Browse papers

176 papers

Mex-3 RNA-binding family member A limits macrophage ferroptosis-associated injury linked to the SLC7A11/GPX4 pathway in diabetic atherosclerosis.

Ma Y et al. · Jul 1, 2026

Background Diabetes accelerates atherosclerotic plaque expansion and loss of stability, but the plaque-resident mechanisms through which the diabetic milieu promotes macrophage lipid-oxidative injury are not fully understood. Methods We used apolipoprotein E-deficient (ApoE -/- ) mice with Mex-3 RNA-binding family member A (MEX3A) deficiency and primary bone marrow-derived macrophage (BMDM) experiments under diabetic conditions to investigate the role of MEX3A in diabetic atherosclerosis and macrophage lipid-peroxidation injury. Results MEX3A loss worsened diabetic atherosclerosis while leaving body weight, glycaemia and lipid measurements largely unchanged relative to diabetes alone. MEX3A deficiency enlarged aortic lesions, enhanced lipid deposition, increased macrophage content, expanded necrotic cores and thinned fibrous caps, while reducing collagen content. In lesional macrophages, loss of MEX3A coincided with increased lipid reactive oxygen species, malondialdehyde, increased labile iron, 4-hydroxynonenal, a disturbed glutathione redox state, mitochondrial abnormalities compatible with ferroptotic stress, lower GPX4/SLC7A11 and higher ACSL4. CRISPR/Cas9-mediated Mex3a knockout in BMDMs recapitulated this phenotype, whereas restoring MEX3A blunted it. RNA immunoprecipitation-qPCR together with actinomycin D decay analyses demonstrated preferential recovery of Slc7a11 and Gpx4 transcripts with MEX3A and decreased stability of Slc7a11 and Gpx4 mRNAs after Mex3a knockout. GPX4 or SLC7A11 overexpression reduced lipid-peroxidation injury in Mex3a-knockout macrophages, whereas Gpx4 or Slc7a11 knockdown weakened the protection conferred by MEX3A re-expression. Ferrostatin-1 partially attenuated macrophage lipid peroxidation and plaque injury. Conclusions Together, these results place MEX3A among the protective regulators of diabetic plaque stability and support a MEX3ASLC7A11/GPX4-linked ferroptosis-associated mechanism in plaque macrophages. Key points MEX3A deficiency worsens diabetic atherosclerosis without further aggravating systemic metabolic indices. Loss of MEX3A promotes plaque lipid deposition, macrophage accumulation, necrotic core expansion and fibrous cap thinning. MEX3A limits macrophage lipid-peroxidation injury linked to the SLC7A11/GPX4 pathway. Ferrostatin-1 partially attenuates macrophage lipid peroxidation and plaque injury associated with MEX3A deficiency.

Medicine

Drug Use and Social Connectivity Related to Hepatitis C Infection Among Rural People Who Use Drugs.

Rains A et al. · Jul 1, 2026

People who use drugs (PWUD) have a disproportionately elevated risk of hepatitis C virus (HCV). Appropriate screening and treatment may be limited, especially in rural environments experiencing healthcare shortages. In order to develop targeted intervention strategies for rural PWUD, we investigated individual and network-level correlates of HCV positivity. Survey data were collected from PWUD from the Illinois region of the Federal Delta Regional Authority (DRA). The primary outcome of interest was HCV positivity by self-report. We explored associations between HCV positivity and individual demographic, drug use, and service utilisation characteristics as well as degree of connectedness within social networks. Three hundred and two participants were included in analyses. At the individual level, HCV positivity was associated with injection drug use, overdose history, and prior receipt of substance use treatment. Two hundred and one participants had at least one connection to a peer via referral chains, most of which contained a mix of HCV-negative and positive individuals. Of note, isolated individuals had comparable rates of HCV positivity compared to their socially connected peers. Degree of connectedness was not associated with HCV positivity. This study highlights the heterogeneity, both with respect to HCV positivity and other characteristics, among networks of rural PWUD. Given that most participants were connected to others, HCV interventions led by peer champions may facilitate improved access to critical services for risk mitigation.

