Dysregulated AEBP1 and COLEC12 Genes in Late-Onset Alzheimer's Disease: Insights from Brain Cortex and Peripheral Blood Analysis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive impairment, often accompanied by alterations in mood, confusion, and, ultimately, a state of acute mental disturbance. The cerebral cortex is considered a promising area for investigating the underlying causes of AD by analyzing transcriptional patterns, which could be complemented by investigating blood samples obtained from patients. We analyzed the RNA expression profiles of three distinct areas of the brain cortex, including the frontal cortex (FC), temporal cortex (TC), and entorhinal cortex (EC) in patients with AD. Functional enrichment analysis was performed on the differentially expressed genes (DEGs) across the three regions. The two genes with the most significant expression changes in the EC region were selected for assessing mRNA expression levels in the peripheral blood of late-onset AD patients using quantitative PCR (qPCR). We identified eight shared DEGs in these regions, including AEBP1 and COLEC12, which exhibited prominent changes in expression. Functional enrichment analysis uncovered a significant association of these DEGs with the transforming growth factor-ß (TGF-ß) signaling pathway and processes related to angiogenesis. Importantly, we established a robust connection between the up-regulation of AEBP1 and COLEC12 in both the brain and peripheral blood. Furthermore, we have demonstrated the potential of AEBP1 and COLEC12 genes as effective diagnostic tools for distinguishing between late-onset AD patients and healthy controls. This study unveils the intricate interplay between AEBP1 and COLEC12 in AD and underscores their potential as markers for disease detection and monitoring.

Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5.

Purpose: Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. Methods: Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. Results: Critical age for the initiation of photoreceptor loss ranged from 48 years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25 µm in the extrafoveal retina and 19 µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Conclusions: Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons.

A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with late-onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing, and the resulting isogenic pair of iPSC lines was differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3-dimensional morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant.

Lower mortality risk in APOE4 carriers with normal cognitive ageing.

Abnormal cognitive ageing, including dementia, poses serious challenges to health and social systems in ageing populations. As such, characterizing factors associated with abnormal cognitive ageing and developing needed preventive measures are of great importance. The ε4 allele of the Apolipoprotein E gene (APOE4) is a well-known genetic risk factor for late-onset Alzheimer's disease. APOE4 carriers are also at elevated risk of cardiovascular diseases which are associated with increased risk of cognitive impairment. On the other hand, APOE4 is known to be associated with reduced risk of multiple common types of cancer-a major age-related disease and leading cause of mortality. We conducted the first-ever study of APOE4's opposing effects on cognitive decline and mortality using competing risk models considering two types of death-death with high-amounts versus low-amounts of autopsy-assessed Alzheimer's neuropathology. We observed that APOE4 was associated with decreased mortality risk in people who died with low amounts of Alzheimer's-type neuropathology, but APOE4 was associated with increased mortality risk in people who died with high amounts of Alzheimer's-type neuropathology, a major risk factor of cognitive impairment. Possible preventive measures of abnormal cognitive ageing are also discussed.

Not Just an Intrapartum Problem: Late-Onset Group B Streptococcus Disease.

Group B streptococcal (GBS) infection is a leading cause of neonatal morbidity and mortality globally. While prevention strategies for early onset GBS disease are well established, methods to prevent late-onset GBS disease do not eliminate disease burden, leaving potential for infection, and devastating consequences for affected neonates. Furthermore, the incidence of late-onset GBS has risen in recent years, with preterm infants at the highest risk of infection and death. Meningitis remains the most common and serious complication associated with late onset disease, occurring in 30 percent of cases. The assessment of risk for neonatal GBS infection should not be limited to the birth process or maternal screening results and intrapartum antibiotic prophylaxis treatment status. Horizontal transmission after birth from mothers, caregivers, and community sources has been observed. Late-onset GBS disease and its sequelae remain a significant risk to neonates, and clinicians should be able to recognize the signs and symptoms to provide timely antibiotic therapy. This article discusses of the pathogenesis, risk factors, clinical manifestations, diagnostics, and treatment of neonatal late-onset GBS infection and identifies implications for practicing clinicians.

