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1.
Adv Mater ; : e2401838, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38748700

RESUMO

The advent of 2D ferroelectrics, characterized by their spontaneous polarization states in layer-by-layer domains without the limitation of a finite size effect, brings enormous promise for applications in integrated optoelectronic devices. Comparing with semiconductor/insulator devices, ferroelectric devices show natural advantages such as non-volatility, low energy consumption and high response speed. Several 2D ferroelectric materials have been reported, however, the device implementation particularly for optoelectronic application remains largely hypothetical. Here, the linear electro-optic effect in 2D ferroelectrics is discovered and electrically tunable 2D ferroelectric metalens is demonstrated. The linear electric-field modulation of light is verified in 2D ferroelectric CuInP2S6. The in-plane phase retardation can be continuously tuned by a transverse DC electric field, yielding an effective electro-optic coefficient rc of 20.28 pm V-1. The CuInP2S6 crystal exhibits birefringence with the fast axis oriented along its (010) plane. The 2D ferroelectric Fresnel metalens shows efficacious focusing ability with an electrical modulation efficiency of the focusing exceeding 34%. The theoretical analysis uncovers the origin of the birefringence and unveil its ultralow light absorption across a wide wavelength range in this non-excitonic system. The van der Waals ferroelectrics enable room-temperature electrical modulation of light and offer the freedom of heterogeneous integration with silicon and another material system for highly compact and tunable photonics and metaoptics.

2.
Expert Opin Drug Saf ; : 1-8, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38700323

RESUMO

OBJECTIVE: Elagolix is approved for the treatment of moderate-to-severe pain associated with endometriosis. However, the long-term safety of elagolix in a large sample of real-world patients is unknown. METHODS: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports were collected and analyzed from January 2019 to June 2023. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of elagolix-related adverse events (AEs). RESULTS: After removing the non-drug-related AE signals, we detected several AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes, which were known during the clinical trial phase. In addition to this, we detected several unexpected important AEs that were not mentioned in the drug insert, including cystitis interstitial, parosmia, and epiploic appendagitis. The median onset time of elagolix-associated AEs was 28.5 days. CONCLUSION: Our study provides a comprehensive picture of the safety of elagolix in the post-marketing setting, while also identifying potential new AE signals. These findings emphasize the importance of continued monitoring of the potential risks of elagolix.

3.
Tzu Chi Med J ; 36(2): 188-194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38645787

RESUMO

Objective: Although pulmonary rehabilitation and regular exercise have improved negative emotions and cognitive capacity within cases of chronic obstructive pulmonary disease (COPD), influence by exercise training upon different cognitive and memory functions in COPD is still controversial. This investigation aimed to assess whether cognitive performance and mental health are affected by the benefits of exercise training within cases of COPD. Materials and Methods: This pilot investigation included thirty-three patients with Global Initiative for Chronic Obstructive Lung Disease stage ≥B. Based on the subjects' rights, all included patients could choose to join either the exercise group or the control group, according to their free will. Twelve patients were assigned to receive exercise treatment over a 2-month period, while the remaining 16 patients were assigned to the control group. Cognitive capacity outcomes were measured using the Wechsler Memory Scale-III Word List Test, Stroop task, and psychomotor vigilance task (PVT). Mood states were assessed through the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Results: Most cases demonstrated major improvement for BDI and BAI scorings post-60-day therapy. During PVT, the omission rate decreased, while the hit rate increased, indicating an improvement in attention performance. Furthermore, this investigation found a significant increase in immediate verbal and recognition memory for word-list test. However, no major performance shifts were found on Stroop analysis. Conclusion: This investigation demonstrated that a 2-month exercise training program resulted in significant improvement in negative emotions, immediate memory, recognition memory, and attention.

4.
Neuron ; 112(7): 1110-1116.e5, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38301647

RESUMO

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.


