hook stent. Its technical and clinical success rates in patients undergoing EUS-HGS were 100% and 92.1%, respectively. The procedure success rate without using a tract dilation device was 94.7%. Four (10.5%) patients developed early AEs, but there were no severe AEs such as stent migration. RBO developed in 26.3% of patients. Re-intervention for RBO had a 100% success rate. The median TRBO was not reached, and the median OS was 191 days. ConclusionsEUS-HGS using the Hook stent demonstrated a high clinical success rate, a low rate of early AEs, and an acceptable stent patency. The Hook stent is safe and feasible for use in patients undergoing EUS-HGS.

Sodium-glucose cotransporter-2 inhibitors in acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

We aimed to assess the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo, initiated within the hospitalization period, in addition to habitual treatment, for treating adult patients with confirmed acute myocardial infarction (AMI). We also conducted subgroup analysis by diabetes mellitus (DM) status and type of AMI. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcome was hospitalization for heart failure (HF). The secondary outcomes were all-cause death, cardiovascular death, and serious adverse events (AEs). We pooled risk ratios (RR) with a 95% confidence interval (CI) for binary outcomes. The between-study variance was assessed using tau2 statistics. We included five RCTs, encompassing 11,211 patients. SGLT2i significantly reduced the risk of hospitalization for HF compared to placebo (RR 0.73; 95% CI [0.61, 0.88]). However, the risk of all-cause death (RR 1.05; 95% CI [0.78, 1.41]) and cardiovascular death (RR 1.04; 95% CI [0.84, 1.29]) was similar between the groups, as well as the risk of serious AEs (RR 1.01; 95% CI [0.90, 1.14]). In the subgroup analysis by DM status and type of AMI, there were no significant subgroup differences for the outcomes of hospitalization for HF and all-cause death. In patients with AMI, treatment with SGLT2i is safe and significantly reduces the risk of hospitalization for HF, but it has no impact on all-cause death and cardiovascular death compared to placebo.

Inhaled Reliever Therapies for Asthma

The optimal inhaled reliever therapy for asthma remains unclear. To compare short-acting β agonists (SABA) alone with SABA combined with inhaled corticosteroids (ICS) and with the fast-onset, long-acting β agonist formoterol combined with ICS for asthma. The MEDLINE, Embase, and CENTRAL databases were searched from January 1, 2020, to September 27, 2024, without language restrictions. Pairs of reviewers independently selected randomized clinical trials evaluating (1) SABA alone, (2) ICS with formoterol, and (3) ICS with SABA (combined or separate inhalers). Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses synthesized outcomes. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to evaluate the certainty of evidence. Asthma symptom control (5-item Asthma Control Questionnaire; range, 0-6, lower scores indicate better asthma control; minimum important difference [MID], 0.5 points), asthma-related quality of life (Asthma Quality of Life Questionnaire; range, 1-7, higher scores indicate better quality of life; MID, 0.5 points), risk of severe exacerbations, and risk of serious adverse events. A total of 27 randomized clinical trials (N = 50 496 adult and pediatric patients; mean age, 41.0 years; 20 288 male [40%]) were included. Compared with SABA alone, both ICS-containing relievers were associated with fewer severe exacerbations (ICS-formoterol risk ratio [RR], 0.65 [95% CI, 0.60-0.72]; risk difference [RD], -10.3% [95% CI, -11.8% to -8.3%]; ICS-SABA RR, 0.84 [95% CI, 0.73-0.95]; RD, -4.7% [95% CI, -8.0% to -1.5%]) with high certainty. Compared with SABA alone, both ICS-containing relievers were associated with improved asthma control (ICS-formoterol RR improvement [MID] in total score, 1.07 [95% CI, 1.04-1.10]; RD, 4.1% [95% CI, 2.3%-5.9%]; ICS-SABA RR, 1.09 [95% CI, 1.03-1.15]; RD, 5.4% [95% CI, 1.8%-8.5%]) with high certainty. In an indirect comparison with ICS-SABA, ICS-formoterol was associated with fewer severe exacerbations (RR, 0.78 [95% CI, 0.66-0.92]; RD, -5.5% [95% CI, -8.4% to -2.0%]) with moderate certainty. Compared with SABA alone, ICS-formoterol (RD, -0.6% [95% CI, -1.3% to 0%]) was not associated with increased risk of serious adverse events (high certainty) and ICS-SABA (RD, 0% [95% CI, -1.1% to 1.2%]) was not associated with increased risk of serious adverse events (moderate certainty). In this network meta-analysis of patients with asthma, ICS combined with formoterol and ICS combined with SABA were each associated with reduced asthma exacerbations and improved asthma control compared with SABA alone.

