bluuebunny/crossref_metadata_2025_split huggingface dataset:
A de novo ACTB gene pathogenic variant in identical twins with phenotypic variation for hydrops and jejunal atresia
Authors: Sibbin Kristina , Yap Patrick , Nyaga Denis , Heller Raoul , Evans Stephen , Strachan Kate , Alburaiky Salam , Nguyen Han M. (Alex) , Hermann‐Le Denmat Sylvie , Ganley Austen R. D. , O'Sullivan Justin M. , Bloomfield Frank H. 
Published: December 2021

AbstractThe beta‐actin gene (ACTB) encodes a ubiquitous cytoskeletal protein, essential for embryonic development in humans. De novo heterozygous missense variants in the ACTB are implicated in causing Baraitser–Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). ACTB pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple‐peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated. Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in ACTB (NM_00101.3:c.1043C>T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild‐type S. cerevisiae strain. There was an obvious growth defect of the yACT1S348L/WT pseudoheterozygote compared to a yACT1WT/WT strain when grown at 22°C but not when grown at 30°C, consistent with the yACT1 S348L variant having a functional defect that is dominant over the wild‐type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins.
The beginnings of the debate between the Mendelians and the Biometricians in psychiatric genetics: David Heron, Karl Pearson, Abraham Rosanoff, and Charles Davenport 1913–1914
Authors: Kendler Kenneth S. 
Published: December 2021

AbstractThe world learned of the heated dispute about the methodology of the early works by Davenport and Rosanoff claiming Mendelian transmission patterns for mental handicap and psychiatric illness in a bold headline in the New York Times on Sunday, November 9, 1913: ENGLISH EXPERT ATTACKS AMERICAN EUGENIC WORK. I here focus on the debate surrounding Rosanoff's 1911 study where he presented evidence that the neuropathic constitution, including, among its manifestations, dementia praecox, and manic‐depressive illness, was an autosomal recessive trait. The “English expert,” David Heron, a student of Pearson's, launched the debate in his 1913 paper which argued that Rosanoff's field work methods were biased, his clinical assessments sloppy, his phenotype far too broad, and his statistical approach flawed. Both Davenport, Rosanoff's mentor, and Rosanoff vigorously defended their methods. Behind this sometimes personal debate was the long simmering controversy about the relative validity of Biometrical genetic (represented by Heron and Pearson) and Mendelian genetic (represented by Rosanoff and Davenport) models for genetic transmission in plants, animals and, especially, humans. A review suggests that most of Heron's criticisms were valid. This episode presages later controversies within psychiatric genetics, for example between twin and linkage researchers in the 1980s and 1990s.
Synthetic Approaches of Aplykurodinone‐1: A Minireview
Authors: Xun Wen , Xu Bo 
Published: December 2021

AbstractAplykurodinone‐1, a marine steroid with intriguing molecular architecture and promising biological activities, has captured the attention of many synthetic chemists. In this paper we have overviewed the synthetic approaches of aplykurodinone‐1 to date, with a focus on the novel strategies utilized to improve the synthetic efficiency. This review summarizes the contribution of different research groups in the total or formal synthesis of aplykurodinone‐1 in either racemic or enantiomeric form.
Benefits of nasal saline treatment in acute rhinosinusitis: Systematic review and meta‐analysis
Authors: Chitsuthipakorn Wirach , Kanjanawasee Dichapong , Hoang Minh P. , Seresirikachorn Kachorn , Snidvongs Kornkiat 
Published: December 2021

