IntroductionCardiorespiratory fitness (CRF), assessed via cardiopulmonary exercise testing (CPET), is a powerful objective marker associated with biological aging, healthspan, and all-cause mortality. Controlled trials have reported improvements in CRF following hyperbaric oxygen therapy (HBOT) protocols utilizing hyperoxic–hypoxic paradox (HHP) principles in healthy athletes and older adults; whether similar changes are observed in a broad, heterogeneous clinical population remained unknown.MethodsRetrospective cohort study of 1,032 consecutive patients with valid maximal/peak effort CPET before and after HBOT (2018–2025). Within-subject changes were quantified across general and indication-specific CPET parameters and stratified by clinical indication, age (<45 to ≥75 years), and sex; effect sizes were benchmarked against sham- and control-anchored trials of the identical protocol.ResultsAll seven prognostic CPET parameters improved significantly post-treatment at the whole cohort level (all p < 0.001; dz = 0.23–0.74), with aerobic-capacity gains evident across clinical indications, age groups and sexes. Peak aerobic capacity (VO2max/kg) rose by +2.29 mL·kg-1·min-1 (95% CI +2.10 to +2.47) and submaximal ventilatory threshold capacity (VO2 at VT1) by +2.12 mL·kg-1·min-1 (95% CI +1.94 to +2.30), with parallel improvements in oxygen pulse (+0.79 mL/beat) and ventilatory efficiency (VE/VCO2 slope −1.07); these represent medium-to-large within-subject effects (dz = 0.74 and 0.73 for peak and threshold capacity). Using magnitude-based thresholds, 53.9% of patients increased VO2max/kg by ≥ 0.5 MET and 26.6% by ≥ 1 MET (82.9% showed some increase); improvement in peak or threshold oxygen uptake occurred in 94.4%.ConclusionIn the largest CPET-based HBOT cohort reported, completion of the HHP-HBOT protocol (2.0 ATA with intermittent air breaks over a mean of 58.8 sessions) was associated with significant within-subject improvements in VO2max and multiple complementary measures of cardiorespiratory fitness. These findings extend prior controlled observations to a large, heterogeneous real-world clinical cohort. Given the retrospective, uncontrolled design, prospective controlled studies are required to determine the specific contribution of HBOT to these changes.
BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder of older adults, characterized by the classic triad of gait disturbance, cognitive impairment, and urinary incontinence. Despite its treatable nature, iNPH remains widely underdiagnosed, and the prediction of shunt responsiveness and optimization of therapeutic outcomes remain major clinical challenges.MethodsWe conducted a narrative review informed by a structured PubMed search of studies published between January 2017 and June 2026. Forty-eight original clinical studies, including randomized controlled trials (RCTs), prospective and retrospective cohort studies, and cross-sectional studies addressing the pathophysiology, diagnosis, treatment, or prognosis of iNPH, were selected for synthesis; foundational trials and guidelines published before 2017 were cited for context.ResultsEmerging, largely correlational evidence links iNPH to impaired glymphatic function, perivascular aquaporin-4 loss, and delayed cerebrospinal fluid (CSF) tracer clearance, although causality remains unproven. Instrumented gait analysis, MRI volumetry, and refined CSF tap test protocols may improve the objectivity of patient evaluation, but most of these tools have been validated only in small single-center cohorts. The first large placebo-controlled RCT (PENS) confirmed gait improvement after shunt surgery, extending earlier evidence from the Japanese SINPHONI and SINPHONI-2 studies, whereas acetazolamide showed no benefit in the DRAIN trial. Adjuvant rehabilitation may enhance gait recovery and reduce fall risk. Multiple clinical, imaging, and neuropsychological predictors of shunt responsiveness have been reported, but no single biomarker achieves sufficient predictive accuracy, and heterogeneity in diagnostic criteria, outcome measures, and follow-up limits comparisons across studies.ConclusionShunt surgery is now supported by randomized evidence for gait outcomes, whereas most diagnostic and prognostic biomarkers remain investigational. Priorities include standardized diagnostic pathways, prospective external validation of multimodal prognostic models, incorporation of patient-reported and caregiver outcomes, and equitable access to specialized care.