Clinical presentation, maternal-fetal, and neonatal outcomes of early-onset versus late onset preeclampsia-eclampsia syndrome in a teaching hospital in a low-resource setting: A retrospective cohort study.

BACKGROUND: Pre-eclampsia-eclampsia syndrome remains the leading cause of maternal and neonatal mortality worldwide. Both from pathophysiologic and clinical stand points, early and late onset preeclampsia are thought to be two different disease entities. However, the magnitude of preeclampsia-eclampsia and maternal-fetal and neonatal outcomes of early and late onset preeclampsia are not adequately investigated in resource-limited settings. This study sought to examine the clinical presentation and maternal-fetal and neonatal outcome of these two entities of the disease in Ayder comprehensive specialized hospital, an academic setting in Tigray, Ethiopia, from January 1, 2015-December 31, 2021. METHODS: A retrospective cohort design was employed. The patient charts were reviewed to see the baseline characteristics and their progress from the onset of the disease in the antepartum, intrapartum and postpartum periods. Women who developed pre-eclampsia before 34 weeks of gestation were defined as having early-onset pre-eclampsia, and those who developed at 34 weeks or later were identified as late-onset preeclampsia. We used chi-square, t-test and multivariable logistic regression analyses to determine differences between early- and late onset diseases in terms of clinical presentation, maternal-fetal, and neonatal outcomes. RESULTS: Among the 27,350 mothers who gave birth at the Ayder comprehensive specialized hospital, 1095 mothers had preeclampsia-eclampsia syndrome, with a prevalence of 4.0% (95% CI: 3.8, 4.2)]. Of the 934 mothers analyzed early and late onset diseases accounted for 253 (27.1%) and 681 (72.9%) respectively. Overall, death of 25 mothers was recorded. Women with early onset disease had significant unfavorable maternal outcomes including having preeclampsia with severity features (AOR = 2.92, 95% CI: 1.92, 4.45), liver dysfunction (AOR = 1.75, 95% CI: 1.04, 2.95), uncontrolled diastolic blood pressure (AOR = 1.71, 95% CI: 1.03, 2.84), and prolonged hospitalization (AOR = 4.70, 95% CI: 2.15, 10.28). Similarly, they also had increased unfavorable perinatal outcomes, including the APGAR score at the 5th minute (AOR = 13.79, 95% CI: 1.16, 163.78), low birth weight (AOR = 10.14, 95% CI 4.29, 23.91), and neonatal death (AOR = 6.82, 95% CI: 1.89, 24.58). CONCLUSION: The present study highlights the clinical differences between early versus late onset preeclampsia. Women with early-onset disease are at increased levels of unfavorable maternal outcomes. Perinatal morbidity and mortality were also increased significantly in women with early onset disease. Therefore, gestational age at the onset of the disease should be taken as an important indicator of the severity of the disease with unfavorable maternal, fetal, and neonatal outcomes.

Diagnóstico y manejo en primer nivel de atención de preeclampsia posparto de inicio tardío. Reporte de caso / Diagnosis and management of late-onset postpartum preeclampsia at the first level of care. Case report