AbstractBackgroundAlthough nasal saline treatments are widely used in treating acute rhinosinusitis (ARS), the evidence in adult patients is inconclusive. Our objective was to assess the add‐on benefits of saline treatment in adults with ARS.MethodsLiterature searches were performed (updated May 9, 2021). Randomized, controlled trials studying the effects of nasal saline treatment in adults with ARS were included. Data were pooled for meta‐analysis. Outcomes were composite symptoms score (CSS), disease‐specific quality‐of‐life (DS‐QoL) score, individual symptom score, endoscopy score, saccharin transit time, cure rate, days to resolution, and adverse events.ResultsEleven studies (718 patients) were included in our investigation. Nasal discharge was the only symptom improved (standardized mean difference [SMD], −0.36; 95% confidence interval [CI], −0.66 to −0.05]. Saline as an add‐on treatment brought no benefit to CSS and DS‐QoL score at both time‐points (3‐10 days and at the end of the study). Other outcomes also showed no benefits with use of saline, including endoscopy score, saccharin transit time, cure rate, days to resolution, and adverse events. Subgroup analyses showed improvement in viral ARS patients for CSS (SMD, −0.60; 95% CI, −1.12 to −0.08) and DS‐QoL score (mean difference, −15.90; 95% CI, −31.78 to −0.02), and also in patients using high‐volume saline (SMD, −0.42; 95% CI, −0.78 to −0.06).ConclusionNasal saline as an add‐on treatment improved rhinorrhea. There was no improvement in CSS and DS‐QoL, except among the subgroup of viral ARS patients using high‐volume saline. There were no differences in adverse events between the saline and non‐saline treatments.
Network analysis of the structure and change in the mini‐mental state examination: A nationally representative sample
Authors: Rotstein Anat 
Published: December 2021

AbstractBackgroundThe structure of the Mini‐Mental state examination (MMSE) is inconsistent across factor analytic studies, and yet to be examined based on network analysis. The current study aims to identify the (I) cross‐sectional network structure and (II) longitudinal network changes of the MMSE.MethodThe MMSE was administered to a nationally representative sample of older adults (age 50 and over) in Ireland twice over 4 years (2012–2013: N = 7207; 2016: N = 5715). Psychometric network analysis was computed at each time point to identify the structure, strength and magnitude of the network associations. Item clustering was examined, and modularity scores were computed to measure the overall strength of clustering. Centrality indices were used to identify the main aspects of the MMSE. Longitudinal differences between the networks were examined.ResultCross‐sectionally, the MMSE network structure clustered into a single community with orientation items identified as most central. Longitudinally, the MMSE was time invariant regarding structure, centrality and magnitude of the positive associations between the items. The average magnitude of the negative associations increased over time [(t(65.15) = 3.78, p < 0.001; time 1: M = − 0.59, SD = 0.58 time 2: M = − 1.65, SD = 1.97] as did their percentage.ConclusionNetwork analysis of the MMSE showed that the measure consisted of a single entity of cognitive functioning irrespective of time. Orientation items were repeatedly identified as most central. Longitudinal changes of the network were evident in increased negative associations between selected cognitive components after 4 years of follow‐up. These changes may be explained by neuro‐cognitive compensation processes.
Late‐onset schizophrenia and the competing risks of dementia and death: A national cohort study
Authors: Levine Stephen Z , Weinstein Galit , Rotstein Anat , Goldberg Yair , Reichenberg Abraham , Sandin Sven , Kodesh Arad 
Published: December 2021

AbstractBackgroundKnowledge is limited regarding the association between very‐late onset schizophrenia and the risks of risks of death and dementia. We aimed examine the associations between very‐late onset schizophrenia and the risks of death and dementia.MethodA prospective Israeli cohort study (N=94,120) of persons without either dementia or schizophrenia (2002 to 2012), aged 60 to 90 in 2012, were followed‐up for dementia or death (2013 to 2017). During follow‐up schizophrenia was classified as present from the age of the first ICD‐9 schizophrenia diagnosis, otherwise as absent. The association between schizophrenia and the competing risk of death and dementia was quantified with Hazard Ratios (HR) and their 95% confidence intervals (CI), fitting six competing risk analyses, unadjusted (Unadj.) and adjusted (Adj.) with increasing complexity. We tested the robustness of the results in nine sensitivity analyses.ResultThe group with schizophrenia had higher rates of death (n=61, 18.5% vs. n=7,028, 7.5%, respectively) and dementia (n=64, 19.5% vs. n=5,962, 6.4%, respectively). In the primary analysis, the group with compared to the group without schizophrenia had higher risks of death (Unadj. HR= 3.10, 95% CI = 2.36, 4.06, P <.001; Adj. HR= 2.89, 95% CI = 2.15, 3.89; P<.001) and dementia (Unadj. HR = 3.81, 95% CI = 2.90, 4.99, P <.001; Adj. HR= 2.67, 95% CI = 1.82, 3.91; P<.001). The results remained significant (P <.05) in all sensitivity analyses, including among persons without antipsychotic exposure.ConclusionVery‐late onset schizophrenia was associated with increased death and dementia risks, possibly due to accelerated aging.
Diseases with abnormal HPA function predict CSF pTau but not CSF Abeta 1‐42 in the EPAD longitudinal cohort study
Authors: Gregory Sarah , Ritchie Craig W , Muñiz‐Terrera Graciela 
Published: December 2021