Assuntos
Doença de Alzheimer , Humanos , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genótipo , Longevidade/genética
5.
Zookeys ; 1190: 107-119, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38304892

RESUMO

Alidussignatus Pic, 1926 is transferred from Mispila to Souvanna, and Souvannasignata (Pic, 1926), comb. nov. is proposed. The lectotype of Alidussignatus is designated. The following synonyms are proposed: Souvannasignata = Athylia (s. str.) quadristigma (Gressitt, 1940), syn. nov. = Souvannaphoumai Breuning, 1963, syn. nov. = Mispila (Dryusa) coomani Breuning, 1968, syn. nov., Mispila (s. str.) tenuevittata (Pic, 1930) = Mispila (s. str.) assamensis Breuning, 1938, syn. nov. The gender of the holotype of Alidusmultilineatus Pic, 1925 is determined. New distributional records for Souvannasignata, Mispilacurvilinea Pascoe, 1869, M.subtonkinea Breuning, 1968 and M.tenuevittata are provided.

6.
Medicina (Kaunas) ; 60(2)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38399588

RESUMO

Background and Objectives: This study examined whether the decline in people's adoption of personal NPIs (e.g., mask wearing) results from the preclusion by vaccination. This study also incorporates the concepts of risk perception and the risk-as-feelings model to elucidate the possible mechanisms behind this preclusion. Materials and Methods: Two cross-sectional surveys (N = 462 in Survey 1 and N = 505 in Survey 2) were administered before and during the first outbreak of COVID-19 in Taiwan. The survey items were designed to measure participants' perceived severity of COVID-19, worry about COVID-19, intention to adopt personal NPIs, and attitudes toward COVID-19 vaccines. Utilizing the risk perception framework, we conducted multigroup SEM (Structural Equation Modeling) to construct the optimal structural model for both samples. Results and Conclusions: The multigroup SEM results showed that worry (i.e., the emotional component of risk perception) fully mediates the influence of the perceived severity of COVID-19 (i.e., the cognitive component of risk perception) on the intention to adopt NPIs in both surveys [z = 4.03, p < 0.001 for Survey 1 and z = 2.49, p < 0.050 for Survey 2]. Before the outbreak (i.e., Survey 1), people's attitudes toward COVID-19 vaccines showed no significant association with their worry about COVID-19 [z = 0.66, p = 0.508]. However, in Survey 2, following the real outbreak of COVID-19, people's attitudes toward COVID-19 vaccines negatively predicts their worry about COVID-19 [z = -4.31, p < 0.001], indirectly resulting in a negative effect on their intention to adopt personal NPIs. This suggests the occurrence of the Peltzman effect. That is, vaccination fosters a sense of safety, subsequently diminishing alertness to COVID-19, and thus reducing the intention to adopt personal NPIs.


Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinas contra COVID-19/uso terapêutico , Máscaras , Estudos Transversais , Vacinação
7.
Rev Esp Enferm Dig ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38345522

RESUMO

A 14-year-old girl underwent colonoscopy due to repeated flesh-washing watery stools and dull pain around the umbilicus for 10 days. She felt tired for 1 month with no other significant discomfort. The hemoglobin (Hb) is 66g/L, and the red blood cell (RBC) count was 3.24*10^12/L in routine blood tests at admission. Abdominal computed tomography (CT) images showed submucosal tumor (SMT) in the descending colon. The abdominal computed tomography (CT) images showed submucosal tumor (SMT) in the descending colon. The SMT, supplied by the superior and inferior mesenteric arteries, showed significant enhancement at the arterial stage. It did not reveal any bowel wall thickening, enlarged lymph nodes, or ascites, suggesting that the SMT was probably a benign submucosal lesion. The submucosal tumor lesion measured in size 25*25mm located at the descending colon. Endoscopic ultrasonography imaging showed a mixed hyperechoic with a regular edge, originating from the submucosa and closely related to the muscularis propria. There were no evident features of malignancy or metastasis. Endoscopic full-thickness resection (EFR) was carried out for en bloc resection. The tumor was located in the submucosa with a clear boundary and intact capsule. The tumor cells exhibited acinar and nested patterns with abundant thin-walled blood vessels. These tumor cells were epithelioid, displaying abundant clear or eosinophilic cytoplasm. The nuclei were round or oval. Immunohistochemical analysis revealed that the tumor cells showed positive staining for HMB-45 and TFE3, but were negative for SMA.

