Citations

BACKGROUND: The impact of life-course blood pressure (BP) trajectories on later-life focal left ventricular (LV) fibrosis by late gadolinium enhancement (LGE) remains elusive. METHODS: MyoFit46 prospectively recruited ≈500 participants from a 1946 birth cohort for a cardiovascular magnetic resonance scan at 77 years, assessing LV LGE calculated using the 3-SD method or 5-SD method. Systolic BP (SBP) and diastolic BP were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, annual rates of BP change (steepness) and area under the BP trajectory (cumulative burden) for each age interval were calculated using mixed-effects models. Associations between life-course BPs and LGE were tested using generalized linear models, adjusted for antihypertensives, demographics, lifestyle, and comorbidities. Time-to-event associations between LGE and incident major adverse cardiovascular event (hospitalizations for coronary artery disease, stroke, heart failure, and atrial/ventricular arrhythmias; n=29) were also evaluated. RESULTS: Among 472 participants (54% male), each 10 mm Hg greater individual SBPs at 36 to 69 years were associated with 6% to 11% greater LV LGE calculated using the 3-SD method (all P ≤0.033), whereas each 10 mm Hg sustained greater SBPs on any age interval from 36 to 69 associated with 16% to 24% greater LGE calculated using the 3-SD method at 77(all P ≤0.005), independent of SBP at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, and 53 to 63 was associated with 6% to 12% greater LGE calculated using the 3-SD method at 77 years. LGE presence was associated with greater major adverse cardiovascular event rates (hazard ratio, 2.5 [95% CI, 1.2–5.2]). CONCLUSIONS: Higher life-course BPs, cumulative burden, and steeper increases were associated with greater older-age LV LGE, which was linked to incident major adverse cardiovascular events. BP trajectories, beyond single-point BP measurements, warrant further investigation as tools to guide BP management strategies.

Abstract Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts. One sentence summary A combination of four mitochondrial functional tests to identify or confirm suspected primary mitochondrial disease in fibroblasts had good sensitivity and excellent specificity, well beyond what was perceived using enzyme assays only.

Abstract Genetic loss of the mitochondrial control enzyme PINK1 leads to Parkinson’s disease, characterized by dopaminergic neuron degeneration and neuroinflammation, yet its role in glia remains poorly understood. To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.

Background: Polydactyly surgery rates and trends are poorly characterized. The purpose of this study was to characterize national pediatric polydactyly management by examining operative and procedural trends over time, evaluating timing of treatment, identifying factors associated with interventions, and comparing costs and complications. Methods: We used the PearlDiver national administrative claims database to identify pediatric patients aged 18 and under with a diagnosis of polydactyly (2010-2023). We analyzed patients who received procedures coded as surgical correction or suture ligation, then characterized rates and factors associated with each intervention, and investigated postoperative complication rates. Results: Of 42 543 polydactyly patients, 3880 patients (9.1%) underwent surgery, and 5612 patients (13.2%) underwent procedures coded as suture ligation. Over the past decade, the incidence of polydactyly diagnosis and surgery has decreased, while rates of procedures coded as suture ligation have not changed significantly. In 2010, 12.0% of patients underwent surgery, compared to 7.3% in 2020. Patients of ages 1 to 2 years comprised the greatest proportion of the population who underwent surgical operations at 1729 patients (36.0%), and patients of ages 0 to 1 year comprised the greatest proportion of the population who underwent suture ligations at 3327 patients (51.0%) ( P < .001). Younger age at diagnosis and higher comorbidity index were associated with a greater likelihood of surgery, while greater mean family income was associated with a lower likelihood. Among treatment categories, surgery was associated with greater 1-year and total payer-reimbursed costs ( P < .05). Conclusions: We observed a declining incidence of pediatric polydactyly and polydactyly surgery. These findings may inform future guideline development and discourse for pediatric hand care.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract The recent FDA approval of the first T-cell receptor–engineered (TCR) T-cell cancer therapy has solidified the treatment as a viable therapeutic strategy. However, only a fraction of patients who received this treatment achieved substantial and long-lasting responses, highlighting the need to understand the molecular underpinnings of these responses and develop more effective strategies to improve this therapy. Previous research has demonstrated that the activation of myeloid differentiation primary response 88 (MyD88) signaling in tumor-specific T cells functions as a robust costimulatory signaling pathway that promotes effective antitumor T-cell responses. In this study, we developed a strategy for improving TCR T-cell therapies by creating a synthetic TCR in which the intracellular domain of CD3ζ and a modified MyD88 are appended to the β-chain of a tumor-reactive TCR. The β:CD3ζ:MyD88 TCR activated MyD88 signaling in a tumor antigen/TCR-specific manner, and β:CD3ζ:MyD88 TCR T cells exhibited enhanced functionality and a reduced propensity to become exhausted. Furthermore, MyD88 signaling promoted T-cell persistence and expansion in vitro. In vivo, tumor-infiltrating β:CD3ζ:MyD88 TCR T cells skewed the immunosuppressive tumor microenvironment toward a less immunosuppressive state. Finally, β:CD3ζ:MyD88 TCR T cells substantially delayed tumor growth kinetics in a melanoma model. These findings introduce an approach for improving TCR-dependent T-cell responses by directly appending signaling domains to the full-length TCR and exemplify the utility of activating MyD88 signaling in tumor-specific T cells. Significance: A chimeric β:CD3ζ:MyD88 TCR reduces exhaustion and improves antitumor T-cell responses, overcoming the limited efficacy of current TCR-engineered T-cell cancer therapies.