AbstractBackgroundHypothalamic‐pituitary‐adrenal axis (HPAa) dysfunction is associated with progression of cognitive decline in Alzheimer's disease (AD). HPAa abnormalities are also associated with diabetes, obesity, anxiety, depression and traumatic life events, all risk factors for AD. We hypothesised that these risk factors would be associated with AD biomarkers via a latent variable representing HPAa dysfunction.MethodWe recorded diabetes, obesity, anxiety, depression and body mass index (BMI) from medical history in the EPAD LCS v1500.0 dataset (n=1273). Participants completed the State Trait Anxiety Inventory (STAI), Geriatric Depression Scale (GDS) and Swedish National Aging Cohort (SNAC) life events questionnaires. AD biomarkers were CSF Ab1‐42, pTau and hippocampal volume. Covariates were selected if significantly associated with exposure and outcome variables. We used structural equation modelling to test the hypothesis.ResultIn the final model, the following associations were found with the HPAa dysfunction latent variable: diabetes (b= ‐0.38, p<0.05), obesity (b= 0.37, p<0.05) and life events (b= ‐0.15, p<0.05), with an increase in the latent variable associated with a decrease in pTau (b=‐0.13, p<0.05). Life events (b= 0.28, p<0.001), STAI (b= 0.17, p<0.01), GDS (b= 0.13, p<0.05) and BMI (b= ‐0.41, p<0.001) loaded onto the HPAa dysfunction latent variable, with an increase in the latent variable associated with an increase in pTau (b= 0.24, p<0.001). Diabetes (b= ‐0.23, p<0.01), obesity (b= 0.17, p<0.05), anxiety (b= 0.15, p<0.01) and life events (b= ‐0.27, p<0.01) loaded onto the HPAa dysfunction latent variable, with an increase in the latent variable associated with an increase in hippocampal volume (b= 0.25, p<0.01). There were no significant associations between the latent variable and CSF Ab1‐42.ConclusionContinuous measures of depression, anxiety, obesity and trauma are associated with increased CSF pTau via the HPAa dysfunction latent variable in the EPAD LCS v1500.0 dataset, whilst diagnostic categories with known HPAa dysfunction are associated with lower CSF pTau and increased hippocampal volume. Those scoring highly on anxiety, depression, life event scales and with a lower BMI may be a group that benefit from early intervention. Further research is important to understand why the continuous measures of disease were associated with higher AD risk compared to diagnoses.
Development of NLRP3 inhibitors for Alzheimer's disease
Authors: Zhang Shijun , Xu Yiming , Blevins Hallie 
Published: December 2021

