Citations

ABSTRACTBackground and AimsAcute liver failure (ALF) is a serious condition, typically in individuals without prior liver disease. Drug‐induced ALF (DIALF) constitutes a major portion of ALF cases. Our research aimed to identify potential genetic predispositions to DIALF.MethodsWe analysed the potential genetic variants associated with DIALF using the whole exome sequencing data from 75 cases, including 40 non‐Finnish European cases in the pilot study. Chi‐square tests were performed for case–control analysis against the 1000 genomes project as the control. A replication study of 44 DIALF cases that included 24 non‐Finnish Europeans was conducted to validate candidate variants. The association between clinical phenotype and genotypes was analysed using one‐way analysis of variance.ResultsEight variants (rs561037, rs561042, rs608339, rs655260, rs1142886, rs1142888, rs1142889 and rs1142890) in the guanylate binding protein 4 (GBP4) were significantly associated with DIALF in non‐Finnish Europeans in the pilot study and confirmed in the replication study. Rs561037 and rs561042 were highly significant with the lowest allele frequencies in both pilot and replication studies. An association was also found between these variants and milder clinical outcomes, indicated by lower peak levels of ALT, AST and higher Karnofsky performance scores.ConclusionOur study identified eight GBP4 missense variants linked to a lower risk of DIALF in the non‐Finnish European population. The GBP4 protein, activated by interferon‐gamma, plays a critical role in innate immunity. These findings suggest that GBP4 variants might influence immune and inflammatory responses in DIALF, though further studies are needed to elucidate the underlying mechanisms.

Abstract Electroconvulsive therapy (ECT) is an effective treatment for severe depression, especially in treatment-resistant cases. However, its potential cognitive side effects necessitate careful dosing to balance therapeutic benefits and cognitive stability. Recent advances in electric field (E-field) modeling offer promising avenues to optimize ECT dosing. This review synthesizes current knowledge on E-field modeling in ECT and explores its clinical applications. It examines the variability in E-field strengths and distributions induced by ECT and their impact on clinical outcomes. Additionally, the relationship between E-field strengths, neuroplasticity, and therapeutic efficacy is discussed. Translational studies of E-field-informed ECT are highlighted, emphasizing individualized optimal amplitude dosing and potential clinical applications. This review provides useful insights into how E-field modeling can improve the effectiveness of ECT while minimizing adverse effects, helping guide future research and clinical practice.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

Lipoprotein(a) [Lp(a)] is a well-established causal risk factor for cardiovascular diseases (CVDs), as reported by multiple Mendelian randomization studies and large epidemiological studies. When elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect has been reported. However, the current literature is conflicting regarding how Lp(a) interacts in the context of controlled LDL-C levels (e.g., <70 mg/dL) and whether reducing LDL-C can modify the atherogenic effect of Lp(a). In some studies, elevated Lp(a) was still significantly associated with a higher risk of cardiovascular events, despite controlled levels of LDL-C. In contrast, multiple studies have reported attenuation of the cardiovascular risk mediated by elevated Lp(a) with lower LDL-C levels. Moreover, the relationship between Lp(a) and triglycerides, high-density lipoprotein, and very low-density lipoprotein remains unclear. In this literature review, we summarize and discuss the current evidence regarding the interactions between Lp(a) and other lipid molecules, how they contribute to the pathogenesis of CVD, and future perspectives, particularly in the current era where promising targeted Lp(a)-lowering therapies are under development.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