Mid-regional pro-adrenomedullin is an independent predictor of cardiovascular outcomes in cardiac surgery, a prospective cohort study in 500 patients

Abstract Background MR-proADM (mid-regional pro-adrenomedullin) is a stable pro-peptide of Adrenomedullin, which is expressed in various cell types such as heart, lung, and renal tissue. It is a prognostic parameter for heart failure (HF) and sepsis as well as all-cause and cardiovascular (CV) mortality. Purpose Considering the characteristics of MR-proADM as a reliable biomarker for adverse events, we aimed to investigate the prognostic impact of MR-proADM in patients undergoing elective cardiac surgery. Methods We prospectively enrolled patients undergoing elective cardiac bypass and/or valve surgery at the department of cardiac surgery between May 2013 and August 2018. Blood samples were taken one day prior to surgery. MR-proADM was measured using an automated immunofluorescence assay. Patients were followed prospectively until endpoints were reached. The primary endpoint was the composite of hospitalization for heart failure (HHF) or CV mortality, the secondary endpoint was postoperative atrial fibrillation (POAF). The multivariate regression model was adjusted for age, sex, NT-proBNP, type of surgery, and CRP-level at baseline. Results A total of 500 patients (146 female [29.2%]; median age 69.8 years [IQR 60.6-75.5]) were followed over a median of 4.6 years (IQR 3.0–5.8). Valve surgery was performed in 214 (42.8%) patients, 160 (32%) underwent a bypass operation and 126 (25.2%) a combined valve and bypass surgery. The median MR-proADM value of the entire study population was 0.58 nmol/L (IQR: 0.44-0.79 nmol/L). Patients were stratified in risk categories based on their MR-proADM values (Low Risk ≤0.63nmol/L, Intermediate Risk 0.63-0.83nmol/L, High Risk &amp;gt;0.84nmol/L). Patients in the highest category presented with higher rates of diabetes mellitus (p &amp;lt;0.001), COPD (p &amp;lt;0.001), HF (p=0.009) and either bypass surgery (p=0.039) or the combination of bypass and valve surgery (p=0.008), compared to patients in the lowest tertile. We observed a significant increase in 5-year’s event rates for HHF/ CV Mortality in patients in higher risk groups (Low Risk 8.6% vs High Risk 37.7%, p &amp;lt;0.001, Figure 1). The adjusted Cox regression model found that MR-pro ADM was independently associated with a risk increase for HHF/ CV Mortality (adjusted HR of 4.45, 95% CI 2.55-8.09; p&amp;lt;0.001, Figure 2) comparing the High Risk to the Low Risk Group. A comparable risk increase could be observed in POAF, with an adjusted HR of 2.61 (High Risk Group vs Low Risk Group, 95% CI 1.46-4.67, p&amp;lt;0.001). Conclusion Within the prospective investigation, MR-pro ADM was found to be an independent predictor for HHF and CV mortality in patients undergoing cardiac bypass and/or valve surgery. Furthermore, there was a consistent predictive potential for POAF. In the era of personalized medicine, preoperative MR-pro ADM levels could help to identify patients at risk for serious adverse events, in order to apply intensified secondary prevention and reduce mortality and morbidity.

Higher dose antiviral therapy for herpes infections is associated with a risk of serious adverse events in older adults with chronic kidney disease.