8.
Acta Neuropathol ; 147(1): 20, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38244079

RESUMO

The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.


Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/genética , Frequência do Gene , Predisposição Genética para Doença , Proteínas de Membrana Transportadoras/genética , Mutação de Sentido Incorreto , Proteínas Relacionadas a Receptor de LDL/genética , Polimorfismo de Nucleotídeo Único
9.
Heart Lung ; 63: 78-85, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37826924

RESUMO

BACKGROUND: Given the ongoing COVID-19 pandemic, it is crucial to prioritize the management of underlying diseases in infected patients, with hypertension being one of the most common conditions. However, there lies a complicated correlation between antihypertensive agents and COVID-19 infection. OBJECTIVES: This study is to systematically evaluate the impact of continuing or discontinuing antihypertensive agents on mortality and infection severity in hospitalized patients with both hypertension and COVID-19. METHODS: A systematic electronic search was conducted on PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov to identify relevant clinical trials published between 1948 and September 2022. Two independent reviewers assessed the quality of the included studies and extracted relevant data. The primary outcome of interest was the relationship between in-hospital mortality and administration of antihypertensive agents. RESULTS: The meta-analysis revealed that continuous administration of antihypertensive agents, compared with discontinuation, significantly reduced in-hospital mortality among hypertension patients with COVID-19 infection [OR=0.49, 95 %CI (0.38, 0.65), p < 0.001, I2=65.3 %]. Specifically, patients receiving ACEI/ARB type agents had even lower mortality rates. Meta-regression analyses were conducted to examine the impact of publication date, sample size, study design, and mean age of the patients, and the results showed that the number of participants in the included studies was the primary source of heterogeneity (p = 0.032). The findings indicated a clear association between the use of antihypertensive agents and reduced mortality in these patients. CONCLUSION: nder the current circumstance of the sustained COVID-19 pandemic, it is recommended to continue the use of antihypertensive agents for patients with hypertension during COVID-19 infection, as it can help reduce the risk of mortality.


Assuntos
COVID-19 , Hipertensão , Humanos , Anti-Hipertensivos/uso terapêutico , COVID-19/complicações , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Pandemias , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia
10.
Micromachines (Basel) ; 14(10)2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37893343

RESUMO

Piezoelectric ceramic actuators utilize an inverse piezoelectric effect to generate high-frequency vibration energy and are widely used in ultrasonic energy conversion circuits. This paper presents a novel drive circuit with input-current shaping (ICS) and soft-switching features which consists of a front AC-DC full-wave bridge rectifier and a rear DC-AC circuit combining a stacked boost converter and a half-bridge resonant inverter for driving a piezoelectric ceramic actuator. To enable ICS functionality in the proposed drive circuit, the inductor of the stacked boost converter sub-circuit is designed to operate in boundary-conduction mode (BCM). In order to allow the two power switches in the proposed drive circuit to achieve zero-voltage switching (ZVS) characteristics, the resonant circuit of the half-bridge resonant inverter sub-circuit is designed as an inductive load. In this paper, a prototype drive circuit for providing piezoelectric ceramic actuators was successfully implemented. Experimental results tested at 110 V input utility voltage show that high power factor (PF > 0.97), low input current total harmonic distortion (THD < 16%), and ZVS characteristics of the power switch were achieved in the prototype drive circuit.

