Citations

Abstract Aims Calcium release channel deficiency syndrome (CRCDS) results from loss-of-function (LOF) variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) without abnormalities on a stress electrocardiogram (ECG). Undetected CRCDS may underlie idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). We aimed to determine the prevalence of potential CRCDS-causative RYR2 variants in IVF and SUDY. Methods and results We reviewed clinical evaluation and RYR2 genetic analysis of 169 IVF patients and 279 SUDY victims. Only ultra-rare (<0.005% in gnomAD) nonsynonymous RYR2 variants were considered potentially pathogenic. Among IVF patients, 6/169 (3%) overall—and 6/67 (9%) with exertion-related SCA—harboured an RYR2 variant and represent potential CRCDS cases. All exhibited normal resting and stress ECGs. Genetic analysis revealed six distinct RYR2 variants, two previously characterized as LOF. In SUDY, 31/279 victims (11%) had a RYR2 variant (30 unique variants), predominantly observed in exertion-related SCD 20/83 (24%) vs. rest-related 11/196 (6%). Of the 14 SUDY victims with functionally characterized RYR2 variants, five (2% of total cohort) had a LOF variant; among the 56 exertion-related SUDY cases, four (7%) had a LOF variant. Conclusion CRCDS may account for 3% of IVF overall and 9% of exertion-related SCA in IVF. Ultra-rare RYR2 variants may underlie up to 11% of SUDY, with 65% of RYR2-positive cases occurring during exertion. LOF-RYR2 variants may contribute to ≥7% of exercise-associated SUDY. Accurate identification of the underlying ryanodinopathy is essential for clinical management of affected patients.

Abstract Context Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a rare, autosomal dominant disorder due to pathogenic heterozygous variants in POLD1. Clinical features of MDPL vary between patients; however, there is no previously reported genotype-phenotype association. Objective This work reports 14 new patients with lipodystrophy due to POLD1 variants and compares phenotypic differences between those with p.Ser605del and missense variants. Methods Genetic sequencing was performed on DNA of 14 patients for POLD1 variants, including exome (n = 10), genome (n = 1), and candidate gene (n = 3) sequencing. Comparisons of demographic, clinical features, and metabolic complications between carriers of POLD1 p.Ser605del and missense variants in our cases and those reported in the literature were made using the Fisher exact test for categorical variables and the t test for continuous variables. Results A total of 9 different POLD1 variants were identified in our patients, including 3 novel variants: p.Asp25Glufs*16, p.Arg507His, and p.Trp781Cys. Compared to individuals with missense variants (n = 15), those with the p.Ser605del (n = 26) POLD1 variant had significantly increased prevalence of mandibular hypoplasia (57% vs 100%, respectively; P = .015), small mouth (36% vs 100%, respectively; P = .015), crowded teeth (44% vs 91%, respectively; P = .046), and hypogonadism in male patients (0% vs 92%, respectively; P = .046). There were no differences in the prevalence of metabolic complications, such as diabetes, hypertriglyceridemia, and hepatic steatosis, in the two groups. Conclusion Individuals with the heterozygous POLD1 p.Ser605del variant had typical MDPL with more severe phenotype compared to those with missense variants with atypical MDPL.

Abstract Context Evidence on the etiology and function of adrenal masses in younger adults is scarce. Objective This work aimed to characterize the clinical, imaging, and biochemical presentation of adrenal masses in 18- to 40-year-olds. Methods A retrospective cohort study was conducted January 2016 to December 2021 at a tertiary academic medical center. Participants included young adults (age 18-40 years) with adrenal masses identified through radiologic registry. Exclusion criteria included preexisting adrenal masses before 2016, hyperplasia, or masses smaller than 1 cm. Outcomes included adrenal mass diagnosis, as determined by reference standard of histopathology, radiologic surveillance, and biochemical evaluation. Results A total of 255 patients (women 142 [56%]; White 156 [61%]; median age 35 years [interquartile range 30-39 years]) were included. Comorbidities included genetic predisposition syndromes (16, 6.3%), preexisting malignancy (70, 27%), obesity (100, 48%), hypertension (89, 35%), and diabetes (25, 10%). The majority of adrenal masses were incidentally found (184, 72%) and median size was 1.9 cm (IQR 1.4-2.7 cm) on detection. Among adrenal masses in young adults, prevalence of malignancy and pheochromocytoma was 16% and 4%, respectively; among adrenal incidentalomas, 5% were malignant. Factors associated with malignancy or pheochromocytoma in multivariable analysis included nonincidental mechanism of discovery (odds ratio [OR] 15.5; 95% CI, 7.2-35.7; P < .001), and larger size (OR 1.5; 95% CI, 1.2-2.0; P < .001). Hormonal evaluation was performed in only 57 (22%) patients and was positive for hormone hypersecretion in 16 (28%) of tested individuals. Conclusion We demonstrated a high prevalence of malignancy and pheochromocytoma in our cohort of young adults with adrenal masses. Completion of appropriate hormonal work-up was infrequent, potentially missing patients with functioning adrenal adenomas.