Antiviral use has been linked to encephalopathy and elevated serum creatinine concentrations in individuals with chronic kidney disease (CKD) in case reports. Using linked healthcare data in Ontario, we conducted a population-based cohort study on adults aged ≥66 years not receiving dialysis and newly prescribed oral acyclovir, valacyclovir, or famciclovir in the outpatient setting (2008-2022) at higher versus lower doses. The primary composite outcome, a hospital visit with encephalopathy or acute kidney injury (AKI) within 14 days of initiating antiviral treatment, was examined in a primary cohort. AKI was assessed in a secondary cohort of older adults with CKD with available linked hospital-based laboratory (lab) data. We used inverse probability of treatment weighting on the propensity score to balance comparison groups on baseline health. Weighted risk ratios (RR) and risk differences (RD) were obtained using modified Poisson and binomial regression. In the primary cohort, higher- versus lower-dose antiviral was not associated with an increased 14-day risk of hospital visit with encephalopathy or AKI. However, Higher- versus lower-dose antiviral was associated with a higher risk of a hospital visit with AKI when assessed using lab values (weighted number of events, 70 of 8407 [0.83%] versus 18 of 8230 [0.22%], respectively; weighted RR, 3.83 [95% CI, 1.87-7.87]; weighted RD, 0.62% [95% CI, 0.37%-0.86%]). In older adults with CKD, starting an antiviral at a higher versus lower dose was associated with a higher risk of AKI, although the absolute risk of this event was <1%.

Effectiveness and Safety of Dupuytren Contracture Treatments: A Systematic Review and Meta-Analysis Using the GRADE Approach.

There is currently no consensus on the optimal treatment for Dupuytren contracture. Prior meta-analyses have been limited by suboptimal data synthesis methodologies. We conducted an updated evidence review comparing the effectiveness and safety of percutaneous needle fasciotomy (PNF), collagenase clostridium histolyticum (CCH), and limited fasciectomy (LF) using the GRADE approach. CENTRAL, MEDLINE, and Embase were searched for randomized controlled trials comparing outcomes following PNF, CCH, and LF for Dupuytren contracture treatment. Outcomes of interest included residual contracture, recurrence rate, hand function, pain, global satisfaction, and adverse events. Time points included 3-months, 1-year, and 2-3 years. Seventeen publications (1,010 patients) were included. High to moderate certainty evidence showed no clinically important difference in long-term contracture reduction (PNF vs. LF (mean difference (MD): 7.6°; 95% CI: 1.8°-13.4°), CCH vs. LF (MD: 4.8°; 95% CI: -1.3°-10.9°)). Moderate certainty evidence indicated that LF provides the lowest risk of long-term recurrence (PNF vs. LF (relative risk (RR): 12.3; 95% CI: 1.6-92.4), CCH vs. LF (RR: 9.5; 95% CI 1.2-73.4)), LF has a higher risk of serious adverse events than PNF (RR: 0.5; 95% CI 0.3-0.9), and CCH has a higher risk of overall adverse events than PNF (RR: 4.8; 95% CI 2.9-7.0). CCH, PNF, and LF are equally effective in long-term contracture reduction. However, LF yields more durable results at a higher risk of rare but serious adverse events. Current evidence suggests the use of PNF over CCH. However, ultimate treatment decisions should be tailored to individual patient preferences.

Patient preferences for advanced therapies in ulcerative colitis using conjoint analysis.