Medicine

The combination of low-intensity resistance exercise and electrical muscle stimulation effectively enhances executive function in men.

Dora K et al. · Jul 1, 2026

Objectives Resistance exercise enhances executive function (EF) more effectively at moderate or higher intensities than at low intensity resistance exercise (LRE), probably with increased neural activity and lactate production to meet brain energy demands. Given that LRE remains widely applicable with less perceived exertion, and electrical muscle stimulation (EMS) increases lactate production and neural activation, we investigated whether combining LRE with EMS (LRE-EMS) effectively enhances EF, without increasing perceived exertion. Design A crossover randomized study. Methods Seventeen young men participated in a crossover randomized study to assess the cognitive effects of LRE alone, EMS alone, and LRE-EMS. The LRE protocol involved knee extensions at 40% one-repetition maximum for 4 sets of 10 repetitions. During the EMS condition, the participants remained seated for 260 s to match the duration of the other conditions, with EMS applied to the lower limb muscles. Subjective perceptions of exertion and fatigue during exercise were recorded. Results IC and lactate were measured at baseline, immediately postexercise, and 15 min postexercise. The LRE condition did not significantly increase IC (p = 0.100), whereas LRE-EMS resulted in significant IC improvements immediately and 15 min postexercise (both p Conclusions Perceived exertion and fatigue were greater with LRE-EMS compared with LRE and EMS. These findings suggest that LRE combined with EMS and EMS alone are effective strategies for cognitive improvement, but increased perceived exertion still exists.

Medicine

Efficacy and safety of sacubitril/valsartan in patients on peritoneal dialysis: a systematic review and meta-analysis.

Silva CLD et al. · Jul 1, 2026

Background Sacubitril/valsartan is a recommended medication for managing heart failure (HF). However, its role in peritoneal dialysis (PD) patients remains uncertain. We conducted this systematic review and singlearm meta-analysis to assess the efficacy and safety of sacubitril/valsartan in this population. Methods We systematically searched PubMed, EMBASE, and Cochrane Central until December 2024 for randomized controlled trials (RCTs) and observational studies assessing changes in left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, systolic blood pressure (SBP), left atrial diameter (LAD), and left ventricular end-diastolic dimension (LVDd) with sacubitril/valsartan use in PD patients. Safety endpoints included hyperkalemia, hypotension, and angioedema. Statistical analyses were performed in R, using proportions for binary and mean differences (MDs) for continuous outcomes. Results Nine studies were included, comprising 8 observational studies and 1 RCT, involving 343 PD patients. LVEF improved significantly (MD 5.22; 95% CI, 3.86 to 6.58; p Conclusion Sacubitril/valsartan was associated with improvements in cardiac function surrogates and blood pressure in PD patients with HF, with an overall acceptable safety profile despite a modest increase in hyperkalemia. These findings suggest potential benefit in this understudied population, though confirmation in adequately powered RCTs remains necessary.

Medicine

Establishing Expert Consensus on Competencies for Safe Ward-Based Postoperative Epidural Analgesia Management: Protocol for a Modified Delphi Study.

Lamprecht CC et al. · Jul 1, 2026

Postoperative epidural analgesia (EA) is an important analgesic strategy for selected surgical procedures. However, clinical practice and training vary across settings, and no consensus-based framework currently defines the competencies required for safe ward-based EA management. A modified Delphi study will establish expert consensus on competencies for ward-based postoperative EA management. Items derived from prior empirical work will be rated by experts across three Delphi rounds: two rounds in which experts rate the relevance of each item on a seven-point Likert scale with controlled feedback between rounds, followed by a third round in which experts rate the required competence level for included items using Miller's pyramid. The study is expected to generate consensus on essential competencies and their required level for safe ward-based postoperative EA management. The findings will inform the development of a competency-based training framework and may contribute to more consistent practice and improved patient safety.

Medicine

Dipolar Order Mapping Based on Spin-Lock Magnetic Resonance Imaging.

