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Drugs & Aging Apr 2024Cumulative anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. However, concomitant use of cholinesterase...
BACKGROUND
Cumulative anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. However, concomitant use of cholinesterase inhibitors (ChEIs) and anticholinergic burden can nullify the benefit of the treatment and worsen Alzheimer's disease (AD). A literature gap exists regarding the extent of the cumulative anticholinergic burden and associated risk factors in AD. Therefore, this study evaluated the prevalence and predictors of cumulative anticholinergic burden among patients with AD initiating ChEIs.
METHODS
A retrospective longitudinal cohort study was conducted using the Medicare claims data involving parts A, B, and D from 2013 to 2017. The study sample included older adults (65 years and older) diagnosed with AD and initiating ChEIs (donepezil, rivastigmine, or galantamine). The cumulative anticholinergic burden was calculated based on the Anticholinergic Cognitive Burden scale and patient-specific dosing using the defined daily dose over the 1 year follow-up period after ChEI initiation. Incremental anticholinergic burden levels were dichotomized into moderate-high (sum of standardized daily anticholinergic exposure over a year (TSDD) score ≥ 90) versus low-no (score 0-89). The Andersen Behavioral Model was used as the conceptual framework for selecting the predictors under the predisposing, enabling, and need categories. A multivariable logistic regression model was used to evaluate the predictors of high-moderate versus low-no cumulative anticholinergic burden. A multinomial logistic regression model was also used to determine the factors associated with patients having moderate and high burdens compared to low/no burdens.
RESULTS
The study included 222,064 older adults with AD with incident ChEI use (mean age 82.24 ± 7.29, 68.9% females, 83.6% White). Overall, 80.48% had some anticholinergic burden during the follow-up, with 36.26% patients with moderate (TSDD scores 90-499), followed by 24.76% high (TSDD score > 500), and 19.46% with low (TSDD score 1-89) burden categories. Predisposing factors such as age; African American, Asian, or Hispanic race; and need factors included comorbidities such as dyslipidemia, syncope, delirium, fracture, pneumonia, epilepsy, and claims-based frailty index were less likely to be associated with the moderate-high anticholinergic burden. The factors that increased the odds of moderate-high burden were predisposing factors such as female sex; enabling factors such as dual eligibility and diagnosis year; and need factors such as baseline burden, behavioral and psychological symptoms of dementia, depression, insomnia, urinary incontinence, irritable bowel syndrome, anxiety, muscle spasm, gastroesophageal reflux disease, heart failure, and dysrhythmia. Most of these findings remained consistent with multinomial logistic regression. CONCLUSION: Four out of five older adults with AD had some level of anticholinergic burden, with over 60% having moderate-high anticholinergic burden. Several predisposing, enabling, and need factors were associated with the cumulative anticholinergic burden. The study findings suggest a critical need to minimize the cumulative anticholinergic burden to improve AD care.
Topics: Humans; Female; Aged; United States; Male; Cholinesterase Inhibitors; Alzheimer Disease; Cholinergic Antagonists; Retrospective Studies; Longitudinal Studies; Medicare
PubMed: 38467994
DOI: 10.1007/s40266-024-01103-2 -
Reproductive Biomedicine Online May 2024Does splitting the human chorionic gonadotrophin (HCG) support in IVF cycles triggered by a gonadotrophin-releasing hormone agonist result in a better progesterone... (Randomized Controlled Trial)
Randomized Controlled Trial
RESEARCH QUESTION
Does splitting the human chorionic gonadotrophin (HCG) support in IVF cycles triggered by a gonadotrophin-releasing hormone agonist result in a better progesterone profile?
DESIGN
Randomized controlled three-arm study, performed at the Fertility Clinic, Odense University Hospital, Denmark. Patients with 12-25 follicles ≥12 mm were randomized into three groups: Group 1 - ovulation triggered with 6500 IU HCG; Group 2 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1500 IU HCG on the day of oocyte retrieval (OCR); and Group 3 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1000 IU HCG on the day of OCR and 500 IU HCG on OCR + 5. All groups received 180 mg vaginal progesterone. Progesterone concentrations were analysed in eight blood samples from each patient.
RESULTS
Sixty-nine patients completed the study. Baseline and laboratory data were comparable. Progesterone concentration peaked on OCR + 4 in Groups 1 and 2, and peaked on OCR + 6 in Group 3. On OCR + 6, the progesterone concentration in Group 2 was significantly lower compared with Groups 1 and 3 (P = 0.003 and P < 0.001, respectively). On OCR + 8, the progesterone concentration in Group 3 was significantly higher compared with the other groups (both P<0.001). Progesterone concentrations were significantly higher in Group 3 from OCR + 6 until OCR + 14 compared with the other groups (all P ≤ 0.003). Four patients developed ovarian hyperstimulation syndrome in Group 3.