11.
Front Psychol ; 14: 1236006, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37711336

RESUMO

Diversified purchases of consumers can help companies balance sales and inventories, which is of great significance to company profits. While existing research has explored the internal factors and external factors that influence consumers' variety-seeking behavior, little is known about the impact of background music, an important environmental cue in retail establishments, on consumer variety-seeking behavior. The present research investigates the influence of background music tempo on consumer variety-seeking behavior, along with its underlying mechanism and boundary condition. Five experiments revealed that background music tempo affects consumers' variety-seeking behavior (Study 1a, 1b & 4). Specifically, fast-tempo background music increases consumers' variety-seeking behavior (Study 1b). Arousal mediates the main effect (Study 2), as fast-tempo background music increases consumers' variety-seeking behavior by enhancing consumers' arousal. Moreover, participants' familiarity with the background music moderates the impact of background music tempo on consumer variety-seeking behavior (Study 3). Only when consumers have a high degree of familiarity with the background music they listen to, the tempo of the background music will have a significant impact on their variety-seeking behavior. These findings provide important theoretical contributions and management implications.

13.
Genes (Basel) ; 14(8)2023 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-37628615

RESUMO

BACKGROUND: Past studies identified a link between weight loss and dementia, but lacked consistent conclusions. We sought to establish this link by examining the weight change profiles before and after dementia diagnosis. METHODS: Using data from the Health and Retirement Study (1996-2020), we examined 13,123 participants. We conducted a nested case-control analysis to assess differences in biennial weight change profile while controlling for BMI, longevity polygenic risk scores, and APOE gene variants. RESULTS: Participants with a memory disorder lost weight (-0.63%) biennially, whereas those without a diagnosis did not (+0.013%, p-value < 0.0001). Our case-control study shows a significant difference (p-value < 0.01) in pre-dementia % weight changes between the cases (-0.29%) and controls (0.19%), but not in post-dementia weight changes. The weight loss group have the highest risk (OR = 2.01; p-value < 0.0001) of developing a memory disorder compared to the stable weight and weight gain groups. The observations hold true after adjusting for BMI, longevity polygenic risk scores, and APOE variant in a multivariable model. CONCLUSIONS: We observe that weight loss in dementia is a physiological process independent of genetic factors associated with BMI and longevity. Pre-dementia weight loss may be an important prognostic criterion to assess a person's risk of developing a memory disorder.


Assuntos
Demência , Transtornos da Memória , Humanos , Estudos de Casos e Controles , Transtornos da Memória/genética , Redução de Peso/genética , Demência/genética , Apolipoproteínas E/genética
14.
Front Pharmacol ; 14: 1208456, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37645441