Selecting an optimal advanced therapy for ulcerative colitis (UC) is difficult because of the increasing number of available therapies. This study assessed UC patients' preferences for drug profiles in decision-making regarding advanced therapies using conjoint analysis. A web-based survey was conducted from October to November 2023 in patients with UC aged ≥ 18 years with prior oral 5-aminosalicylic acid treatment (UMIN000052327). We quantified the importance of drug attributes (location of administration, route/frequency of administration, speed of onset-of-action, maintenancesustainability, risk of serious adverse events within 1 year, and novelty of the drug) and the part-worth utility of attribute levels in mild and severe symptom scenarios, including among employed versus unemployed patients. Of 372 patients who completed the survey, 365 were evaluated. Patient preferences were generally highly individualized. The route/frequency of administration was the most important attribute in both the mild and severe symptom scenarios. Oral administration was preferred in the mild symptom scenario, whereas no specific preference was observed in the severe symptom scenario. The route/ frequency of administration was more valued in the mild symptom scenario than in the severe one, whereas speed of onset of action was more valued in the severe symptom scenario. No significant difference was found in the preference for drug profiles between employed and unemployed patients. Patient preferences for the route/frequency of administration, as well as other drug profiles, change with disease severity but demonstrate substantial interindividual variability. Therefore, shared decision-making is important to incorporate patients' perspectives into the selection of advanced therapies.

Presenting JAK inhibitor safety information to dermatology patients

AbstractJanus Kinase (JAK) inhibitors are treatment options for dermatologic conditions such as atopic dermatitis, psoriasis, vitiligo, and alopecia areata. Guidance on how to counsel patients on these novel treatments is limited. The purpose of this review is to provide options providers can use to discuss JAK inhibitors with dermatology patients. The PubMed database was searched for terms including “dermatology JAK inhibitor safety” and “presenting information to patients.” Relevant literature was selected for inclusion. Black box warnings were placed on JAK inhibitors after a large, controlled trial in rheumatoid arthritis patients did not prove that tofacitinib was as safe as tumor necrosis factor inhibitors; in clinical trials for dermatologic conditions, JAK inhibitors had low risks of serious adverse events. Patient barriers to comprehending treatment information include conflicting information and limited time for discussion of risks. To address these barriers, suggested approaches have included speaking in simple phrases, providing reliable sources, and offering educational materials appropriate for different cultures. When discussing risks, physicians may use anecdotes and frame risks and side effects in ways that decrease anxiety. JAK inhibitors have uncommon severe side effects and related concerns that may be hard for patients to overcome, even when benefits exceed risks. Standard educational approaches can be complemented by anecdotes and framing to help diminish patients' anxiety.

Effectiveness of Resmetirom in Reducing Cholesterol Levels in Patients With Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) associated with metabolic syndrome and increased cardiovascular risk. Resmetirom, a novel liver-directed selective thyroid hormone receptor-β (THR-β) agonist, has shown promise in addressing both hepatic and systemic lipid metabolism. This systematic review and meta-analysis aimed to evaluate the efficacy of resmetirom in improving cholesterol levels in NASH patients. A systematic literature search was conducted across multiple databases including PubMed, Embase, Cochrane Library, andClinicalTrials.gov, identifying three randomized controlled trials for inclusion. The meta-analysis revealed that resmetirom significantly reduced low-density lipoprotein cholesterol (LDL-C) levels compared to placebo (MD: -23.62; 95% CI: -37.32 to -9.93; p < 0.001). Similarly, triglyceride (TG) levels showed a significant reduction in the resmetirom group (MD: -33.86; 95% CI: -47.79 to -19.92; p < 0.001). Importantly, there was no significant difference in the risk of serious adverse events between resmetirom and placebo groups (RR: 1.09; 95% CI: 0.73 to 1.63; p = 0.67). These findings suggest that resmetirom effectively improves lipid profiles in NASH patients without compromising safety. However, the analysis was limited by the small number of studies, all from the same research group, and high heterogeneity in results. Future research should include more diverse studies, longer follow-up periods, and cost-effectiveness evaluations. Despite these limitations, resmetirom shows promise as a potential treatment for managing dyslipidemia and cardiovascular risk in NASH patients, potentially influencing future treatment guidelines for both liver and cardiovascular health in this population.

Current state and potential applications of neonatal Fc receptor (FcRn) inhibitors in hematologic conditions.