Gao Z et al. · Jul 1, 2026

Inhomogeneous magnetization transfer (ihMT) is sensitive to dipolar order associated with motion-restricted macromolecules and can be characterized by the dipolar relaxation time T1D$$ {T}_{1D} $$ . In this study, we propose a spin-lock MRI framework for T1D$$ {T}_{1D} $$ quantification. Specifically, we introduce a T1D$$ {T}_{1D} $$ -sensitive metric, RATIOdosl$$ RATI{O}_{dosl} $$ , derived from the distinct relaxation rate Rdosl$$ {R}_{dosl} $$ , defined as the difference between dual-frequency and single-frequency R1ρ$$ {R}_{1\rho } $$ measurements. To enable dual-frequency spin-lock acquisition, we developed a dedicated rotary-echo spin-lock sequence. Based on this framework, we further estimated T1D$$ {T}_{1D} $$ and the macromolecular proton fraction (MPF) within a unified acquisition. The proposed method was evaluated using numerical simulations, phantom experiments, and in vivo imaging in the healthy human brain. Simulations demonstrated high sensitivity of RATIOdosl$$ RATI{O}_{dosl} $$ to T1D$$ {T}_{1D} $$ and supported the robustness of the proposed approach under the investigated conditions. Phantom experiments showed measurable ihMT contrast and supported the feasibility of T1D$$ {T}_{1D} $$ estimation using RATIOdosl$$ RATI{O}_{dosl} $$ . In vivo experiments demonstrated simultaneous T1D$$ {T}_{1D} $$ and MPF mapping using only three spin-lock-prepared images. Across 10 healthy volunteers, mean white matter T1D$$ {T}_{1D} $$ values ranged from approximately 3.70 to 4.80 ms. By requiring only three contrast-prepared images, the proposed technique provides a rapid framework for simultaneous T1D$$ {T}_{1D} $$ and MPF mapping and may facilitate further investigation of dipolar-order-sensitive microstructural imaging in vivo.

Medicine

Getting It Right the Second Time: How Can we Optimize First-Generation Cephalosporin Dosing for Skin and Soft Tissue Infections in the 21st Century?

Ryder JH et al. · Jul 1, 2026

Optimal cephalexin and cefadroxil dosing for skin and soft tissue infections (SSTIs) is unclear. We summarize clinical and pharmacokinetic/pharmacodynamic (PK/PD) data that compare dosing strategies for SSTIs. Additionally, we conduct population PK target attainment simulations for varying doses of cephalexin and cefadroxil for Staphylococcus aureus and Group A Streptococcus. Although some clinical data support lower doses in mild SSTIs, higher doses optimize PK/PD parameters in moderate-severe SSTIs, especially due to Staphylococcus aureus. Further prospective clinical and PK/PD studies, especially in obese adults, would be beneficial.

Medicine

Serum Advanced Glycation End Products as Drivers of Poor Tendon Outcomes in Diabetes? An Emerging Hypothesis and Narrative Review.

Gutierrez EJ et al. · Jul 1, 2026

Introduction Tendon injuries in individuals with diabetes are difficult to reverse, and the mechanisms driving poor healing, extracellular matrix disruption, and altered biomechanics remain poorly understood. Many individuals with prediabetes or diabetes are also overweight or obese, and increased visceral adiposity alters adipokine levels and promotes chronic inflammation. While multiple factors influence tendon healing and extracellular matrix (ECM) remodelling, we suggest that circulating advanced glycation end-products (AGEs) may drive delayed healing, collagen disorganization, and compromised biomechanical properties in diabetes. Methods A comprehensive narrative review of the literature was conducted using PubMed and Embase to synthesize current and emerging evidence on the relationship between AGEs, tendon properties, and tendon healing in diabetes. Experimental, translational, and clinical studies, as well as relevant review articles involving cell, animal, and human models, were critically analysed. Results This narrative review explores the limited evidence linking serum AGE accumulation and Receptor for Advanced Glycation End-Product (RAGE) activation to tendon pathology and poor healing. Traditionally, tendon dysfunction in diabetes has been attributed to non-enzymatic collagen crosslinking. However, there is mixed evidence demonstrating increased tendon AGE content or stiffness in diabetic patients compared to age-matched controls, suggesting alternative mechanisms. Therefore, we outline recent in vitro, animal, and human studies on AGE and RAGE in tendons and propose future directions. Conclusion We propose that a systemic rise in serum AGEs impairs tendon healing by activating RAGE and disrupting cellular pathways required for repair. Future studies investigating the role of AGEs and other circulating factors may provide insights into the high incidence of tendon injuries and impaired healing in individuals with diabetes and related metabolic disorders.

