Citations

Abstract Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

Abstract Up to 80% of the world's population with epilepsy lives in low and middle‐income countries. Around one‐third of these patients will have drug‐resistant epilepsy, for which epilepsy surgery is an option. Unfortunately, many of these regions, as well as some more developed nations, lack sufficient epilepsy surgery units and trained neurosurgeons. With this in mind, the International League Against Epilepsy (ILAE) formed the Epilepsy Surgery Education Taskforce to address the shortage of further educational opportunities for surgeons and neurologists and to promote the creation of more epilepsy surgery units around the world. In this article, we publish our findings from a web‐based international survey, in which we investigated the global distribution and experience of neurosurgeons who perform epilepsy surgery, their educational paths, and opinions on the further need for epilepsy surgery education, as well as the resources available to them. We report a detailed analysis of the 202 survey replies received from 35 different countries across six continents. The lack of adequate numbers of epilepsy surgery units in the Southern Hemisphere is notable, and the aim of this task force with other ILAE committees, is to improve access to epilepsy surgery for patients and to enhance training for their health care providers.

Abstract Purpose: Although the B-cell receptor (BCR) signal plays a critical role in chronic lymphocytic leukemia (CLL) cell survival and a target of current therapies (ibrutinib targets Bruton’s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the “CLL cell-survival signaling network” is largely undefined. Experimental Design: Patients with CLL were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. Results: We detected that compared with normal B cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its noncanonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR signal in CLL cells via LYN/Bruton’s tyrosine kinase axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR inhibitors or venetoclax (a BCL2 inhibitor), induced apoptosis synergistically in CLL cells. Conclusions: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some patients with CLL.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Abstract Objective To study pregnancy outcomes and complications in women with congenital adrenal hyperplasia (CAH). Methods A retrospective multicenter study was conducted at tertiary reference centers in 5 countries (Austria, Germany, Italy, Sweden, USA), including 72 adult women with CAH (nonclassic [NC] n = 34, simple virilizing [SV] n = 21, salt wasting [SW] n = 17). Results A total of 133 pregnancies, 112 live births, and 25 abortions were documented. Prolonged latency to pregnancy was observed (median 11 months in SW, 24 months in SV, 8 months in NC), with a notable use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Over half of the women in each group took more than 12 months to conceive. The average number of live births (1.4-1.6 children per woman) was similar across CAH phenotypes and comparable to the general population. Spontaneous abortion rates (18.0%) were also similar across phenotypes. Primary cesarean section rates (60.9%) were higher than in the general population, though 23.8% of women with SV and 29.4% of women with SW gave birth naturally, despite most having undergone genital surgery. Children categorized as small for gestational age were 20.5%. Pregnancy, delivery, and postpartum complications were rare for mothers and neonates. Conclusion The study indicates a prolonged latency to pregnancy and high use of fertility treatments in CAH patients, regardless of phenotype. Abortion rates were not increased, and overall pregnancy and perinatal outcomes were favorable.

AbstractAimMinimally invasive transanal platforms are now the standard of care for select low‐risk rectal tumours. However, existing platforms come with persistent technical challenges. The da Vinci SP Surgical System™ offers a new alternative designed to work effectively in narrow spaces. This technology has the potential to enhance the feasibility and proximal extent of complex transanal resections. This study aimed to describe the morbidity and technical success in patients undergoing single‐port robotic transanal minimally invasive surgery (SPR‐TAMIS). Secondary outcomes include rates of local recurrence.MethodsA retrospective analysis was conducted on all patients who underwent SPR‐TAMIS at our institution between February 2019 and December 2023.ResultsThe study included 31 patients (19 men, 12 women) with a mean age of 61 ± 13.3 years. The average tumour distance from the anal verge was 10 cm. Thirty patients completed SPR‐TAMIS, with one patient requiring conversion to robotic sigmoidectomy due to location in the mid‐sigmoid colon. The mean operating time was 106 ± 42 min. Twenty‐eight out of 30 patients underwent full‐thickness excision and all but two were successfully closed. All specimens were resected intact, and margins were negative in 93.5% of cases. The average tumour size was 13 ± 34 cm2, with 13 lesions classified as adenomas and 16 as adenocarcinomas. All patients who did not undergo associated procedures were discharged on the day of surgery. Two patients experienced 30‐day morbidity. At a mean follow‐up of 18 months (± 13), no local or systemic recurrences were identified.ConclusionSPR‐TAMIS for excision of low‐risk rectal tumours is associated with high rates of technical success and low 30‐day morbidity. Further research is needed to compare SPR‐TAMIS with other techniques to determine potential advantages over current transanal platforms.