Astrocytes are essential for neuronal health, and astrocyte reactivity is a hallmark of neuroinflammation, a key regulator of Alzheimer’s disease (AD) pathology. Despite increasing evidence linking neuroinflammation and astrocyte reactivity to AD, the precise role of astrocytes in disease progression remains unclear. In this study, we used a three-dimensional (3D) human cell culture model of AD (3D-AD cultures), which exhibits amyloid-β (Aβ)-driven tau pathology, alongside 3D-control cultures to investigate the involvement of astrocytes in Aβ accumulation and tau phosphorylation. Astrocyte ablation using L-alpha-aminoadipate, an astrocyte-selective gliotoxin, increased Aβ40 levels and tau phosphorylation at Thr231 without significantly affecting Aβ42 levels, resulting in a reduced Aβ42/Aβ40 ratio in 3D-AD cultures, suggesting that astrocytes may exert protective effects against tau pathology. Conversely, inducing astrocyte reactivity with a combination of neuroinflammatory factors (TNF-α, IL-1α, and C1q; TIC) elevated Aβ40 and Aβ42 levels but did not significantly affect tau phosphorylation at Thr231, highlighting a role for neuroinflammatory astrocyte reactivity in Aβ pathology. We also observed rapid ERK activation and increased pro-inflammatory cytokine release during TIC-induced astrocyte reactivity, followed by complement C3 upregulation. Pharmacological ERK inhibition attenuated the TIC-induced increase in lactate dehydrogenase (LDH) release but did not prevent the increase in Aβ levels, suggesting that ERK signaling contributes to TIC-induced cytotoxicity without directly mediating the associated Aβ accumulation. Collectively, these findings suggest that astrocytes act as key modulators of AD pathology by protecting against Aβ and tau accumulation under baseline conditions while promoting Aβ buildup and neuroinflammatory toxicity when they become reactive.
BackgroundDiabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with hypertension being a key modifiable risk factor. However, associations between specific blood pressure (BP) phenotypes and concurrent DKD risk remain poorly understood.MethodsThis cross-sectional study analyzed 1,240 adults with diabetes from community health records in Shanghai. Concurrent DKD was defined by UACR ≥30 mg/g or eGFR <60 mL/min/1.73 m2. BP phenotypes (140/90 mmHg threshold) were classified as normal (NBP), isolated systolic (ISH), isolated diastolic (IDH), and systolic-diastolic hypertension (SDH). Multivariable logistic regression (LR) estimated adjusted odds ratios (aORs). The cohort was split 80:20 into training (n = 992) and test (n = 248) sets. Five machine learning algorithms were evaluated using strict within-training-fold preprocessing.ResultsConcurrent DKD was present in 331/1,240 participants (26.69%). After adjustment, ISH and SDH were significantly associated with higher DKD odds versus NBP. On the independent test set, ROC-AUCs were 0.776 for XGBoost and 0.771 for LR, with no statistically significant discrimination difference. XGBoost showed a slightly lower Brier score, while LR offered superior calibration stability and nomogram interpretability.ConclusionISH and SDH are associated with a higher prevalence of concurrent DKD in adults with diabetes. Routine clinical features and BP phenotypes provide moderate discrimination. These models function for opportunistic concurrent risk pattern recognition rather than predictive screening, supporting further external validation prior to clinical implementation.
BackgroundDespite effective antiretroviral therapy (ART), many people living with HIV (PLWH) exhibit persistent immune dysfunction associated with premature biological aging. This review synthesized evidence on the mechanisms, biomarkers and clinical implications of HIV-associated immunosenescence.MethodsPubMed, Scopus, Web of Science and Embase were searched from inception to 11 July 2026. Original human studies examining biological mechanisms, biomarkers or clinical manifestations of immunosenescence among adults living with HIV were eligible. Study selection, data extraction and methodological appraisal followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and design-specific Joanna Briggs Institute (JBI) criteria. Findings were synthesized narratively because of substantial clinical and methodological heterogeneity.ResultsThirty-seven studies were included. Persistent T-cell activation and altered differentiation were the most consistently reported immune-aging features. Frequently evaluated parameters included the CD4/CD8 ratio; loss of CD28; expression of CD57, programmed cell death protein 1 (PD-1) and killer cell lectin-like receptor G1 (KLRG1); co-expression of CD38 and human leukocyte antigen-DR (HLA-DR); interleukin-6 (IL-6), C-reactive protein (CRP), soluble CD14 (sCD14) and soluble CD163 (sCD163); microbial-translocation markers; telomere length; and emerging epigenetic, mitochondrial and senescence-associated secretory phenotype measures. Cytomegalovirus (CMV)-related immune responses were associated with highly differentiated T-cell populations in several studies, although generalized T-cell activation remained the stronger independent correlate in some adjusted analyses. Immune-aging biomarkers were associated with incomplete immune recovery, frailty and non-AIDS morbidity, but heterogeneous definitions and predominantly cross-sectional designs limited causal inference and direct comparison. Certainty was moderate for persistent T-cell activation and differentiated T-cell phenotypes, low for most inflammatory, microbial-translocation, CMV and clinical associations, and very low for emerging molecular biomarkers.ConclusionHIV-associated immunosenescence comprises overlapping cellular, inflammatory and molecular abnormalities that may persist during suppressive ART. Longitudinal studies using standardized definitions are required to validate parsimonious biomarker panels, establish temporality and determine whether biomarker-guided interventions improve healthy-aging outcomes among PLWH.