AbstractBackgroundNLRP3 inflammasome is a cytosolic and multimeric protein complex that plays essential roles in innate immune responses. Dysregulation of this protein complex has been linked to neuroinflammation and the development of Alzheimer's disease. Therefore, NLRP3 inflammasome represents an attractive target for effective AD treatment development.MethodSmall molecule inhibitors based on a recently identified lead NLRP3 inhibitor were designed, synthesized, and biologically characterized using biochemical and cellular assays. In vivo selectivity and target engagement were also tested using mice and 3xTg AD mice.ResultA series of analogs were successfully synthesized and a new chemical scaffold was also designed to provide NLRP3 inhibitors. Studies in murine macrophages demonstrated that the inhibitory potency can be improved by structural modifications and a new lead compound was identified with an IC50 of 0.1 µM. This lead compound also binds to the recombinant NLRP3 protein with a KD of 0.5 µM. Studies in mice also confirmed that this lead compound is a BBB penetrant. Further in vivo studies demonstrated that this lead compound selectively reduces the IL‐1ß and engage the NLRP3 inflammasome in 3xTg AD mice.ConclusionA new lead NLRP3 inhibitor was identified via medicinal chemistry optimization to show selective inhibition on the NLRP3 inflammasome both in vitro and in vivo. The results strongly encourage further testing of this lead inhibitor for its functional activity in AD mice.
Frequency of preclinical Alzheimer’s disease in Japanese clinical study settings: A meta‐analysis
Authors: Sato Kenichiro , Niimi Yoshiki , Ihara Ryoko , Suzuki Kazushi , Iwata Atsushi , Iwatsubo Takeshi 
Published: December 2021

AbstractBackgroundUnderstanding the accurate frequency of preclinical Alzheimer’s disease (AD), those with positive evidence of amyloid accumulation in brain but without significant cognitive decline, is an important basis of conducting clinical trials for the development of disease‐modifying therapies for AD. Many of earlier studies reporting the frequency of preclinical AD among cognitive normal (CN) individuals have based on the clinical study cohort from Western countries (e.g., 38% in ADNI cohort or 33% in AIBL cohort), and the evidence about the frequency in Asian country cohorts is limited. In Japan, J‐ADNI cohort is one of the few cohorts that published the frequency of preclinical AD: it was 23% in J‐ADNI, to be lower than in ADNI or AIBL. The potential region‐specific difference in the frequency of preclinical AD may have influence on the required number of participants to recruit to AD clinical trials. In this study, we aim to estimate the frequency of preclinical AD in the clinical study settings in Japan, using meta‐analysis by incorporating some additional unpublished Japanese cohort study data.MethodWe reviewed earlier literatures reporting frequency of preclinical AD among CN (CDR‐global = 0) participants, and also reviewed the original data of 4 Japanese cohort study (i.e., AMED‐Preclinical, Brain/Minds Aging Imaging Study, J‐ADNI, and A4 study screening conducted in Japan), and included those who were diagnosed as CN (CDR = 0) at the study participation. These cohort data were meta‐analyzed with random‐effect model.ResultIn total, 238 CN participants in 5 different groups were evaluated, and among them 44 turned out to be amyloid positive. The overall frequency of preclinical AD (of any stage) was estimated as 18% (95% CI: 13‐23%), with the low statistical heterogeneity of I2 = 0% (as plotted on a forest plot in Figure). In meta‐regression while incorporating 14 earlier literature data, being the Japanese cohort had no association with the frequency of preclinical AD (p = 0.305).ConclusionIn the current meta‐analysis, there were no evidence to suggest the frequency of preclinical AD in clinical study settings of Japan is different from that of Western countries.
Stroke and dementia, leading causes of neurological disability and death, potential for prevention
Authors: Avan Abolfazl 
Published: December 2021