Objective Extracorporeal cardiopulmonary resuscitation (ECPR) utilizes veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in cardiac arrest patients to reduce the risk of mortality and multiorgan dysfunction from systemic hypoperfusion. We aimed to compare clinical outcomes of patients receiving ECPR versus conventional cardiopulmonary resuscitation (CCPR) for refractory cardiac arrest. Data Sources This was a systematic review and meta-analysis. A librarian searched the main databases, Ovid MEDLINE (including epub ahead of print, in-process & other non-indexed citations), Ovid EMBASE and Ovid Cochrane Central Register of Controlled Trials from inception through July 2024. Study Selection We included randomized controlled trials and observational studies that compared the outcomes of ECPR to CCPR in cardiac arrest patients. Primary outcomes were neurological sequelae and survival. Data Extraction We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two reviewers independently screened articles, extracted data on selected articles and performed risk of bias assessments using ROBINS-I for non-randomized controlled trials and the revised Cochrane risk of bias tool for randomized controlled trials with disagreements settled by a third independent reviewer. Data Synthesis Out of 3458 studies identified and screened, 28 studies including 304,360 cardiac arrest patients met eligibility criteria and were included. Survival at hospital discharge was 20% for ECPR versus 3.3% for CCPR (OR 0.48 [CI 0.27, 0.84]). Favorable neurological outcome at hospital discharge was 11.8% for ECPR versus 1.9% for CCPR (OR 0.41 [CI 0.17, 1.01]). Complications from bleeding were ten times higher in the ECPR group (35.3% vs 3.7%; OR 0.08 [0.03, 0.24]). Conclusions ECPR appeared to be superior to CCPR for improved neurological outcome and survival in cardiac arrest patients, although bleeding was increased. There was large heterogeneity in the included studies and outcomes reported. Future prospective studies may improve the identification of subgroups of patients that will benefit most from ECPR. Systematic review and meta-analysis registration: PROSPERO - CRD42023394128.

Cephalosporins have traditionally been administered as an intermittent infusion. With the knowledge that cephalosporins demonstrate a time-dependent pharmacodynamic profile, administration via continuous infusion may provide more effective antibiotic exposure for successful therapy. Proposed benefits of administration via continuous infusion include less IV manipulation, decreased potential for antibiotic resistance, and potential cost savings. The objective of this review was to provide a detailed assessment of available evidence for the use of continuous infusion cephalosporins and practical dosing and administration recommendations. Studies were gathered and assessed for inclusion via a literature search of PubMed and Ovid MEDLINE using mesh terms [“continuous infusion” and “cephalosporin”], “intermittent infusion”, [“intermittent versus continuous” and “cephalosporin”], “continuous infusion cephalosporin”, as well as specific drug names. References from included studies were also evaluated for inclusion. Data which compared the two administration methods (continuous infusion vs. intermittent infusion) were evaluated. Thirty-five studies were analyzed among several cephalosporins with variable delivery. Dosing regimens utilized in the selected studies were assessed with known compatibility and stability data and further summarized.

The implementation of clinical 7T MRI presents both opportunities and challenges for advanced medical imaging. This tutorial provides practical considerations and experiences with 7T MRI in clinical settings. We first explore the history and evolution of MRI technology, highlighting the benefits of increased signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and susceptibility at 7T. Technical challenges such as increased susceptibility artifacts and RF inhomogeneity are also discussed, along with innovative adaptations. This review also discusses hardware and software considerations, including new parallel transmission head coils and advanced image processing techniques to optimize image quality. Safety considerations, such as managing tissue heating and susceptibility to artifacts, are also discussed. Additionally, clinical applications of 7T MRI are examined, focusing on neurological conditions such as epilepsy, multiple sclerosis, and vascular imaging. Emerging trends in the use of 7T MRI for spectroscopy, perfusion imaging, and multinuclear imaging are explored, with insights into the future of ultra-high-field MRI in clinical practice. This review aims to provide clinicians, technologists, and researchers with a roadmap for successfully implementing 7T MRI in both research and clinical environments.