Disease Onset Research Articles

Clinical characteristics of cystic encephalomalacia in children.

To investigate the primary causes and clinical characteristics of cystic encephalomalacia (CE) in children. The clinical data of 50 children who were admitted to our hospital due to CE between January 2008 and December 2020 were retrospectively reviewed. Their primary causes, clinical manifestations and cranial magnetic resonance imaging features were analyzed. Among all patients, 5 had prematurity, 19 had hypoxic-ischemic encephalopathy (HIE), 13 had intracranial infection, 14 had traumatic brain injury and hemorrhage, 4 had cerebral infarction, 2 had congenital genetic diseases, and 1 had hypoglycemia. The average time from primary disease onset to CE diagnosis was 70.1 ± 61.0 days. The clinical manifestations included speech or motor developmental delay (n = 33), epilepsy (n = 31), dystonia (n = 27), limb paralysis (n = 16), and visual or auditory impairment (n = 5). Patients with HIE as the primary cause of CE had a significantly higher occurrence of dystonia, while a significantly higher incidence of paralysis was observed in those with cerebral infarction as the primary cause. CE in children is mainly caused by HIE, intracranial infection, and cerebral hemorrhage. The major clinical manifestations included speech or motor developmental delay, epilepsy, and dystonia. Magnetic resonance imaging is an important tool for the diagnosis of CE.

The influence of obesity, diabetes mellitus and smoking on fuchs endothelial corneal dystrophy (FECD)

To detect environmental factors, which may be possible risk factors in the disease course of Fuchs’ endothelial corneal dystrophy (FECD). Evaluation of patients with FECD registered in the FECD genetics database of the Center for Ophthalmology, University Hospital Cologne. For the evaluation, disease onset, central corneal thickness, best spectacle corrected visual acuity (BSCVA, logMAR), and modified Krachmer grading (grades 1–6) were correlated with the presence of diabetes mellitus (DM), body mass index (BMI), and smoking behavior. To put the age-related increase in Krachmer grading into perspective, a correction of grading were formed. Depending on the variables studied, differences between groups were examined by Mann–Whitney U test and chi-square test. The significance level was 5%. 403 patients with FECD were included in the analysis. The mean age of the patients was 70.0 ± 10.32 (range 28–96) years. The mean age at diagnosis of those patients was 63.1 ± 13.2 years. The female-to-male ratio was 1.46:1. Patients with a BMI > 30.0 kg/m2 developed FECD significantly earlier than patients with a BMI < 30 kg/m2, p = 0.001. Patients with DM showed significantly more often an Krachmer grade of 5, p = 0.015. Smoking had a negative effect on Krachmer grading (p = 0.024). Using the mediation analysis, the presence of DM correlated Krachmer Grade 5 (p = 0.015), and the presence of DM correlated with BMI > 30.0 kg/m2 (p = 0.012). In addition to smoking and DM our study shows for the first time that obesity may have a negative impact on the development of FECD. Whether dietary interventions and hormones can influence the development or progression of the disease needs to be investigated in future studies.

Lung Ultrasound to Evaluate Fluid Status and Optimize Early Volume-Expansion Therapy in Children with Shiga Toxin-Producing Escherichia Coli-Haemolytic Uremic Syndrome: A Pilot Study.

Background: Shiga toxin-producing Escherichia coli-haemolytic uremic syndrome (STEC-HUS) can result in kidney and neurological complications. Early volume-expansion therapy has been shown to improve outcomes, but caution is required to avoid fluid overload. Lung ultrasound scanning (LUS) can be used to detect fluid overload and may be useful in monitoring hydration therapy. Methods: This prospective observational pilot study involved children with STEC-HUS who were recruited from a regional paediatric nephrology centre. B-line quantification by LUS was used to assess fluid status at the emergency department (ED) admission and correlated with the decrease in patient weight from the target weight. A control group of children on chronic dialysis therapy with episodes of symptomatic fluid overload was also enrolled in order to establish a B-line threshold indicative of severe lung congestion. Another cohort of "healthy" children, without renal or lung-related diseases, and without clinical signs of fluid overload was also enrolled in order to establish a B-line threshold indicative of euvolemia. Results: LUS assessment was performed in 10 children with STEC-HUS at ED admission, showing an average of three B-lines (range 0-10). LUS was also performed in 53 euvolemic children admitted to the ED not showing kidney and lung disease (healthy controls), showing a median value of two B-lines (range 0-7), not significantly different from children with STEC-HUS at admission (p = 0.92). Children with STEC-HUS with neurological involvement during the acute phase and those requiring dialysis presented a significantly lower number of B-lines at admission compared to patients with a good clinical course (p < 0.001). Patients with long-term renal impairment also presented a lower number of B-lines at disease onset (p = 0.03). Conclusions: LUS is a useful technique for monitoring intravenous hydration therapy in paediatric patients with STEC-HUS. A low number of B-lines at ED admission (<5 B-lines) was associated with worse short-term and long-term outcomes. Further studies are needed to determine the efficacy and safety of an LUS-guided strategy for reducing complications in children with STEC-HUS.

Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.

Measuring multi-year changes in the Symbiodiniaceae algae in Caribbean corals on coral-depleted reefs.

Monitoring coral cover can describe the ecology of reef degradation, but rarely can it reveal the proximal mechanisms of change, or achieve its full potential in informing conservation actions. Describing temporal variation in Symbiodiniaceae within corals can help address these limitations, but this is rarely a research priority. Here, we augmented an ecological time series of the coral reefs of St. John, US Virgin Islands, by describing the genetic complement of symbiotic algae in common corals. Seventy-five corals from nine species were marked and sampled in 2017. Of these colonies, 41% were sampled in 2018, and 72% in 2019; 28% could not be found and were assumed to have died. Symbiodiniaceae ITS2 sequencing identified 525 distinct sequences (comprising 42 ITS2 type profiles), and symbiont diversity differed among host species and individuals, but was in most cases preserved within hosts over 3 yrs that were marked by physical disturbances from major hurricanes (2017) and the regional onset of stony coral tissue loss disease (2019). While changes in symbiont communities were slight and stochastic over time within colonies, variation in the dominant symbionts among colonies was observed for all host species. Together, these results indicate that declining host abundances could lead to the loss of rare algal lineages that are found in a low proportion of few coral colonies left on many reefs, especially if coral declines are symbiont-specific. These findings highlight the importance of identifying Symbiodiniaceae as part of a time series of coral communities to support holistic conservation planning. Repeated sampling of tagged corals is unlikely to be viable for this purpose, because many Caribbean corals are dying before they can be sampled multiple times. Instead, random sampling of large numbers of corals may be more effective in capturing the diversity and temporal dynamics of Symbiodiniaceae metacommunities in reef corals.

Advancing Genomics in Urologic Tumors: Navigating Precision Therapeutic Pathways

Urologic cancers, with bladder cancer as a pivotal subtype, pose substantial challenges to global health, necessitating a profound understanding of their molecular underpinnings. This article explores recent genomic research, with a focus on transitional cell carcinoma, the primary histological form of transitional cell carcinoma, aiming to elucidate the intricate molecular processes that underlie the onset and advancement of disease. Leveraging advanced genomic and transcriptomic analyses such as next-generation sequencing (NGS) and molecular subtyping techniques, this review delves into the diverse genetic and molecular subtypes inherent in bladder cancer. It emphasizes the critical role of molecular subtyping in guiding treatment decisions and refining patient stratification for precision medicine approaches. Furthermore, the review examines emerging diagnostic biomarkers such as methylation markers and single nucleotide polymorphism (SNP) sites, highlighting their potential in enabling early detection and targeted therapies. Their integration promises to enhance diagnostic accuracy and therapeutic monitoring in bladder cancer patients. Collaboration among multidisciplinary teams comprising clinicians, researchers, and bioinformaticians is paramount for unraveling the molecular complexities of urologic cancers and advancing personalized cancer care. This thorough review seeks to offer a detailed examination of the existing understanding on urologic oncology, offering valuable insights into the molecular intricacies of urothelial carcinoma and while also laying the groundwork for future research directions aimed at optimizing patient outcomes globally.

Natural history and clinical outcomes of patients with hypertrophic cardiomyopathy from thin filament mutations.

Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM-Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM-Thin to better understand the natural history and clinical outcomes of this disease. A literature review of HCM-Thin identified 21 studies with a total of 177 patients that were suitable for analysis. There were three outcomes of interest, which included a heart failure composite, a ventricular arrhythmia composite and a heart failure and arrhythmia composite outcome. Kaplan-Meier (KM) survival analyses for freedom from each of the abovementioned composite outcomes were completed for the entire cohort and stratified by age of onset and sarcomeric variant. The heart failure composite occurred in 24 (13.6%) patients, the ventricular arrhythmia composite occurred in 30 patients (16.9%) and the combined heart failure and arrhythmia composite occurred in 50 patients (28.2%). In regard to left ventricular ejection fraction (LVEF), the majority of patients were preserved (LVEF>50%) compared with mildly reduced (LVEF 41%-50%) and reduced (LVEF≤40%) (respectively 26.6% vs. 0.6% vs. 3.4%). The median maximal left ventricular wall thickness (LVWT) was 19.0mm [interquartile range (IQR) 5.3]. Only 10.7% of the cohort had evidence of left ventricular outflow tract (LVOT) obstruction. Those with paediatric-onset HCM had earlier onset and were at higher risk for each endpoint than their adult counterparts. When stratified by genetic variant, patients with TNNI3 and TPM1 were at a higher risk of the heart failure composite endpoint and the combined heart failure and arrhythmia composite endpoint in comparison with those with the other genetic variants. HCM-Thin is associated with significant morbidity and mortality, with a high arrhythmia burden despite low rates of cardiac obstruction and mild hypertrophy. The paediatric onset of disease and certain sarcomeric variants appear to be associated with a worse prognosis than their adult-onset and other sarcomeric variant counterparts. HCM-Thin seems to have a distinct phenotype, which may require a different management approach.