AbstractBackgroundAccumulating evidence indicates that biological sex may influence clinical manifestation within the spectrum of frontotemporal lobar degeneration (FTLD), implying differences in cognitive reserve. Nonetheless, investigations into the impact of biological sex during the preclinical and minimally symptomatic stages of FTLD are lacking.MethodWe included 275 mutation carriers (158 females; 127 with C9orf72, 68 with GRN, and 80 with MAPT mutations) and 161 non‐carrier familial controls (97 females) from the ALLFTD Consortium (Staffaroni et al., Nat Medicine 2022). Participants underwent magnetic resonance imaging (MRI; 348 baseline, 338 longitudinal) and neuropsychological evaluations (394 baseline, 507 longitudinal). Behavioral symptoms were characterized with the Revised Self‐Monitoring Scale (RSMS) and the Neuropsychiatric Inventory (NPI severity scores). MRI‐derived regional volume estimates (RVE) were computed. Cognitive measures and RVE were normalized against sex‐matched controls. Cognitive composites (language, executive function, and visuospatial function) were calculated by averaging raw scores for each domain. Clinical characteristics and RVE comparisons were made between male and female participants. We adopted the residuals approach to explore behavioral and cognitive reserve by fitting a linear regression model for executive z‐scores as the response value and age, education, and RVE as explanatory variables.ResultIn mutation carriers, sex was not a significant differentiator in age, education level, disease severity, or mutation frequency. Most mutation carriers (188, 68%) were asymptomatic or mildly symptomatic at baseline. However, female mutation carriers exhibited significantly lower visuospatial performance at baseline (Cohen's d = ‐0.34, 95% CI[‐0.58, ‐0.09], p=.001). This difference remained significant among asymptomatic GRN mutation carriers (Cohen’s d = ‐0.73, 95% CI[‐1.22, ‐0.23], p=0.003) but not in other mutations. Following the residuals approach, female mutation carriers showed higher executive performance than males for the same amount of both frontotemporal and global atrophy as quantified by RVE (Cohen's d=0.45, 95 % CI[0.22, 0.67], p<.001). The observed higher executive reserve in women was particularly pronounced in C9orf72 carriers (Cohen's d=0.77, 95% CI[0.35, 1.20], p<.001) but not significant in GRN (p=0.48) and MAPT carriers (p=0.07). No differences in behavioral reserve reached statistical significance.ConclusionFemale sex might modulate early cognitive performance and confer higher executive reserve in FTLD mutation carriers.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n=71; hospitalized, n=9, non‐hospitalized, n=62 during the acute infection) and controls (n=50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p=0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n = 71; hospitalized,n = 9,non‐hospitalized,n = 62 during the acute infection) and controls(n = 50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p = 0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

Background: Pulmonary hypertension (PH) is a complex condition associated with significant morbidity and mortality. Traditional diagnostic and management approaches for PH often face limitations, leading to delays in diagnosis and potentially suboptimal treatment outcomes. Artificial intelligence (AI), encompassing machine learning (ML) and deep learning (DL) offers a transformative approach to PH care. Materials and Methods: We systematically searched PubMed, Scopus, and Web of Science for original studies on AI applications in PH, using predefined keywords. Out of more than 500 initial articles, 45 relevant studies were selected. Risk of bias was evaluated using PROBAST (Prediction model Risk of Bias Assessment Tool). Results: This review examines the potential applications of AI in PH, focusing on its role in enhancing diagnosis, disease classification, and prognostication. We discuss how AI-powered analysis of medical data can improve the accuracy and efficiency of detecting PH. Furthermore, we explore the potential of AI in risk stratification, leading to treatment optimization for PH. Conclusions: While acknowledging the existing challenges and limitations and the need for continued exploration and refinement of AI-driven tools, this review highlights the significant promise of AI in revolutionizing PH management to improve patient outcomes.

Bioprosthetic aortic valve degeneration (BAVD) is a significant clinical concern following both transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). The increasing use of bioprosthetic valves in aortic valve replacement in younger patients and the subsequent rise in cases of BAVD are acknowledged in this review which aims to provide a comprehensive overview of the incidence, diagnosis, predictors, and management of BAVD. Based on a thorough review of the existing literature, this article provides an updated overview of the biological mechanisms underlying valve degeneration, including calcification, structural deterioration, and inflammatory processes and addresses the various risk factors contributing to BAVD, such as patient demographics, comorbidities, and procedural variables. The difficulties in early detection and accurate diagnosis of BAVD are discussed with an emphasis on the need for improved imaging techniques. The incidence and progression of BAVD in patients undergoing TAVR versus SAVR are compared, providing insights into the differences and similarities between the two procedures and procedural impacts on valve longevity. The current strategies for managing BAVD, including re-intervention options of redo surgery and valve-in-valve TAVR, along with emerging treatments are discussed. The controversies in the existing literature are highlighted to offer directions for future investigations to enhance the understanding and management of BAVD.