White Matter Hyperintensity Burden and Decline in Driving Performance Among Older Adults
Higher WMH burden, especially in posterior regions, was associated with progressive driving self-regulation and increased errors in those developing cognitive impairment. Antihypertensive use attenuated WMH-associated unsafe driving. Posterior WMH may represent a biomarker for identifying older drivers at risk and may inform mobility-preserving interventions in aging populations.
KEY FINDINGS: In this cohort study of older drivers, higher WMH burden, especially in posterior regions, was associated with progressive driving self-regulation and increased errors in those developing cognitive impairment. Antihypertensive use attenuated WMH-associated unsafe driving. Posterior WMH may represent a biomarker for identifying older drivers at risk and may inform mobility-preserving interventions in aging populations.
BACKGROUND: White matter hyperintensity (WMH) burden is associated with cognitive decline, but its association with driving performance among older adults and the associations of modifiable risk factors remain unclear. Aim of this study was to evaluate the association of total and regional WMH burden with longitudinal naturalistic driving performance in cognitively normal older adults and evaluate moderating associations of cognitive decline and antihypertensive therapy.
DETAILS: This prospective longitudinal cohort study enrolled community-dwelling older adults (>=65 years) in the Driving Real-World In-Vehicle Evaluation System Project. Baseline 3-T brain magnetic resonance imaging (MRI) scans and data from continuous in-vehicle driving monitoring were collected from January 1, 2015, to December 31, 2024 (mean [SD] follow-up, 5.6 [1.8] years), with annual cognitive and clinical assessments. Monthly driving trip frequency, trip distance, unique destinations, driving entropy, and safety events. Longitudinal associations were evaluated using linear mixed-effects models adjusted for demographic characteristics, socioeconomic status, and vascular risk. Among 220 participants (mean [SD] age, 72.9 [5.0] years; 119 men [54%]) with low vascular risk (mean [SD] Framingham Stroke Risk Profile, 6.4% [1.3%]), greater baseline WMH burden was correlated with lower driving frequency (ß = -0.16; 95% CI, -0.27 to -0.06; P = .002), reduced driving entropy (ß = -0.17; 95% CI, -0.27 to -0.06; P = .002), and fewer unique destinations (ß = -0.17; 95% CI, -0.27 to -0.07; P = .001). Longitudinally, higher WMH was associated with faster declines in driving frequency (ß = -0.08; 95% CI, -0.13 to -0.04; P < .001), entropy (ß = -0.11; 95% CI, -0.17 to -0.06; P < .001), and unique destinations (ß = -0.09; 95% CI, -0.14 to -0.04; P < .001). Growth in posterior WMH burden showed the strongest association with increased crash risk (ß = 1.71; 95% CI, 1.17-2.24; P < .001) among those developing cognitive impairment (38 [17%]). Among participants, 135 used antihypertensive therapy and 113 underwent follow-up MRI. Antihypertensive therapy, particularly angiotensin-converting enzyme inhibitors, was associated with attenuated WMH-related risky driving before adjustment, but not after adjustment (ß = -0.17; 95% CI, -0.37 to 0.03; unadjusted P = .02; false discovery rate-adjusted P = .08). Sensitivity analyses confirmed associations were independent of Alzheimer dementia pathology.
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Source: Parihar, M., Chen, Y., Xu, B., et al. White Matter Hyperintensity Burden and Decline in Driving Performance Among Older Adults. JAMA Network Open. 2026; 9;(1): e2554501. Published: January 29, 2026. DOI: 10.1001/jamanetworkopen.2025.54501
Fracture Risk Remains High and Largely Unaddressed After Kidney Transplantation
Kidney transplant recipients had a 21% 10-year fracture risk, unchanged over two decades. Twenty-eight percent of those with a fracture sustained another fracture, with the highest incidence at 6-12 months. Only 10% received anti-osteoporosis therapy and 17% underwent DXA within 1 year, highlighting an unmet need for post-fracture risk assessment and intervention.
KEY FINDINGS: Kidney transplant recipients continue to experience substantial fracture risk, with approximately one in five developing a fracture within 10 years after transplantation. Fracture rates remained largely unchanged over two decades, and an initial fracture was followed by a particularly high risk of another fracture. The limited use of anti-osteoporosis therapy and DXA assessment after fracture highlights an important gap in post-transplant bone health management.