Exploring the Dynamic Interplay Between the Human Micro-Biome and Cancer Development, Progress and Therapy

INTRODUCTION: The human microbiome is essential for both promoting health and preventing the onset of disease. The complex association between the microbiome and cancer has been clarified by recent research, which has important ramifications for cancer diagnosis, prevention, and treatment. With an emphasis on possible causes and a discussion of treatment options, this review seeks to investigate the dynamic interplay between the microbiome and the development of cancer. OBJECTIVE: This review aims to explore in detail the complex connection between the human microbiome and the development of cancer. METHODOLOGY: We looked through English-language publications from 2015 onward on Web of Science, PubMed, Medline, Embase and Google Scholar for research on the relationship between the human microbiome and the development of cancer. CONCLUSION: There exist numerous ways by which the human microbiome is crucial to the pathogenesis of cancer.

Efficacy and safety of advanced hybrid closed loop systems in children with type 1 diabetes younger than 6 years.

Tight glycemic control is essential for the normal growth and development of preschool children. The aim of our study was to evaluate the impact of advanced hybrid closed loop (AHCL) systems in a real-life setting in children younger than 6 years. We conducted a two-center prospective study. We enrolled 19 patients with a median age at disease onset of 2.6 years [interquartile range (IQR) 1.6; 4.4] and a median disease duration of 1.4 years (IQR 0.9; 2.8) who were switched to AHCL from multiple daily injections or open-loop insulin therapy and with a 6-month follow-up. Clinical data, sensor glycemic metrics, and pump settings were collected and analyzed. After 6 months of follow-up, there was a significant reduction in median HbA1c (p = 0.0007) and glucose management indicator (p = 0.03). A reduction in both mild (>180 mg/dL) (p = 0.04) and severe (>250 mg/dL) (p = 0.01) hyperglycemia was observed after 1 month of auto mode, and in mild hyperglycemia, it persisted up to 6 months (p = 0.02). A small increase in time below range (<70 mg/dL) was observed (p = 0.04) without a significant difference in time <54 mg/dL (p = 0.73). Time in range increased significantly, reaching a 10% increment (p = 0.03) compared with baseline. A significant reduction in the average sensor glucose was observed (p = 0.01) while coefficient of glucose variability (CV%) remained stable (p = 0.12). No episodes of ketoacidosis or severe hypoglycemia have been recorded. AHCL systems are effective and safe for children younger than 6 years and should be considered as a valid therapeutic option from diabetes onset.

Mind the gap in kidney care: Translating what we know into what we do.

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure,or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay.

Progress on early diagnosing Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions. The disease follows a continuum, starting with preclinical stages, progressing to mild cognitive and behavioral impairment, ultimately leading to dementia. Early detection of AD is crucial for better diagnosis and more effective treatment. However, the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive, and mostly are still not able to detect early disease state. Consequently, there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD. Various non-cognitive manifestations, including behavioral abnormalities, sleep disturbances, sensory dysfunctions, and physical changes, have been observed in the preclinical AD stage before occurrence of notable cognitive decline. Recent research advances have identified several biofluid biomarkers as early indicators of AD. This review focuses on these non-cognitive changes and newly discovered biomarkers in AD, specifically addressing the preclinical stages of the disease. Furthermore, it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.

Biomechanical modeling and imaging for knee osteoarthritis – is there a role for AI?

ObjectiveThis mini review aims to assess the latest advancements in the field of osteoarthritis (OA) research, particularly focusing on the early detection and prediction of disease progression through the use of advanced imaging technologies utilizing biomechanical modeling and artificial intelligence (AI). DesignThe review consolidates and discusses findings from studies that utilize biomechanical modeling and/or machine learning algorithms to identify pathological changes in joint tissues indicative of OA or prediction of disease progression. It also briefly reviews future research and how these methods could be used as a part of OA management. ResultsAI algorithms have proven highly effective in recognizing the subtle changes in joint tissues associated with OA and in identifying patients at high risk for the disease. While these automated tools facilitate early diagnosis, they typically do not provide personalized intervention strategies to prevent disease progression. AI-enhanced biomechanical modeling has the potential to simulate the effects of various conservative interventions (e.g., weight management, optimal footwear, and gait retraining) on slowing OA progression, which could be pivotal for patient engagement and preventive care. ConclusionsThe integration of AI with biomechanical modeling holds significant promise for enhancing the management of OA by not only predicting disease onset and progression but also by enabling personalized intervention plans. Future research should focus on the development of these models to include personalized, preventive strategies that could effectively engage patients and potentially delay or prevent the onset of OA. This approach could revolutionize patient care by making early, targeted intervention feasible.