Introducción: La hipertensión postparto de inicio tardío se presenta desde las 48 horas hasta las 6 semanas postparto, afectando al 2% de los embarazos relacionados o no con antecedentes de hipertensión gestacional. La preeclampsia posparto tiene una incidencia del 5,7% a las 72 horas del parto y está asociada a varios factores maternos como la edad (≥ 35 años), etnia (negra) y obesidad (IMC ≥ 30), presentando mayor riesgo en embarazos múltiples, madres añosas (mayores de 35 años) hogares con bajos ingresos económicos. Los síntomas más frecuentes de esta patología son cefalea, disnea, trastornos visuales y edema periférico.Objetivo: Describir la experiencia en un centro de salud de atención primaria, el manejo de una paciente diagnosticada de preeclampsia posparto de inicio tardío, así como las caracte-rísticas clínicas y factores de riesgo.Presentación del caso: Se presenta el caso de una paciente indígena de 32 años con antece-dente de parto gemelar quien en su control del puerperio a las 72 horas presentó hipertensión arterial, cefalea frontal, edema periférico y proteinuria estableciéndose el diagnóstico de pree-clampsia posparto de inicio tardío. No fue posible la referencia a un segundo nivel de atención por las características culturales de la paciente por lo cual recibió manejo clínico y tratamiento en el primer nivel de atención presentando una evolución favorable sin complicaciones. Conclusiones y recomendaciones: La hipertensión posparto de inicio tardío es una patolo-gía poco frecuente en el puerperio, infradiagnosticada, con complicaciones cardiovasculares a corto y largo plazo, por lo cual su diagnóstico, diferenciación y manejo debe ser óptimo en base a las recomendaciones existentes.

Introduction: Late-onset postpartum hypertension occurs from 48 hours to 6 weeks pos-tpartum, affecting 2% of pregnancies related or not to a history of gestational hypertension. Postpartum preeclampsia has an incidence of 5.7% at 72 hours postpartum and is associa-ted with several maternal factors such as age (≥ 35 years), ethnicity (black) and obesity (BMI ≥ 30), presenting higher risk in multiple pregnancies, elderly mothers (older than 35 years) low-income households. The most frequent symptoms of this pathology are headache, dysp-nea, visual disturbances and peripheral edema.Objective: To describe the experience in a primary care health center, the management of a patient diagnosed with late-onset postpartum preeclampsia, as well as the clinical characte-ristics and risk factors.Case presentation: We present the case of a 32-year-old indigenous patient with a history of twin birth who in her puerperium control at 72 hours presented arterial hypertension, frontal headache, peripheral edema and proteinuria establishing the diagnosis of late-onset pos-tpartum preeclampsia, after which treatment was initiated at the first level of care, making referral difficult due to cultural characteristics. Conclusions and recomendations: Late-onset postpartum hypertension is an infrequent pathology in the puerperium, underdiagnosed, with short and long-term cardiovascular com-plications, so its diagnosis, differentiation and management should be optimal based on existing recommendations

Cortical gyrification differences between early- and late-onset obsessive-compulsive disorder: neurobiological evidence for neurodevelopmentally distinct subtypes.

BACKGROUND: Identifying more homogenous subtypes of patients with obsessive-compulsive disorder (OCD) using biological evidence is critical for understanding complexities of the disorder in this heterogeneous population. Age of onset serves as a useful subtyping scheme for distinguishing OCD into two subgroups that aligns with neurodevelopmental perspectives. The underlying neurobiological markers for these distinct neurodevelopmental differences can be identified by investigating gyrification changes to establish biological evidence-based homogeneous subtypes. METHODS: We compared whole-brain cortical gyrification in 84 patients with early-onset OCD, 84 patients with late-onset OCD, and 152 healthy controls (HCs) to identify potential markers for early neurodevelopmental deficits using the local gyrification index (lGI). Then, the relationships between lGI in clusters showing significant differences and performance in visuospatial memory and verbal fluency, which are considered trait-related neurocognitive impairments in OCD, were further examined in early-onset OCD patients. RESULTS: The early-onset OCD patients exhibited significantly greater gyrification than those with late-onset OCD patients and HCs in frontoparietal and cingulate regions, including the bilateral precentral, postcentral, precuneus, paracentral, posterior cingulate, superior frontal, and caudal anterior cingulate gyri. Moreover, impaired neurocognitive functions in early-onset OCD patients were correlated with increased gyrification. CONCLUSIONS: Our findings provide a neurobiological marker to distinguish the OCD population into more neurodevelopmentally homogeneous subtypes, which may contribute to the understanding of the neurodevelopmental underpinnings of an etiology in early-onset OCD consistent with the accumulated phenotypic evidence of greater neurodevelopmental deficits in early-onset OCD than in late-onset OCD.