BACKGROUND: Kidney transplant recipients remain at increased risk of fractures compared with the general population. However, the magnitude of this risk in the current transplant era and the likelihood of subsequent fractures after an initial event have not been fully characterized. This study evaluated post-transplant fracture risk and prognosis over two decades.
DETAILS: This retrospective cohort study included all adults who underwent a first single-organ kidney transplant between 2000 and 2022 in Denmark. Nationwide health registries provided demographic, diagnostic, procedural, prescription, transplantation, and mortality data. The study assessed cumulative incidence of first and subsequent fractures, with death treated as a competing risk, and examined fracture incidence across different transplant periods.
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The cohort comprised 3977 kidney transplant recipients, with a median age of 50 (40, 60) years; 1487 (37%) were female. Before transplantation, 503 (13%) had a history of any fracture and 176 (4%) had experienced a major osteoporotic fracture.
Among 3977 kidney transplant recipients, 788 experienced a post-transplant fracture. The 10-year risk of any fracture was 21% (95% confidence interval 20–23). Crude fracture incidence remained unchanged across the study period from 2000 to 2022, although age- and sex-standardized estimates showed a slight decline. Fractures occurred predominantly at peripheral skeletal sites.
Twenty-eight percent of patients who sustained a fracture experienced a subsequent fracture, with the greatest incidence occurring 6–12 months after the initial event. The 2-year cumulative incidence of any subsequent fracture was 13% (95% CI 11–16), increasing to 24% (95% CI 21–28) at 5 years.
Despite the fracture burden, only 10% of patients received anti-osteoporosis therapy within 1 year after a fracture, and 17% underwent dual-energy X-ray absorptiometry (DXA) within 1 year.
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Source: Ystrøm, I. K., Christiansen, C. F., Ivarsen, P., et al. Fracture Risk After Kidney Transplantation: Unchanged and Unaddressed: A Registry-Based Cohort Study Across Two Decades. Clinical Kidney Journa. 2026; 19(3): sfag029. Published: March, 2026. DOI: 10.1093/ckj/sfag029.
Potassium Binders May Support Continued RAAS Inhibitor Therapy in Chronic Kidney Disease and Heart Failure
Second-generation potassium binders were associated with greater persistence of RASi and MRA therapy than first-generation binders. Continued RASi use was associated with lower observed mortality and hospitalization, but not with a clear difference in 3P-MACE. These findings suggest potassium binders may facilitate sustained RAASi therapy in CKD and HF.
KEY FINDINGS: In this Swedish nationwide observational cohort, second-generation potassium binders were associated with greater persistence of RASi and MRA therapy at 6 months than first-generation binders. RASi persistence was also associated with lower observed all-cause mortality and hospitalization, although no clear difference in 3P-MACE was identified. The findings support the potential role of potassium binders in maintaining guideline-directed RAASi therapy in patients with CKD and/or HF.
BACKGROUND: Renin–angiotensin–aldosterone system inhibitors (RAASi) provide important cardiorenal benefits in chronic kidney disease (CKD) and heart failure (HF), but their use can increase the risk of hyperkalemia. Hyperkalemia frequently leads to RAASi discontinuation despite the benefits of continued therapy. This study evaluated whether potassium binders, particularly second-generation agents, were associated with greater persistence of RAASi and mineralocorticoid receptor antagonist (MRA) therapy.
DETAILS:
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Source: Furuland, H., Larsson, A. O., Uhde, M., et al. Potassium Binders and Continuation of Renin–Angiotensin System Inhibitors/Mineralocorticoid Receptor Antagonist in Chronic Kidney Disease and Heart Failure (the DEMONSTRATE Database. Journal of Internal Medicine. 2026; 300(2): 179-192. Published: Augusts, 2026. DOI: 10.1111/joim.70087.
First Birth by Cesarean Delivery Associated With Reduced Subsequent Live Birth and Increased Use of Assisted Reproduction
First birth by cesarean delivery was associated with an 11% lower likelihood of a subsequent live birth and a 28% greater likelihood of IVF or any ART use to achieve a second birth. The findings persisted across elective and emergency cesarean deliveries, although causality cannot be established from this observational study.
KEY FINDINGS: In this large population-based cohort, women whose first birth was by cesarean delivery had an 11% lower likelihood of a second live birth within the 12-year study period and were 28% more likely to use IVF or any ART to achieve a subsequent birth after adjustment for measured confounders. The associations were observed for both elective and emergency cesarean deliveries. No meaningful association with miscarriage was identified, and the difference in interpregnancy interval was small.