Background Patients with anti-leucine-rich glioma-inactivated 1 (anti-LGI1) autoimmune encephalitis (AIE) frequently present with faciobrachial dystonic seizures (FBDS), which are often under-detected due to their subtle motor features and lack of consistent EEG correlates. Conventional in-hospital monitoring and patient-reported seizure diaries are limited, particularly during nocturnal periods. In this pilot feasibility study, we evaluated the use of a wearable device (Empatica E4) to objectively monitor FBDS-related motor and autonomic activity in seven patients with anti-LGI1 AIE and four control subjects. Methods Wearable recordings included accelerometry (ACC), electrodermal activity (EDA), photoplethysmography (PPG) and skin temperature. A support vector machine-based algorithm was developed to identify disorder-related events using ACC and EDA features. Analyses were restricted to sleep periods to minimise confounding from voluntary movements. Results Pretreatment recordings from two patients (P1 and P2) showed significantly elevated motor event frequency, ACC magnitude and EDA activity compared to controls. Post-treatment recordings demonstrated marked reductions in these metrics, consistent with patient-reported clinical improvement. Other patients showed variable results depending on treatment timing and signal quality. Conclusion Our pilot study demonstrates the feasibility of using wearable technology for objective, real-world monitoring and assessment of patient status in anti-LGI1 AIE. Nocturnal monitoring offers a low-noise baseline for detecting seizure-related activity and may support earlier diagnosis, more accurate evaluation of treatment response and reduced reliance on resource-intensive inpatient evaluations. Future studies should expand monitoring to daytime periods and validate findings against conventional modalities such as video-EEG and electromyography polygraphy.