GBS vaccines in the UK: a round table discussion

Background Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access. Meeting A round-table discussion, held at St George’s University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation. Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (&gt;95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified. Conclusions With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway.

Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69years (mean ± SD)]. Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Risk factors for exfoliation glaucoma - Current evidence and perspectives.

Exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) represent a complex matrix of ocular age-related neurodegenerative changes. Numerous decades of research on this disease entity have highlighted the unique clinical features of ocular protein-complex aggregates, which lead to tissue dysfunction of the ocular outflow channels, leading to irreversible optic nerve damage and glaucoma. While genetic studies have reported several genes associated with XFS and XFG, numerous studies have shown their association with common systemic diseases such as ischemic heart disease, cerebrovascular accidents, and hypertension. Environmental factors are also reported to play a role in the disease pathogenesis by epigenetic control of gene expression and partly explain the difference in the prevalence rates of the disease process. Despite the identification of possible triggers for the disease onset or for the development of glaucoma, the exact mechanisms or the role of several reported risk factors in disease pathogenesis remain a mystery. This review comprehensively evaluated the several risk factors in XFS and XFG while discussing the interactive interplay between the risk factors that determine the disease onset or phenotype in XFS and XFG.

Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review.

Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. A consistent feature of many cases is pulmonary infiltrates, or respiratory failure. This systematic literature review aims to summarise the pulmonary manifestations of IgG4-RD, including clinical outcomes and treatment. This review was registered on PROSPERO (CRD42023416410). Medline, Embase and Cochrane databases were searched for articles discussing IgG4-RD syndrome. Information was extracted on demographics, type and prevalence of pulmonary manifestations, treatment and clinical outcomes. Initially, after deduplication, 3123 articles were retrieved with 18 ultimately included. A pooled total of 724 patients with IgG4-RD were included, 68.6% male, mean age 59.4 years (SD 5.8) at disease onset. The most frequently described pulmonary manifestation was mediastinal lymphadenopathy (n = 186, 48.8%), followed by pulmonary nodules (n = 151, 39.6%) and broncho-vascular thickening (n = 85, 22.3%). Where treatment was reported, the majority of patients received glucocorticoids (n = 211, 93.4%). Other immunosuppressive therapy included cyclophosphamide (n = 31), azathioprine (n = 18), with mycophenolate mofetil (n = 6), rituximab (n = 6), methotrexate (n = 5) and other unspecified immunomodulators (50). Clinical outcomes were reported in 263 patients, where 196 patients had remission of their disease, 20 had relapse, 35 had stable disease, four had progression and eight patients died from complications of IgG4-RD. This systematic review summarises pulmonary manifestations, treatments and outcomes in patients with IgG4-RD. Pulmonary involvement in IgG4-RD is relatively common, leading to high levels of morbidity and mortality. Glucocorticoids remain the mainstay of treatment, but further work is required to explore the management of patients with pulmonary manifestations in association with IgG4-RD.

Causal Associations Between Gut Microbiota, Gut Microbiota-Derived Metabolites, and Alzheimer's Disease: A Multivariable Mendelian Randomization Study.

Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer's disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored. Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods. We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence. Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%). Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect.

Medical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats

The COVID-19 pandemic exposed a global deficiency of systematic, data-driven guidance to identify high-risk individuals. Here, we illustrate the utility of routinely recorded medical history to predict the risk for 1883 diseases across clinical specialties and support the rapid response to emerging health threats such as COVID-19. We developed a neural network to learn from health records of 502,460 UK Biobank. Importantly, we observed discriminative improvements over basic demographic predictors for 1774 (94.3%) endpoints. After transferring the unmodified risk models to the All of US cohort, we replicated these improvements for 1347 (89.8%) of 1500 investigated endpoints, demonstrating generalizability across healthcare systems and historically underrepresented groups. Ultimately, we showed how this approach could have been used to identify individuals vulnerable to severe COVID-19. Our study demonstrates the potential of medical history to support guidance for emerging pandemics by systematically estimating risk for thousands of diseases at once at minimal cost.

Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease.

The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report

BackgroundLipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1–27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness.Case presentationA 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels.ConclusionHerein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.