The neonatal fragment crystallizable (Fc) receptor (FcRn) transports IgG across mucosal surfaces and the placenta and protects IgG from degradation. Numerous clinical trials are investigating therapeutic FcRn inhibition for various immune-mediated neuromuscular and rheumatologic conditions; however, FcRn inhibition also represents a potential therapy for IgG-mediated hematologic conditions (e.g., immune thrombocytopenia, autoimmune hemolytic anemia, immune thrombotic thrombocytopenic purpura, acquired hemophilia, red blood cell/platelet alloimmunization). Current evidence derived from both in vitro and in vivo studies suggests that FcRn inhibitors effectively reduce total IgG levels without impacting its production or altering the levels of other immunoglobulin isotypes. Moreover, the risk of serious adverse events, including serious infections, appears to be lower than that seen with other commonly used immunomodulatory/immunosuppressive therapies, albeit in the setting of limited clinical trial data. Ultimately, additional clinical trials that include varied patient populations are required prior to incorporating these agents into standard treatment algorithms for most hematologic conditions. However, based on the pathophysiology of IgG-mediated hematologic disorders and the mechanism of action of FcRn inhibitors, these agents may represent a future novel therapeutic strategy for patients with hematologic conditions caused by IgG antibodies.

Optimizing surgical performance and safety in endoresection of uveal melanoma.

To present a standardized surgical technique for endoresection of uveal melanoma (UM) minimizing the risk of serious adverse events, including fatal gas embolism. Ten UM patients underwent endoresection following proton beam radiotherapy for radiotherapy-related vascular complications. Vortex veins located in correspondence of the tumor base had been cauterized at the time of tantalum markers placement. Endoresection was performed following complete 25G vitrectomy, endolaser and endodiathermy. The tumor was removed using a subretinal or transretinal approach depending on retinal infiltration. If needed, perfluorodecalin (PFD) was injected to stabilise the retina. Fluid-silicone oil (SO) or PFD-SO exchange was performed, avoiding air. Endoresection was successfully performed in all eyes with no intraoperative complications. Mean follow-up (FU) was 10.8 ± 3.2 months. One patient was enucleated due to neovascular glaucoma. At the last FU, the remaining patients had the eye preserved and no signs of local recurrence or neovascular glaucoma. Our standardized surgical technique for UM endoresection appeared to be safe, minimizing the risk of serious intraoperative and postoperative adverse events.

POSITIVE IMPACT OF TRANEXAMIC ACID IN VARIOUS MEDICAL SETTINGS

The role of successful hemostasis cannot be overemphasized. Bleeding can occur due to various reasons and its cause is not always evident. Any delay in restoring the proper hemostasis is associated with increased risk of complications and therefore results in increased mortality. Discovered in 1962 by Japanese researchers Shosuke and Utako Okamoto, tranexamic acid (TXA) is an anti-fibrinolytic agent that inhibits plasminogen activation by blocking the lysine binding sites on plasminogen. Thanks to its ability to inhibit fibrinolysis it stabilizes the preformed fibrin mesh-work and has a beneficial effect in reducing blood loss in wide range of clinical settings. TXA has been shown to reduce the risk of perioperative bleeding in patients undergoing noncardiac surgeries. CRASH trials provided the largest body of evidence confirming effectiveness of early administration of TXA, defined as administration within 3 hours after trauma, in reducing mortality in patients with severe injuries and traumatic brain injury. Recent evidence indicates that TXA administration in treatment of postpartum hemorrhage results in notable mortality reduction. Topical or locally injected tranexamic acid may reduce blood loss and improve visibility of the surgical field. More high-quality studies are needed to determine safety, efficacy and dosage. The risk of serious adverse events, especially vascular occlusive events, in patients receiving TXA compared to placebo group did not differ significantly.

Dose reduction and discontinuation due to the combination of CDK4/6 inhibitors and endocrine drugs: a systematic review and meta-analysis.

With the widespread use of CDK4/6 inhibitors, the number of discontinuations and reductions due to adverse events is increasing. Therefore, we examined the risk of dose reduction, discontinuation, and occurrence of serious adverse events and death due to adverse events when CDK4/6 inhibitors are combined with endocrine drugs. We searched English-language articles published up to February 10, 2024, using RR values (risk ratio) to indicate the risk of discontinuation, dose reduction, death, and the risk of serious adverse events. When CDK4/6 inhibitors were used in combination with endocrine drugs, abemaciclib resulted in the highest risk of discontinuation, dose reduction, and serious adverse events. Ribociclib caused the highest risk of death. When using CDK4/6 inhibitors in the clinical setting, a comprehensive evaluation should be performed to avoid dosage reductions and discontinuations and to choose the most appropriate treatment regimen.