RESUMO

Background: Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the treatment of attention deficit/hyperactivity disorder (ADHD). However, a comprehensive analysis of their safety profiles across various age groups and genders in real-world contexts has yet to be conducted. In this study, a pharmacovigilance analysis was performed using the FDA Adverse Event Reporting System (FAERS) database to examine differences in adverse events between methylphenidate, atomoxetine, and Amphetamine. Methods: From January 2014 to September 2022, FAERS reports listing "Methylphenidate," "Dexmethylphenidate," "Atomoxetine," "Amphetamine," "Lisdexamfetamine," "Dextroamphetamine," and "Methamphetamine" as primary suspects were analyzed after removing duplicate reports. We used the standardized Medical Dictionary for Regulatory Activities (MedDRA) query generalized search for adverse events at the preferred term level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals according to the proportional reporting ratio (PRR). In order to delve into potential safety concerns, we undertook a two-step analysis of the data. Initially, the data was segmented based on age cohorts: 0-5 years, 6-12 years, 13-18 years, and individuals aged ≥19 years. Following this, after partitioning the data into males and females within the 0-18 years age group, and similarly for those aged ≥19 years, further analysis was conducted. Results: The pharmacovigilance analysis uncovered substantial safety signals in the standardized MedDRA queries. Methylphenidate was associated with dyskinesia (PRR = 21.15), myocardial infarction (PRR = 12.32), and hypertension (PRR = 8.95) in children aged 0-5, 6-12, and 13-18 years, respectively, as well as neonatal exposures via breast milk (PRR = 14.10) in adults aged ≥19 years. Atomoxetine was linked to hostility/aggression (PRR = 15.77), taste and smell disorders (PRR = 6.75), and hostility/aggression (PRR = 6.74) in children aged 0-5, 6-12, and 13-18 years, respectively, as well as hostility/aggression (PRR = 14.00) in adults aged ≥19 years. Amphetamine was associated with psychosis and psychotic disorders (PRR = 16.78), hostility/aggression (PRR = 4.39), and Other ischaemic heart disease (PRR = 10.77) in children aged 0-5 years, 6-12 years, and 13-18 years, respectively, and hostility/aggression in adults aged ≥19 years (PRR = 9.16). Significant and noteworthy adverse event signals were also identified at the preferred term level. Specifically, methylphenidate was associated with myocardial infarction, acute myocardial infarction, coronary artery dissection, electrocardiogram QT prolonged, growth retardation, self-destructive behavior, suicidal ideation, and completed suicide. Atomoxetine was linked to electrocardiogram QT prolonged, growth retardation, and tic. Amphetamine was recorded for coronary artery dissection, suicidal ideation, and completed suicide. It was observed that male patients, including both children and adults, showed a more significant and frequent occurrence of adverse events compared to females, particularly in terms of cardiac disorders. The intensity and quantity of adverse event signals were distinctly different between the two genders, with males having a higher number of signals. All detected safety signals were confirmed using signals obtained from the disproportionality analysis. Conclusion: This pharmacovigilance analysis demonstrated significant variations in the safety profiles of methylphenidate, atomoxetine, and Amphetamine across different age groups and between different genders. Following an in-depth analysis of the FAERS database, we discerned prominent safety signals. Notably, the strength of the signals associated with coronary artery dissection induced by methylphenidate and amphetamine, as well as those related to suicide, demand particular attention. Consequently, it remains imperative to persist in monitoring these medications, assessing the associated risks, and carrying out comparative studies particularly geared towards ADHD drugs.

15.
medRxiv ; 2023 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-37547016

RESUMO

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of APOE loss-of-function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of older controls and patients with AD and identified six heterozygote carriers of APOE LoF variants. Five carriers were controls (ages 71-90) and one was an AD case with an unremarkable age-at-onset between 75-79. Two APOE ε3/ε4 controls (Subjects 1 and 2) carried a stop-gain affecting the ε4 allele. Subject 1 was cognitively normal at 90+ and had no neuritic plaques at autopsy. Subject 2 was cognitively healthy within the age range 75-79 and underwent lumbar puncture at between ages 75-79 with normal levels of amyloid. The results provide the strongest human genetics evidence yet available suggesting that ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option.

16.
Int J Mol Sci ; 24(13)2023 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-37445616

RESUMO

The Apolipoprotein E (APOE) locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Genótipo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Apolipoproteína E4/genética
17.
bioRxiv ; 2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-37461597

RESUMO

The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset >75 years. All offspring were affected with AD with ages at onset ranging from 53yrs-74yrs. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.

18.
J Alzheimers Dis Rep ; 7(1): 279-297, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37220618

RESUMO

Background: Pathological amyloid-ß and α-synuclein are associated with a spectrum of related dementias, ranging from Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) to Parkinson disease dementia (PDD). While these diseases share clinical and pathological features, they also have unique patterns of pathology. However, epigenetic factors that contribute to these pathological differences remain unknown. Objective: In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant AD (DLBAD), and PDD. Methods: We employed an Illumina Infinium 850k array and RNA-seq to quantify these differences in DNA methylation and transcription, respectively. We then used Weighted Gene Co-Network Expression Analysis (WGCNA) to determine transcriptional modules and correlated these with DNA methylation. Results: We found that PDD was transcriptionally unique and correlated with an unexpected hypomethylation pattern compared to the other dementias and controls. Surprisingly, differences between PDD and DLB were especially notable with 197 differentially methylated regions. WGCNA yielded numerous modules associated with controls and the four dementias: one module was associated with transcriptional differences between controls and all the dementias as well as having significant overlap with differentially methylated probes. Functional enrichment demonstrated that this module was associated with responses to oxidative stress. Conclusion: Future work that extends these joint DNA methylation and transcription analyses will be critical to better understanding of differences that contribute to varying clinical presentation across dementias.