Triple Genetic Diagnosis in a Patient with Late-Onset Leukodystrophy and Mild Intellectual Disability.

We describe the complex case of a 44-year-old man with polycystic kidney disease, mild cognitive impairment, and tremors in the upper limbs. Brain MRI showed lesions compatible with leukodystrophy. The diagnostic process, which included clinical exome sequencing (CES) and chromosomal microarray analysis (CMA), revealed a triple diagnosis: autosomal dominant polycystic kidney disease (ADPKD) due to a pathogenic variant, c.2152C>T-p.(Gln718Ter), in the PKD1 gene; late-onset phenylketonuria due to the presence of two missense variants, c.842C>T-p.(Pro281Leu) and c.143T>C-p.(Leu48Ser) in the PAH gene; and a 915 Kb duplication on chromosome 15. Few patients with multiple concurrent genetic diagnoses are reported in the literature; in this ADPKD patient, genome-wide analysis allowed for the diagnosis of adult-onset phenylketonuria (which would have otherwise gone unnoticed) and a 15q11.2 duplication responsible for cognitive and behavioral impairment with incomplete penetrance. This case underlines the importance of clinical genetics for interpreting complex results obtained by genome-wide techniques, and for diagnosing concurrent late-onset monogenic conditions.

Clinical differences between early-onset and mid-and-late-onset Parkinson's disease: Data analysis of the Hellenic Biobank of Parkinson's disease.

BACKGROUND: Age at onset is one of the most critical factors contributing to the clinical heterogeneity of Parkinson's disease (PD), and available evidence is rather conflicting. OBJECTIVE: The aim of this study is to investigate the clinical differences between early-onset PD (EOPD) and mid-and-late-onset PD (MLOPD) in the Greek population, based on the existing data of the Hellenic Biobank of PD (HBPD). METHODS: HBPD contains information of PD cases from two centers in Greece during 2006-2017. Patients with the A53T mutation in the SNCA gene or mutations in the GBA1 gene were excluded. Associations between clinical characteristics (motor and non-motor symptoms, side of onset, first symptom, motor complications) and MLOPD versus EOPD were explored with a single logistic regression model adjusting for gender, family history of PD, disease and dopaminergic therapy duration, disease severity (UPDRS III), levodopa equivalent daily dose, as well as each of the other clinical characteristics. RESULTS: 675 patients (129 EOPD, 546 MLOPD) were included. EOPD was more frequently associated with dystonia (OR 0.19, 95% CI 0.08-0.50, p < 0.01) and motor complications (0.23, 0.07-0.76, 0.02), compared to MLOPD. Bilateral onset (9.38, 1.05-84.04, 0.045) and autonomic dysfunction (2.31, 1.04-5.11, 0.04) were more frequently associated with MLOPD. CONCLUSIONS: EOPD and MLOPD display distinct clinical profiles, regarding motor and non-motor symptoms, side of onset and motor complications in the Greek population. These differences may reflect diverse pathophysiological backgrounds, potentially attributed to genetic or age-related epigenetic influences.

Analysis of family stigma and socioeconomic factors impact among caregivers of patients with early- and late-onset Alzheimer's disease and frontotemporal dementia.

To the best of our knowledge, there are no research studies about socioeconomic factors, family stigma, and their psychological impact on early-onset dementia caregivers. We assessed the impact of family stigma and socioeconomic factors on psychological outcomes, quality of life (QoL), and caregiver burden among 150 caregivers of patients with early-onset Alzheimer's disease due to E280A mutation in presenilin 1 (EOAD), frontotemporal dementia (FTD), and late-onset Alzheimer's disease (LOAD). Caregivers of patients with EOAD presented a higher frequency of socioeconomic risk factors. Caregivers of FTD presented higher levels of family stigma and a higher prevalence of negative outcomes. We found family stigma to be a more suitable predictor of all outcomes. After adjusting for the type of dementia, dementia stage and behavioral changes, and caregiver age and education, family stigma was the most important factor associated with a higher risk of caregiver burden and a reduction in QoL in terms of energy fatigue and emotional wellbeing among early-onset dementia caregivers.