Medicine

HIV Care Retention and Cost Analysis in Multi-Month ART Dispensing: A Randomized Controlled Trial in China.

Shang W et al. · Jul 1, 2026

Introduction Multi-month dispensing (MMD), as a differentiated service delivery model, can reduce the frequency of clinic visits, waiting time and travel costs for clinically stable people living with HIV. This study aimed to evaluate the impact of 6-month MMD of antiretroviral therapy (ART) on retention and conduct a cost analysis in China. Methods We conducted a randomized, non-blind, non-inferiority study from December 2022 to March 2023 at The First Hospital of China Medical University. Eligible participants were randomly assigned to a 3-month dispensing group (n = 789) or a 6-month dispensing group (n = 799) and followed up for 18 months. The proportion of patients continuing ART after 18 months, virological suppression rate ( Results A total of 1588 participants were included (median age 40.0 years, IQR 34.0-50.0; 94.8% male), with no significant between-group differences in demographic and clinical characteristics (all p>0.05). In the intention-to-treat analysis, treatment retention rates at 18 months were 94.9% (749/789) in the 3-month dispensing group and 94.2% (753/799) in the 6-month dispensing group. The risk difference (6-month minus 3-month) was -0.7% (95% CI -2.9% to 1.5%); non-inferiority was demonstrated as the lower bound of the 95% CI (-2.9%) exceeded the pre-specified margin of -5%. Viral suppression rates ( 2 = 0.0421, p = 0.8375). In terms of cost, the 6-month dispensing group had two fewer annual outpatient visits (3 vs. 5), with total treatment costs reduced by 27.7% (¥931.82 vs. ¥1288.85) and work value loss decreased by 16.7% (¥174.20 vs. ¥209.04 yearly). Conclusions Six-month MMD of ART did not reduce treatment retention; instead, it decreased patients' clinic visit costs, thereby meeting cost-effectiveness criteria. Clinical trial number ChiCTR2200066438.

Medicine

Herpes Simplex Virus Hepatitis: An Overlooked Cause of Acute Liver Failure Across a Broad Spectrum of Immunocompromise.

Mondelli MU et al. · Jul 1, 2026

Background and aims Herpes simplex virus (HSV) infection is common worldwide, but hepatic involvement is rare. HSV hepatitis is an uncommon yet frequently catastrophic cause of acute hepatitis and acute liver failure (ALF), accounting for Methods We describe three cases of HSV hepatitis presenting with distinct risk profiles and clinical manifestations and review the diagnostic and therapeutic challenges associated with this condition. Results Clinical presentation was nonspecific in all cases, and mucocutaneous lesions were absent or delayed, contributing to diagnostic uncertainty. All patients exhibited marked aminotransferase elevation with relatively modest hyperbilirubinemia ("anicteric hepatitis"), frequently accompanied by cytopenias and coagulopathy. Delayed recognition was associated with rapid clinical deterioration, whereas earlier initiation of intravenous acyclovir was associated with biochemical and clinical improvement. Diagnosis was established using polymerase chain reaction-based detection of HSV DNA in blood and tissue samples. Conclusions HSV hepatitis remains an under-recognized cause of ALF across a broad spectrum of immunocompromised and seemingly immunocompetent patients. Given the narrow therapeutic window and favourable safety profile of acyclovir, empiric intravenous antiviral therapy should be considered in patients with ALF of indeterminate aetiology while diagnostic testing is pending, particularly in high-risk clinical settings. Increased awareness of this overlooked diagnosis may improve outcomes and prevent avoidable mortality.

Medicine