19.
Int J Qual Stud Health Well-being ; 18(1): 2207926, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37166456

RESUMO

PURPOSE: To explore the opinions that baby boomers in Taiwan have about ageing, books written by members of this demographic were taken as the research object. METHODS: A total of 12 books were collected, and a content analysis was used to examine how baby boomers describe old age. RESULTS: Four themes were identified: 1) Greater mental maturity and strength, 2) a decline in the mastery of life, 3) risks related to encountering misfortune in the future, and 4) self-encouragement and vigilance. CONCLUSIONS: Members of the baby boomer generation in Taiwan believe that they can lead a good life in old age through their own efforts, and they tend to emphasize that they should make contributions in their old age. They especially want to show their abilities and dedication to family and maintain a good relationship with their children.


Assuntos
Envelhecimento , Crescimento Demográfico , Criança , Humanos , Taiwan
20.
Hepatol Commun ; 7(5)2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37141513

RESUMO

BACKGROUND: Endoscopy plays an important role in the management of acute variceal bleeding (AVB) in patients with cirrhosis. This study aimed at determining the optimal endoscopy timing for cirrhotic AVB. METHODS: Patients with cirrhosis with AVB across 34 university hospitals in 30 cities from February 2013 to May 2020 who underwent endoscopy within 24 hours were included in this study. Patients were divided into an urgent endoscopy group (endoscopy <6 h after admission) and an early endoscopy group (endoscopy 6-24 h after admission). Multivariable analysis was performed to identify risk factors for treatment failure. Primary outcome was the incidence of 5-day treatment failure. Secondary outcomes included in-hospital mortality, need for intensive care unit, and length of hospital stay. A propensity score matching analysis was performed. In addition, we performed an analysis, in which we compared the 5-day treatment failure incidence and the in-hospital mortality among patients with endoscopy performed at <12 hours and 12-24 hours. RESULTS: A total of 3319 patients were enrolled: 2383 in the urgent endoscopy group and 936 in the early endoscopy group. After propensity score matching, on multivariable analysis, Child-Pugh class was identified as an independent risk factor for 5-day treatment failure (HR, 1.61; 95% CI: 1.09-2.37). The incidence of 5-day treatment failure was 3.0% in the urgent endoscopy group and 2.9% in the early group ( p = 0.90). The in-hospital mortality was 1.9% in the urgent endoscopy group and 1.2% in the early endoscopy group ( p = 0.26). The incidence of need for intensive care unit was 18.2% in the urgent endoscopy group and 21.4% in the early endoscopy group ( p = 0.11). The mean length of hospital stay was 17.9 days in the urgent endoscopy group and 12.9 days in the early endoscopy group ( p < 0.05). The incidence of 5-day treatment failure in the <12-hour group was 2.3% and 2.2% in the 12-24 hours group ( p = 0.85). The in-hospital mortality was 2.2% in the <12-hour group and 0.5% in the 12-24 hours group ( p < 0.05). CONCLUSIONS: The data suggest that performance of endoscopy within 6-12 or within 24 hours of presentation among patients with cirrhosis with AVB led to similar treatment failure outcomes.


Assuntos
Varizes Esofágicas e Gástricas , Hemorragia Gastrointestinal , Humanos , Estudos de Coortes , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/complicações , Estudos Retrospectivos , Cirrose Hepática/complicações , Endoscopia Gastrointestinal
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