Late-onset Fabry disease: the cardiac sequela.

We describe a patient with Fabry disease (FD) who initially presented with atrial fibrillation without left ventricular hypertrophy (LVH) 14 years before being correctly diagnosed with FD. In the interim, he survived a myocardial infarction complicated by ventricular fibrillation, and his severe LVH was misdiagnosed as sarcomeric hypertrophic cardiomyopathy. In the following 4 years, he developed proteinuric kidney disease, neuropathy, sensorineural hearing loss and gastrointestinal symptoms. The patient was eventually readmitted for an overt heart failure (HF) exacerbation and was seen by an HF cardiologist. The constellation of systemic findings led to further diagnostic testing, including an endomyocardial biopsy, tests to determine alpha-galactosidase A enzyme activity and α-galactosidase A gene (GLA) analysis. The results of the patient's tests were consistent with FD and he was started on enzyme replacement therapy. To our knowledge, this is the first detailed description of a late-onset phenotype of FD with c.146 G>C GLA variant. In addition, this case serves as a potent reminder to pay meticulous attention to 'red flags' accompanying LVH.

Epidemiological and clinical characteristics of patients with late-onset Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jacob disease (CJD) is a fatal neuro-degenerative disease, characterized by rapid and intense deterioration, mainly cognitive, leading to death. The typical onset of the disease is around the age of 67. PURPOSE: To characterize the demographic and clinical features of the population of CJD patients with late-onset disease. METHODS: In this retrospective study, the Israeli national database of prion diseases was screened for CJD patients with disease age of onset > 80 years between 1960 and 2016. Patient's demographic and clinical data were collected including sex, type of disease (sporadic/ genetic), clinical presentation, lab results including tau protein level, imaging, and EEG characteristics. Then, the clinical and demographic data of patients with late onset (> 80 years) (L) and patients with usual age of onset (< 80 years) (U) were compared. RESULTS: The study included 728 patients, 23 patients (3.3%) with late-onset disease (82.2.4±4 years, range 80-88) and 705 with usual disease onset (61.31 ± 9.47 years, range 34-80). Sporadic CJD was more common in the late-onset group (18/23 patients (78.2%) (L) vs. 256/705 patients (36.3%) (U)) (p = 0.0001, chi-square test). Classical EEG finding of periodic sharp wave activity were seen more often in the late-onset patients (55% (L) vs. 32.5% (U)) (p = 0.05, chi-square test). The rest of the demographic and clinical features were similar in both groups. CONCLUSION: Late- and usual-onset diseases are similar in most of demographic and clinical features suggesting a common disease type with normal distribution of age of onset.

Pontocerebellar atrophy is the hallmark neuroradiological finding in late-onset Tay-Sachs disease.

PURPOSE: Late-onset Tay-Sachs disease (LOTS) is a form of GM2 gangliosidosis, an autosomal recessive neurodegenerative disorder characterized by slowly progressive cerebellar ataxia, lower motor neuron disease, and psychiatric impairment due to mutations in the HEXA gene. The aim of our work was to identify the characteristic brain MRI findings in this presumably underdiagnosed disease. METHODS: Clinical data and MRI findings from 16 patients (10F/6 M) with LOTS from two centers were independently assessed by two readers and compared to 16 age- and sex-related controls. RESULTS: Lower motor neuron disease (94%), psychiatric symptoms-psychosis (31%), cognitive impairment (38%) and depression (25%)-and symptoms of cerebellar impairment including dysarthria (94%), ataxia (81%) and tremor (69%), were the most common clinical features. On MRI, pontocerebellar atrophy was a constant finding. Compared to controls, LOTS patients had smaller mean middle cerebellar peduncle diameter (p < 0.0001), mean superior cerebellar peduncle diameter (p = 0.0002), mesencephalon sagittal area (p = 0.0002), pons sagittal area (p < 0.0001), and larger 4th ventricle transversal diameter (p < 0.0001). Mild corpus callosum thinning (37.5%), mild cortical atrophy (18.8%), and white matter T2 hyperintensities (12.5%) were also present. CONCLUSION: Given the characteristic clinical course and MRI findings of the pontocerebellar atrophy, late-onset Tay-Sachs disease should be considered in the differential diagnosis of adult-onset cerebellar ataxias.