Abstract Background Inflammatory bowel disease (IBD) is associated with increased risk of major adverse cardiovascular events (MACE), likely driven by systemic inflammation. Treating inflammation may reduce this risk. We aimed to investigate MACE across different therapies in patients with IBD. Methods We used Swedish nationwide registers (2007–2023) to describe MACE rates (ischemic heart disease, stroke, heart failure, and cardiovascular mortality) in patients with IBD receiving different therapies. For contextualization, we compared MACE rates during therapy exposure periods in patients with IBD with matched (by age, sex, and residence) general population comparators without IBD. Comparisons included exposure periods naïve to immunomodulators/advanced therapies and periods of different treatments (immunomodulators, TNF-α inhibitors (TNFi), vedolizumab, ustekinumab, and Janus kinase inhibitors). Each patient could contribute with multiple periods, with a new period starting upon switch of therapy. Incidence rates (IRs) and adjusted hazard ratios (aHRs) were estimated by using Cox regression (Model 1: conditioned on matching variables; Model 2: additional adjustment for Charlson Comorbidity Index). Among patients with IBD, we performed 1:1 propensity score (PS)-matched analysis, with exposure periods of TNFi or vedolizumab as the reference, to compare MACE rates between advanced therapies. In these comparisons, we adjusted for demographics, disease characteristics, healthcare utilization, prior treatment, and cardiovascular risk factors. Results We included 106,894 patients with IBD with 99,661 exposure periods naïve to immunomodulators/advanced therapy, 60,573 exposure periods of immunomodulators, and 71,551 of advanced therapies. Distribution of age, sex and disease duration differed substantially across therapy exposures (data not shown). Compared with the general population, MACE rates in patients with IBD were similar across therapies (IRs=3.0-13.0/1,000 person-years; aHRs=1.02-1.49) (Table 1), and significantly increased only for exposure periods naïve to immunomodulators/advanced therapy, immunomodulators, or ustekinumab. In PS-matched comparisons, no significant differences were found between periods of TNFi, vedolizumab and other advanced therapies (Table 2). Conclusion Therapy exposure periods in patients with IBD showed only slightly increased MACE rates compared to corresponding periods in the general population, and significantly so only for periods naïve to immunomodulators/advanced therapy and exposure to immunomodulators or ustekinumab. In PS-matched analyses of patients with IBD, no significant differences in MACE rates were observed when comparing exposure periods of different advanced therapies. Conflict of interest: Eriksson, Carl: Served as speaker/advisory board member for Janssen Cilag AB and Tillotts Pharma. Forss, Anders: Served as speaker/advisory board member for Janssen Cilag AB and Tillotts Pharma. Singh, Siddharth: Dr. Singh has research grants from Pfizer. Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova ( 2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson &amp Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp &amp Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson &amp Johnson, Merck Sharp &amp Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp &amp Dohme and Takeda. Sun, Jiangwei: No conflicts Söderling, Jonas: Dr. Söderling has worked on projects at Karolinska Institutet and SWIBREG partly financed by grants from Ferring and Janssen. Everhov, Åsa H: Dr Everhov has worked on projects at Karolinska Institutet and SWIBREG, partly financed by grants from Ferring and Janssen. Bröms, Gabriella: Dr. Bröms has served as a speaker for Takeda and Janssen and worked on projects at Karolinska Institutet, partly financed by Janssen, UCB and Pfizer. James, Stefan: Dr. James reports institutional research grants from Novo Nordisk, Astra Zeneca, Amgen, Jansen, Alnylam and proctor fees from Medtronic. Ludvigsson, Jonas: Dr. Ludvigsson has coordinated an unrelated study for the Swedish IBD Quality Register (SWIBREG). That study received funding from Jansen Corporation. Ludvigsson has also received financial support from MSD/Merck for unrelated research on inflammatory bowel disease, and for developing a paper reviewing national healthcare registers in China. Ludvigsson has an ongoing research collaboration with Takeda about celiac disease and is discussing additional collaboration on chronic liver disease with this company. Olen, Ola: Karolinska Institutet has received research grants from Pfizer, Janssen, AbbVie, Takeda, Ferring, Bristol Myers Squibb, and Alfasigma for projects led by Olén. Ola Olén has also received fees for lectures from Pfizer, Janssen, Bristol Myers Squibb, and Takeda.

Abstract Background The amygdala is closely connected to the olfactory bulb and involved in olfactory processing as well. It is a particularly susceptible region that accumulates a‐synuclein pathology in Parkinson's disease (PD). Our previous work revealed olfactory bulb gene alterations related to neuroinflammation, and neurotransmitter dysfunction to be associated with olfactory function. We aimed to extend this work and assess gene expression changes, affected pathways and co‐expression networks by transcriptomic profiling of the amygdala in subjects with and without clinicopathologically defined PD. Method Bulk RNA sequencing was performed on frozen human amygdala of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative Disorders. Result Differential expression analysis, corrected for age, sex and post‐mortem interval revealed 40 significantly differentially expressed genes (DEGs) in PD. Downregulated genes were mainly related to altered hemoglobin expression while upregulated genes included inflammatory markers and glutamine transporter. Significantly enriched pathways were involved in oxygen and carbon dioxide transport, cellular oxidant detoxification and regulation of glutamine secretion. Cell enrichment revealed these genes to be mainly expressed in neurons. Co‐expression network analysis using Weighted correlation network analysis (WGCNA ) subsequently identified four significant modules correlated with both PD and premortem olfactory dysfunction which were involved in pathways related to neuroinflammatory processes, mitochondrial, endoplasmic reticulum and lysosomal dysfunction. Conclusion These preliminary results suggest cellular alterations in the amygdala related to mitochondrial dysfunction, altered oxygen homeostasis, oxidative stress, inflammation as well as glutamatergic neurotransmitter dysfunction that may contribute to neurodegeneration in PD.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.