AbstractBackgroundStroke and dementia share a number of modifiable risk factors and are the leading cause of disability and the second leading cause of death worldwide, after cardiovascular diseases. We aim to realize the potentially preventable disability and deaths related to ischemic heart disease, stroke and dementia, and their changes from 2010 to 2019.MethodWe report the Global Burden of Disease study (GBD) 2019 estimations for disability‐adjusted life years (DALYs) and death numbers and rates per 100,000 population related to ischemic heart diseases, stroke, and Alzheimer’s disease and other dementias in the world, as well as their risk attributed DALYs and deaths and their changes between 2010 and 2019.ResultIn 2019, neurological disorders have remained globally the leading cause of DALYs (273.1 million) and second leading cause of deaths (9.4 million) after cardiovascular diseases (excluding stroke). Stroke and dementia combined contributed to 87.2% (8.2 million) of neurological deaths and 61.7% (168.5 million) of neurological DALYs in 2019. From 2010 to 2019, the absolute number of deaths and DALYs from ischemic heart disease, stroke, and dementias increased, while their age‐standardized rates decreased (ischemic heart disease: ‐9.7% and ‐9.8%, stroke: ‐14.7% and ‐13.7%, and dementia: ‐1.2% and ‐0.3%, respectively). For stroke, 86.4% of DALYs and for dementias 32.8% of DALYs are attributable to risk factors. Globally, hypertension (54.8%) and unhealthy diet (30.0%) pose the greatest risk for stroke DALYs, and smoking (15.1%) and obesity (12.5%) for dementia DALYs.ConclusionStroke and dementia are increasing in numbers, but show decreasing age‐standardized mortality and disability rates. They account for 62% DALYs and 87% deaths due to neurological diseases, pose risks for each other, offering the possibility of their joint delay, mitigation or prevention. It will require global, population, and individual management to flatten the curve of stroke and dementia.
Staving off dementia through prevention of word retrieval problems in aging
Authors: Jokel Regina , Graham Naida , Somji Imran , Romeril Susan , Ackerman Penina , Piccini Maria Jose 
Published: December 2021

AbstractBackgroundAfter the age of 40, everyone experiences instances of a temporary inability to retrieve a familiar word known as the annoying, and often embarrassing, tip‐of‐the‐tongue (TOT) phenomenon. The frequency of occurrence of TOTs is increased in individuals experiencing language decline associated with Alzheimer's disease. Current research demonstrates that building cognitive reserve may stave off the onset of dementia. Engaging in meaningful activities focused on word retrieval may afford the building of lexical reserve and, consequently, stave off the onset of language decline.Method30 cognitively healthy seniors (65+) engaged in a daily practice with word finding activities on a website built to improve word retrieval. They practiced for one hour on 20 consecutive days. Before and after the daily practice, they completed a category fluency task in which they generated responses to 11 semantic categories. The goal was to evaluate potential benefits of practice on reducing the frequency of TOTs and improving word retrieval abilities.ResultA paired‐samples t‐test performed on pre‐ and post‐intervention data showed a significant improvement in the total score across all categories, suggesting benefits from daily practice.ConclusionThe results suggest that in healthy seniors, engaging in activities focused on word retrieval may improve word finding and reduce TOTs. Ultimately, this could boost cognitive reserve necessary to stave off the onset of language decline in dementia. Practice effects on TOTs in spontaneous speech are currently being analyzed.
Projection of net savings to U.S. state Medicaid programs from reduced nursing home utilization due to an Alzheimer’s treatment
Authors: Mattke Soeren , Lam Jenny , Cho Sang Kyo , Jun Hankyung , Hanson Mark 
Published: December 2021

AbstractBackgroundThe approval of a disease‐modifying Alzheimer’s treatment could provide relief to U.S. state budgets that were hit hard by the COVID‐19 pandemic, as mostly Medicare would cover treatment cost, whereas Medicaid would see savings from reduced nursing home utilization.MethodWe project savings from 2021 to 2040 with a simulation model.ResultTreatments would avoid payments of up to $186 billion for around 1.1 million nursing home patient‐years, an average 5.06% relative reduction of Medicaid spending on nursing home care. Higher per capita savings were projected for older states, those with higher Medicaid payment rates, those with more nursing home residents covered by Medicaid, and those with a lower federal contribution (Figure).ConclusionTreatments would avoid payments of up to $186 billion for around 1.1 million nursing home patient‐years, an average 5.06% relative reduction of Medicaid spending on nursing home care. Higher per capita savings were projected for older states, those with higher Medicaid payment rates, those with more nursing home residents covered by Medicaid, and those with a lower federal contribution.