First Description of Late-Onset Autoinflammatory Disease Due to Somatic NLRC4 Mosaicism.

OBJECTIVE: Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late-onset uncharacterized autoinflammatory disease. METHODS: Genetics studies were performed using Sanger sequencing and next-generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. RESULTS: We studied a 57-year-old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti-interleukin-1 (anti-IL-1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease-associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2-4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL-18. CONCLUSION: Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain-of-function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult-onset uncharacterized autoinflammatory disease.

Differential Involvement of the Locus Coeruleus in Early- and Late-Onset Alzheimer's Disease: A Potential Mechanism of Clinical Differences?

Sporadic early-onset Alzheimer's disease (sEOAD) is often associated with atypical clinical features, yet the cause of this heterogeneity remains unclear. This study investigated post-mortem atrophy of the locus coeruleus (LC) in sEOAD and late-onset Alzheimer's disease (LOAD). Levels of LC atrophy, as estimated by pathologist-rating of hypopigmentation, were compared between sEOAD (n = 115) and LOAD (n = 672) participants while controlling for other measures of pathological progression. Subsequent analyses compared low vs. high LC atrophy sEOAD subgroups on neuropsychological test performance. Results show nearly 4 times greater likelihood of higher LC atrophy in sEOAD as compared to LOAD (p < .005). sEOAD participants with greater LC atrophy displayed significantly worse performance on various baseline measures of attentional functioning (p < .05), despite similar global cognition (p = .25). These findings suggest the LC is an important potential driver of clinical and pathological heterogeneity in sEOAD.

Serotype distribution and incidence of invasive early onset and late onset group B streptococcal disease amongst infants in Singapore.

BACKGROUND: The current group B streptococcal (GBS) preventive measures had reduced invasive GBS early onset disease (EOD) incidences worldwide, but the late onset disease (LOD) incidences had remained unchanged. Administration of a safe and effective GBS vaccine in addition to the current strategies were thought to be the next steps in reducing the incidences of invasive GBS infection especially LOD. In this study, we aimed to examine the causative GBS serotypes in invasive GBS disease, determine the incidences of EOD and LOD, and compare the risk factors between EOD and LOD. METHODS: A retrospective study of infants ≤ 90-day-old over an 8-year period (2010-2017). The incidences of EOD and LOD were obtained by using patients with EOD and LOD who were born in our institution as the numerator and the live births in our institution per year of the study period as the denominator. Available GBS isolates were serotyped by the National Public Health Laboratory using capsular serotyping methods. The risk factors of EOD and LOD were compared. RESULTS: A total of 71 infants were identified; 16 (22.5%) and 55 (77.5%) of them had EOD and LOD, respectively. Serotype III (n = 42, 71.2%) was the most common serotype amongst the 59 isolates available for serotyping. Serotypes Ia, Ib, II, III, and V accounted for 98.3% (n = 58) of the invasive GBS diseases. The overall incidence was 0.42 per 1000 live births. The mean incidences of EOD and LOD were 0.13 per 1000 live births and 0.29 per 1000 live births, respectively. On multivariate analysis, risk factors for LOD as compared to EOD were: Chinese ethnicity (OR 27.1, 95% CI 3.0-243.1, p = 0.003) and negative/unknown maternal GBS status (OR 20.0, 95% CI 2.0-250.0, p = 0.012). Prematurity and intrapartum risk factors (peripartum maternal pyrexia, prolonged rupture of membrane) of EOD were not associated with LOD. CONCLUSIONS: The LOD incidence had remained higher than EOD incidence in our cohort. A GBS vaccine that covers the major causative serotypes found in our cohort can potentially reduce the overall GBS disease burden in the country.