Abstract Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier versus later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier versus later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed-effects models to estimate how much earlier versus later each individual progresses on plasma phosphorylated tau (p-tau)217, amyloid PET, tau PET and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cut-off points, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R = 0.38–0.47) in the MCSA and stronger (R = 0.74–0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET Alzheimer’s disease biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

Abstract Background Immunotherapy has yet to make significant gains in glioblastoma (GBM) treatment, due in part to GBM-mediated immune suppression. Increasing evidence points to critical roles for tumor-derived extracellular vesicles (EVs) and immunosuppressive myeloid cells as key factors in this process. Methods Immunophenotyping of the tumor-immune microenvironment was performed using ultrasonic aspirate collected during GBM resection by high-dimensional flow cytometry. EVs collected from patient-derived GBM cell lines were used to condition myeloid cells collected from healthy donors to generate immunosuppressive myeloid cells. siRNA was used to knockdown TIGIT and/or NLRP3 expression prior to EV conditioning. T cell co-culture studies were performed with donor-matched T cells. Results Immune phenotyping of the tumor microenvironment and EV-conditioned myeloid cells revealed similar immunomodulatory protein expression across myeloid cell populations, with particularly elevated TIGIT expression. Knockdown of TIGIT reduced the immunosuppressive polarization of myeloid cells, resulting in improved T cell function. This finding proceeded in an NLRP3-dependent manner, with substantial co-expression of TIGIT and NLRP3 expression prior to knockdown, and concomitant knockdown of NLRP3 abrogating the effect of TIGIT knockdown. TIGIT expression correlated with increased IL-13 expression, and IL-13 blockade unmasked a pro-inflammatory myeloid cell phenotype. Conclusion TIGIT expression in myeloid cells in the GBM microenvironment is a functional marker of immunosuppressive activity, with TIGIT knockdown reducing IL-13 expression and unmasking the pro-inflammatory activity of NLRP3. This study bolsters our understanding of the immunosuppressive complexities of the GBM microenvironment and supports attenuation of immunosuppressive myeloid cell activity as a strategy to restore immune function in GBM.

Background Multimorbidity is common in patients with atrial fibrillation (AF); however, the impact of the number and type of comorbid conditions on outcomes remains uncertain. Methods This cohort study included patients with new‐onset AF from a Midwest region between 2013 and 2017. Eighteen chronic conditions at the time of AF were classified into groups: cardiometabolic, other somatic, and mental health. Cox regression determined associations between the number of each condition type with death, ischemic stroke/transient ischemic attack, and congestive heart failure, stratified by age. Results Among 16 509 patients with AF (mean age, 74 years; 43% women), the mean number of cardiometabolic, other somatic, and mental health conditions was 2.7, 1.4, and 0.5, respectively. The number and type of conditions had a varying impact on outcomes and differed by age. A higher number of cardiometabolic conditions were associated with increased risk of death within 90 days only in people aged ≥85 years (≥4 conditions versus 0: hazard ratio [HR], 1.74 [95% CI, 1.05–2.87]), whereas for death after 90 days, associations were strongest in the youngest age group (<65 years: HR, 1.83 [95% CI, 1.35–2.46]; 65–74 years: HR, 1.34 [95% CI, 1.04–1.73]; 75–84 years: HR, 1.32 [95% CI, 1.09–1.60]; ≥85 years: HR, 1.14 [95% CI, 0.96–1.35]). Associations with outcomes were generally strongest in the youngest age group and attenuated with older age for higher number of other somatic conditions, whereas the pattern was less consistent for mental health conditions. Conclusions Along with cardiometabolic‐related conditions, other somatic and mental health conditions are important predictors of outcomes in AF, with effects differing by age, and should be considered when caring for these patients.