BACKGROUND: Cesarean delivery is one of the most common obstetric interventions worldwide. Although cesarean delivery can be medically necessary and life-saving, its potential long-term effects on subsequent reproductive outcomes remain incompletely understood. This study evaluated whether cesarean delivery at first birth was associated with subsequent live birth, use of in vitro fertilization (IVF) or other assisted reproductive technologies (ART), interpregnancy interval, and miscarriage.
DETAILS: This retrospective population-based cohort study included women who had their first spontaneously conceived, singleton live birth in Victoria, Australia, between January 2005 and December 2015. Follow-up for subsequent births continued through December 2017. Women with prior ART use, multiple pregnancies, stillbirths, missing mode of delivery, or unreliable linkage between first and second births were excluded.
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The final cohort included 298,241 women: 205,164 (68.8%) had a vaginal first birth and 93,077 (31.2%) had a cesarean delivery. Among the cesarean deliveries, 33,041 (35.5%) were elective and 60,036 (64.5%) were emergency procedures. A total of 184,061 (61.7%) women had both their first and second births during the 12-year study period.
The primary outcomes were the likelihood of a second live birth within the study period and the requirement for IVF or other ART to achieve a second birth. Secondary outcomes included interpregnancy interval and miscarriage. Analyses adjusted for maternal age, Socio-Economic Indexes for Areas (SEIFA) quintile, chronic hypertension, and preexisting diabetes; age at second birth was additionally considered for outcomes involving a second birth.
First birth by cesarean delivery was associated with a lower probability of a subsequent live birth. The crude hazard ratio was 0.86 (95% CI, 0.85—0.87), while the adjusted hazard ratio was 0.89 (95% CI, 0.88—0.90), corresponding to an 11% reduction after adjustment. The association persisted in the cohort restricted to women whose first birth occurred before 2013, with an adjusted hazard ratio of 0.89 (95% CI, 0.88—0.90).
Among women who had a second live birth, IVF use was increased by 70% in the crude analysis (RR, 1.70; 95% CI, 1.52—1.89) and by 28% after adjustment (adjusted RR, 1.28; 95% CI, 1.15—1.43). Use of any ART was also increased by 28% (adjusted RR, 1.28; 95% CI, 1.15—1.43). These associations persisted when analyses were stratified by elective versus emergency cesarean delivery and when restricted to term births.
No significant difference in miscarriage was identified after adjustment (adjusted RR, 1.01; 95% CI, 0.98—1.03). Although cesarean delivery was associated with a small increase in the median interpregnancy interval, the adjusted median difference was 0.08 months (95% CI, 0.01—0.16), which the investigators considered unlikely to be clinically significant.
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Source: Pritchard, N. L., Hiscock, R. J., Hastie, R., et al. The Impact of First Birth by Cesarean Delivery on Subsequent Reproductive Outcomes—a Population Cohort Study. American Journal of Obstetrics & Gynecology. 2026; 235(2): 338-346. Published: August, 2026. DOI: 10.1016/j.ajog.2026.03.006.
Paternal Valproate Use During Spermatogenesis Not Linked to Neurodevelopmental Disorders in Offspring
A large Swedish-Norwegian cohort found no significant association between paternal valproate use during spermatogenesis and neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam use. Findings were consistent across dose-response analyses and among fathers with epilepsy, supporting reassessment of paternal valproate restrictions.
Summary
A population-based cohort study in Sweden and Norway.
[Posted 17/Aug/2026]
AUDIENCE: Neurology, Psychiatry
KEY FINDINGS: In this large Nordic population-based cohort, paternal valproate monotherapy during spermatogenesis was not significantly associated with neurodevelopmental disorders in offspring compared with paternal lamotrigine or levetiracetam monotherapy. Findings were consistent across dose-response analyses and among fathers with epilepsy. The results do not support an increased neurodevelopmental risk from paternal valproate exposure, although limitations inherent to registry-based observational research remain.
BACKGROUND: Valproate is an effective antiseizure medication, but its established teratogenic effects with maternal exposure have led to regulatory restrictions for women of reproductive potential. Concerns about possible paternal effects on offspring neurodevelopment have also prompted precautionary recommendations for men. This study evaluated whether paternal valproate use during spermatogenesis was associated with neurodevelopmental disorders (NDDs) in offspring.