Health care practitioners' experience-based opinions on providing care after a positive newborn screen for Pompe disease.

The addition of Pompe disease (PD) and other conditions with later-onset forms to newborn screening (NBS) in the United States (US) has been controversial. NBS technology cannot discern infantile-onset PD (IOPD) from later-onset PD (LOPD) without clinical follow-up. This study explores genetic health care practitioners' (HCPs) experiences and challenges providing NBS patient care throughout the US and their resultant opinions on NBS for PD. An online survey was distributed to genetic counselors, geneticists, NBS follow-up care coordinators, and nurse practitioners caring for patients with positive NBS results for PD. Analysis of 78 surveys revealed the majority of participating HCPs support inclusion of PD on NBS. Almost all HCPs (93.3%) feel their state has sufficient resources to provide follow-up medical care for IOPD; however, only three-fourths (74.6%) believed this for LOPD. Common barriers included time lag between NBS and confirmatory results, insurance difficulties for laboratory testing, and family difficulties in seeking medical care. HCPs more frequently encountered barriers providing care for LOPD than IOPD (53.9% LOPD identified ≥3 barriers, 31.1% IOPD). HCPs also believe creation of a population of presymptomatic individuals with LOPD creates a psychological burden on the family (87.3% agree/strongly agree), unnecessary medicalization of the child (63.5% agree/strongly agree), and parental hypervigilance (68.3% agree/strongly agree). Opinions were markedly divided on the use of reproductive benefit as a justification for NBS. Participants believe additional education for pediatricians and other specialists would be beneficial in providing care for patients with both IOPD and LOPD, in addition to the creation of evidence-based official guidelines for care and supportive resources for families with LOPD.

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer's disease. This gene contains a (GGC)13, spanning its core promoter and 5' untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.

Neurodevelopmental Outcomes at 18-24 Months of Corrected Age in Very Low Birth Weight Infants with Late-onset Sepsis.

BACKGROUND: Preterm infants are prone to sepsis owing to their immature innate immunity and prolonged hospitalization. We aimed to evaluate the association between late-onset sepsis (LOS) during hospitalization and neurodevelopmental delay at 18-24 months of corrected age in very low birth weight infants (VLBWIs), and to ascertain this association when adjusted for perinatal risk factors. METHODS: This is a population-based study of VLBWIs born at 23-32 weeks of gestation between January 2014 and December 2017 who were enrolled in the Korean Neonatal Network. Bayley scales of infant development were evaluated at 18-24 months of corrected age in 2,098 infants. To test for LOS as a risk factor for neurodevelopmental delay, multiple logistic regression was used and adjusted for parental education status and clinical variables. RESULTS: Blood culture positive LOS was identified in 419 (20.0%) infants. Cognitive and motor delays were found in 392 (18.7%) and 347 (16.5%) infants, respectively. When multivariate analysis was performed, LOS had a significant association with cognitive delay (odds ratio, 1.48; 95% confidence interval, 1.02-2.16), but no association with motor delay in VLBWIs. Both delays were significantly more frequent in cases of intraventricular hemorrhage (IVH) ≥ grade 3, periventricular leukomalacia (PVL), and intrauterine growth restriction (IUGR) and duration of mechanical ventilation. Male sex and necrotizing enterocolitis ≥ grade 2 had an effect on motor delay, whereas paternal college graduation affected cognitive delay. CONCLUSION: In VLBWIs with LOS, there is a heightened risk of cognitive delays at 18-24 months of corrected age. Brain injury, such as severe IVH and PVL, duration of mechanical ventilation, and IUGR, were also associated with cognitive and motor delays.