Monash Health Collection:

Association of Enlarged Perivascular Spaces and Total Small Vessel Disease Burden With Kidney Function.

Tue, 06 Oct 2026 00:00:00 GMT

Title: Association of Enlarged Perivascular Spaces and Total Small Vessel Disease Burden With Kidney Function. Authors: Nash P.S.; Ambler G.; Best J.G.; Wilson D.; Du H.; Al-Shahi Salman R.; Jager H.R.; Lip G.Y.H.; Goeldlin M.B.; Beyeler M.; Bucke P.; El-Koussy M.; Mattle H.P.; Panos L.; van Dam-Nolen D.H.K.; Dubost F.; Hendrikse J.; Kooi M.E.; Mess W.H.; Nederkoorn P.J.; Christ N.; Bellut M.; Gunkel S.; Karayiannis C.C.; Ly J.; Singhal S.; Slater L.-A.; Kim Y.D.; Lee K.-J.; Lim J.-S.; Hara H.; Nishihara M.; Tanaka J.; Yoshikawa M.; Demirelli D.S.; Tanriverdi Z.; Uysal E.; Coutts S.B.; Chappell F.M.; Makin S.D.; Fung Mak H.K.; Teo K.C.; Wong D.Y.K.; Hert L.; Kubacka M.; Lyrer P.A.; Polymeris A.A.; Wagner B.; Zietz A.; Abrigo J.; Cheng C.; Chu W.C.; Leung T.W.; Seiffge D.J.; Fischer U.; Jung S.; Bos D.; Fluri F.; Phan T.G.; Srikanth V.K.; Heo J.H.; Bae H.-J.; Yakushiji Y.; Orken D.N.; Smith E.E.; Wardlaw J.M.; Kai Lau G.K.; Engelter S.T.; Peters N.; Soo Y.O.Y.; Song T.-J.; Simister R.J.; Wheeler D.C.; Werring D.J. Abstract: Background and Objectives - Enlarged perivascular spaces (EPVSs) in the basal ganglia (BG-EPVS) are an important marker of cerebral small vessel disease (cSVD), and EPVS in the centrum semiovale (CSO-EPVS) are part of the diagnostic criteria for cerebral amyloid angiopathy. We aimed to investigate associations of EPVS with reduced estimated glomerular filtration rate (eGFR) and glomerular hyperfiltration (higher than normal eGFR), which have scarcely been studied previously. Methods - In this cross-sectional study, we used pooled individual patient data from the Microbleeds International Collaborative Network which includes patients with ischemic stroke or transient ischemic attack. We investigated associations of impaired kidney function, defined as an eGFR of 30-60 or <30 mL/minute/1.73 m2, and glomerular hyperfiltration, defined as eGFR above the age-adjusted and sex-adjusted 95th centile, with BG-EPVS and CSO-EPVS severity. EPVS were rated according to a validated 5-point ordinal scale, and combined cSVD burden was rated using a validated 5-point ordinal scale with 1 point assigned for the presence of each of the following: severe white matter hyperintensities, >=1 cerebral microbleed, >=1 lacune, and BG-EPVS >=11. Normal glomerular filtration was defined as eGFR >=60 without hyperfiltration. We used multivariable ordinal logistic regression models to estimate risk of increased EPVS and cSVD burden severity adjusted for age, sex, and comorbidities. Results - Seven thousand two hundred fifty-four patients (mean age 71 +/- 13 years, 43% female) were included in the analysis, 357 with glomerular hyperfiltration, 1, 692 with eGFR 30-60, and 256 with eGFR <30. Compared with normal glomerular filtration, hyperfiltration was independently associated with BG-EPVS (adjusted odds ratio [aOR] 1.38, 95% CI 1.11-1.70, p < 0.001) and CSO-EPVS (aOR 1.34, 95% CI 1.08-1.64, p = 0.011). Associations of eGFR 30-60 and eGFR <30 with EPVS were not statistically significant. Compared with normal glomerular filtration, eGFR <30 (aOR 1.27, 95% CI 1.03-1.57) was independently associated with increased cSVD burden, but eGFR 30-60 (aOR 1.06, 95% CI 0.95-1.20) and hyperfiltration (aOR 1.15, 95% CI 0.98-1.34) were not. Discussion - Glomerular hyperfiltration was independently associated with EPVS severity, in both the basal ganglia and centrum semiovale. eGFR <30 was independently associated with total cSVD burden. A key limitation was a lack of repeated eGFR measurements.Copyright © 2026 The Author(s). Published by Wolters Kluwer Health, LLC. on behalf of the American Academy of Neurology.

A phase 1, first-in-human study of safimaltib, a MALT1 inhibitor, in B-lymphocytic malignancies.