A novel antigen biomarker for detection of high-level of Loa loa microfilaremia.

Loiasis is a disease caused by the nematode Loa loa. Serious adverse events sometimes occur in people with heavy L. loa microfilaremia after ivermectin treatment. In regions of Central Africa where loiasis is endemic, this significantly impedes global elimination programs for lymphatic filariasis and onchocerciasis that use mass distribution of ivermectin. Improved diagnostic tests to identify individuals at increased risk of serious adverse events could facilitate efforts to eliminate lymphatic filariasis and onchocerciasis in this region. We previously identified the L. loa protein Ll-Bhp-1 in loiasis patient sera. Here, we further characterize Ll-Bhp-1 and report development of an antigen capture ELISA to detect this antigen. This assay detected Ll-Bhp-1 in 74 of 116 (63.8%) loiasis patient sera. Ll-Bhp-1 levels were significantly correlated with L. loa microfilarial counts, and the sensitivity of the assay was highest for samples from people with high counts, (94% and 100% in people with ≥20,000 and ≥50,000 microfilaria per milliliter of blood, respectively). The antigen was not detected in 112 sera from people with other filarial infections, or in 34 control sera from the USA. This Ll-Bhp-1 antigen assay is specific for loiasis, and highly sensitive for identifying people with high L. loa microfilarial counts who are at increased risk for serious adverse events after ivermectin treatment. L. loa antigen detection has the potential to facilitate loiasis mapping efforts and programs to eliminate lymphatic filariasis and onchocerciasis in Central Africa.

Improvements in daytime sleepiness and disrupted nighttime sleep with once-nightly sodium oxybate in people with narcolepsy type 1 and type 2: a plain language summary.

This is a plain language summary of a published article in the journal Sleep. Narcolepsy is a sleep condition that has 2 different subtypes: narcolepsy type 1 and narcolepsy type 2. These are called NT1 and NT2 for short. Sodium oxybate (SXB) is approved to treat excessive daytime sleepiness (EDS) and cataplexy. People with NT1 and NT2 both have EDS, but cataplexy is only present in people with NT1. Limited information is available about how SXB works in people with NT2. This is because previous trials have included only people with NT1 or people with unspecified narcolepsy. For more than 20years, the only available formulation of this medicine had to be given twice during the night. Many people with narcolepsy find that chronically waking up in the middle of the night for a second dose of SXB is disruptive to themselves or others in their household. People have also reported sleeping through alarm clocks, missing their second dose, and feeling worse the next day. Some people have accidentally taken the second dose too early, putting them at risk for serious adverse effects. These adverse effects may include slow breathing, low blood pressure, or sedation. The US Food and Drug Administration (FDA) approved a medicine called LUMRYZ™ (sodium oxybate) for extended-release oral suspension in May 2023. LUMRYZ is a once-nightly formulation of SXB (ON-SXB for short) and is taken as a single dose before bedtime. This medicine treats EDS and muscle weakness (also known as cataplexy) in people with narcolepsy. A clinical trial called REST-ON studied ON-SXB to find out if it was better at treating narcolepsy symptoms than a medicine with no active ingredients (placebo). This summary describes a study that tested whether ON-SXB was better than placebo at treating narcolepsy symptoms in people with NT1 or NT2. This study showed that compared to people who took placebo, people who took ON-SXB were able to stay awake longer during the day, felt less sleepy during the daytime, had less cataplexy, and had more improvements in their symptoms overall than people who took placebo. ON-SXB has been proven effective for people with NT1 or NT2. Unlike prior formulations of SXB, ON-SXB is taken once at bedtime, without requiring waking up in the middle of the night for a second dose.