DETAILS: This population-based cohort study used nationwide Swedish and Norwegian health registries. It included singleton live births at >=22 completed gestational weeks between 1 January 2007 and 31 December 2020 in Sweden and between 1 January 2010 and 31 December 2018 in Norway. After exclusions, 4681 children in Sweden and 1572 children in Norway were included for analysis.
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The analysis compared children whose fathers received valproate monotherapy during spermatogenesis with children whose fathers received lamotrigine or levetiracetam monotherapy. Outcomes included NDDs, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID), and disorders of psychological development. Analyses were adjusted for relevant parental and child characteristics, including parental age, psychiatric diagnoses, psychotropic medication use, epilepsy diagnosis, and, in Sweden, parental education and maternal cohabitation/marital status.
The study specifically examined paternal antiseizure medication exposure during spermatogenesis, corresponding to the approximately 3 months before conception. Dose-response analyses and analyses restricted to fathers with epilepsy were also conducted.
Among the children included in the primary comparison, 2051 were born to fathers who used valproate monotherapy during spermatogenesis. No significant association was identified between paternal valproate exposure and NDDs compared with paternal lamotrigine or levetiracetam exposure. The findings remained consistent in dose-response analyses and when the analysis was restricted to fathers with epilepsy.
During follow-up in Sweden, 406 children were diagnosed with an NDD, including 287 with ADHD, 140 with ASD, 55 with ID, and 79 with disorders of psychological development. In Norway, 60 children were diagnosed with an NDD, including 35 with ADHD, 13 with ASD, 5 with ID, and 26 with disorders of psychological development.
For ASD, the pooled adjusted hazard ratio was 1.29 (95% CI 0.89 to 1.85). The study authors noted that point estimates were slightly above 1.0 in some analyses but did not reach statistical significance.
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Source: Razaz, N., Soderling, J., Tomson, T., et al. Risk of Neurodevelopmental Disorders Associated With Paternal Use of Valproate During Spermatogenesis. Journal of Neurology, Neurosurgery & Psychiatry. 2026; 97-8: 671-679. Published: August, 2026. DOI: 10.1136/jnnp-2025-337441.
FDA Approves Engineered Viral Immunotherapy for Treatment-Resistant Advanced Melanoma
FDA approved Tudriqev, an engineered HSV-1-based viral immunotherapy, for adults with treatment-resistant advanced melanoma. The therapy produced tumor responses in 24.2% of patients with a median response duration of 14.1 months. Ongoing Phase III evaluation will further assess long-term efficacy and safety.
KEY FINDINGS: FDA approval of Tudriqev introduces an engineered viral immunotherapy option for adults with treatment-resistant advanced melanoma. By combining direct tumor destruction with immune activation, this therapeutic approach expands the available immunotherapy landscape for patients with limited options after progression on standard treatments. Continued evaluation through confirmatory studies will determine its long-term clinical role in melanoma management.
BACKGROUND: Patients with advanced melanoma whose disease progresses despite available systemic therapies have limited treatment options and significant unmet clinical needs. The U.S. Food and Drug Administration (FDA) approved a new engineered viral immunotherapy designed to provide a treatment option for adults with advanced melanoma that is resistant to prior therapies.
DETAILS: The FDA approved Tudriqev (vusolimogene oderparepvec, formerly RP1), an engineered oncolytic viral immunotherapy developed by Replimune, for adults with unresectable or metastatic melanoma that has progressed following treatment with an anti–PD-1 therapy and, when appropriate, targeted therapy for BRAF-mutated disease. Tudriqev is an engineered herpes simplex virus type 1 (HSV-1)-based therapy administered through intratumoral injection. The treatment is designed to selectively replicate within tumor cells, promote tumor cell destruction, and stimulate an immune response against cancer cells. The FDA approval was based on clinical evidence demonstrating tumor responses in patients with advanced melanoma who had limited therapeutic alternatives. The therapy represents an additional immunotherapeutic approach that uses direct tumor targeting combined with immune system activation. In clinical evaluation, Tudriqev demonstrated tumor reduction or elimination in 24.2% of treated patients, with a median duration of response of 14.1 months. The FDA approval provides a new treatment option for patients with advanced melanoma whose disease has become resistant to prior immunotherapy approaches. A confirmatory Phase III study is ongoing to further evaluate the therapy’s clinical benefit and long-term outcomes.
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