Tue, 06 Oct 2026 00:00:00 GMT

Title: A phase 1, first-in-human study of safimaltib, a MALT1 inhibitor, in B-lymphocytic malignancies. Authors: Hertzberg M.; Cheah C.Y.; Opat S.; Kalac M.; Abrisqueta P.; Ribrag V.; Bachy E.; Ysebaert L.; Qiu L.; Joffe E.; Yi S.; Zinzani P.L.; Tedeschi A.; Nishimura N.; Lemech C.R.; Bussolari J.; Deng C.; Assefa A.T.; Van Hemelryck S.; Snoeys J.; Hodkinson B.P.; Fourneau N.; Cao Y.; Srinivasan S.; Guo Y.; Soete V.; Soriano Paradinas I.; Fontan L.; Philippar U.; Gerecitano J.F.; Morschhauser F. Abstract: Following preclinical findings, we evaluated safimaltib (MALT1 protease inhibitor; JNJ-67856633) in relapsed/refractory B-cell non-Hodgkin lymphomas or chronic lymphocytic leukemia in a multi-center, phase-1, dose-escalation/dose-expansion study (NCT03900598). Primary endpoints were recommended phase-2 dose (RP2D) and safety. Among 226 patients, 56.2% had diffuse large B-cell lymphoma (DLBCL); 47.3% received >=4 prior therapy lines. RP2D was once-daily, 300-mg, oral safimaltib+/-loading dose. Most common adverse events (AEs) were hyperbilirubinemia (48.2%; off-target related), anemia (36.7%), neutropenia (31.4%), and thrombocytopenia (27.4%). Dose reduction mitigated safimaltib-related AEs. Objective response rate was 28.8% (95% CI: 23.0%-35.1%), including 9 (3.9%) complete responses. All patients with non-germinal-center B-cell-like DLBCL and >=1 B-cell-receptor pathway activating mutation (n=5) responded to safimaltib. Safimaltib exhibited on-target activity in translational studies, affecting NF-kappaB-regulated cytokines. Proof-of-principle activity in this first MALT1-targeting study in hematologic malignanices suggest MALT1 may be a feasible target in humans and supports further investigation despite observed off-target effects.

Short-chain fatty acids and blood pressure.

Tue, 06 Oct 2026 00:00:00 GMT

Title: Short-chain fatty acids and blood pressure. Authors: R. Muralitharan R.; Marques F.Z.

Early Arterial Oxygen Tension Thresholds for Mechanically Ventilated Patients with Non-traumatic Acute Brain Injury: A Bayesian Analysis of Three Large Neurocritical Care Datasets.

Tue, 06 Oct 2026 00:00:00 GMT

Title: Early Arterial Oxygen Tension Thresholds for Mechanically Ventilated Patients with Non-traumatic Acute Brain Injury: A Bayesian Analysis of Three Large Neurocritical Care Datasets. Authors: Premraj L.; Camarda C.; Romero-Garcia N.; Seymour B.; Subramaniam A.; Badenes R.; Battaglini D.; Shaefi S.; Pilcher D.; Cho S.-M.; White N.M.; Burrell A.; Cinotti R.; Robba C.; Udy A.A. Abstract: PURPOSE: Optimal arterial oxygen tension (PaO2) thresholds in mechanically ventilated patients with nontraumatic acute brain injury (ABI), defined as intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (SAH), and acute ischemic stroke (AIS), remain uncertain. We aimed to identify ABI-specific early PaO2 thresholds associated with lowest intensive care unit (ICU) mortality in mechanically ventilated ICU patients and compare these with guideline recommendations. METHOD(S): This retrospective multicenter cohort study utilized the Australian and New Zealand Intensive Care Society Adult Patient Dataset (ANZICS-APD; N = 11,264). Bayesian logistic regression was performed with day 1 PaO2 as the independent variable and ICU mortality as the dependent variable. Priors were derived from the Medical Information Mart for Intensive Care-IV (MIMIC-IV; N = 1789) and Extubation in Neurocritical care Observational Study (ENIO; N = 544) datasets. Day 1 PaO2 thresholds were identified by calculating the range of values within 4% of the minimum mortality. The risk of ICU mortality across these PaO2 groups was compared with the European Society of Intensive Care Medicine (ESICM) recommendations. RESULT(S): Of the 11,264 patients in the ANZICS-APD suitable for analysis, 4846 had ICH, 4319 had aneurysmal SAH, and 2099 had AIS. Across all ABI types, day 1 PaO2 > 299 mm Hg was rare (< 10%), with remaining patients distributed equally across the < 80, 80-120, and 120-299 mm Hg categories. The association between day 1 PaO2 and ICU mortality differed by ABI subtype: SAH showed a more pronounced U-shaped relationship than ICH and AIS. PaO2 thresholds that minimized ICU mortality (ICH: 80-230 mm Hg; SAH: 100-190 mm Hg; AIS: 100-160 mm Hg) were broader than current ESICM (PaO2 between 80 and 120 mm Hg) guideline recommendations yet conferred equivalent risk of ICU mortality. Extreme hyperoxia (> 299 mm Hg) was associated with increased risk of ICU mortality across all ABI subtypes [P(OR > 1) = 84-99%]. CONCLUSION(S): In mechanically ventilated patients with nontraumatic ABI, we defined generalizable early PaO2 thresholds that were broader than current recommendations while conferring equivalent ICU mortality risk. PaO2 exposure beyond these ranges may be harmful.Copyright © 2026. The Author(s).