CONCLUSION
Sequential HCG support after a GnRH agonist trigger provides a better progesterone concentration in the luteal phase.
Topics: Humans; Female; Chorionic Gonadotropin; Gonadotropin-Releasing Hormone; Adult; Embryo Transfer; Progesterone; Pregnancy; Ovulation Induction; Fertilization in Vitro; Pregnancy Rate; Oocyte Retrieval; Luteal Phase
PubMed: 38452605
DOI: 10.1016/j.rbmo.2023.103415 -
Disease Models & Mechanisms Jun 2024P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are...
P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.
Topics: Humans; Adenosine Triphosphatases; Cerebellar Ataxia; Computer Simulation; Genetic Diseases, Inborn; Golgi Apparatus; HEK293 Cells; Intellectual Disability; Mutation; Phospholipid Transfer Proteins; Protein Stability; Protein Transport
PubMed: 38436085
DOI: 10.1242/dmm.050546 -
BMC Genomics Feb 2024Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.
RESULTS
The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10) and rs2228260 within XBP1 (P = 3.68 × 10). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10) and a gene-based association was identified with ERBB4 (P = 1.59 × 10). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.
CONCLUSIONS
Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.
Topics: Female; Humans; Body Mass Index; Genome-Wide Association Study; Overweight; Case-Control Studies; Polycystic Ovary Syndrome; Obesity
PubMed: 38408933
DOI: 10.1186/s12864-024-09990-w -
Critical Care Medicine Jun 2024To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding... (Observational Study)
Observational Study
OBJECTIVES
To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices.
DESIGN
Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022.
SETTING
Ten academic institutions in the United States and Europe.
PATIENTS
Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test.
INTERVENTIONS
Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o2 /F io2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o2 /F io2 ratio less than or equal to 250.
MEASUREMENTS AND MAIN RESULTS
The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006).
CONCLUSIONS
In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.
Topics: Humans; COVID-19; Male; Female; Middle Aged; Prospective Studies; Intubation, Intratracheal; Severity of Illness Index; Aged; Respiration, Artificial; Europe; Organ Dysfunction Scores; Hospital Mortality; United States; SARS-CoV-2; Critical Illness
PubMed: 38391282
DOI: 10.1097/CCM.0000000000006229 -
Alzheimer's & Dementia : the Journal of... Apr 2024Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique...
INTRODUCTION
Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.
METHODS
We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.
RESULTS
We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.
DISCUSSION
MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.
HIGHLIGHTS
Long-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Genetic Predisposition to Disease; Genome-Wide Association Study; Microtubule-Associated Proteins; Polymorphism, Single Nucleotide; Sequence Analysis
PubMed: 38380866
DOI: 10.1002/alz.13718 -
Journal of Immunology Research 2024The immunological signatures driving the severity of coronavirus disease 19 (COVID-19) in Ghanaians remain poorly understood. We performed bulk transcriptome sequencing...
The immunological signatures driving the severity of coronavirus disease 19 (COVID-19) in Ghanaians remain poorly understood. We performed bulk transcriptome sequencing of nasopharyngeal samples from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected Ghanaians with mild and severe COVID-19, as well as healthy controls to characterize immune signatures at the primary SARS-CoV-2 infection site and identify drivers of disease severity. Generally, a heightened antiviral response was observed in SARS-CoV-2-infected Ghanaians compared with uninfected controls. COVID-19 severity was associated with immune suppression, overexpression of proinflammatory cytokines, including , , , and , and activation of pathways involved in keratinocyte proliferation. was among the differentially regulated interferon-stimulated genes in our mild and severe disease cohorts, suggesting that it may play a critical role in SARS-CoV-2 pathogenesis. By comparing our data with a publicly available dataset from a non-African (Indians) (GSE166530), an elevated expression of antiviral response-related genes was noted in COVID-19-infected Ghanaians. Overall, the study describes immune signatures driving COVID-19 severity in Ghanaians and identifies immune drivers that could serve as potential prognostic markers for future outbreaks or pandemics. It further provides important preliminary evidence suggesting differences in antiviral response at the upper respiratory interface in sub-Saharan Africans (Ghanaians) and non-Africans, which could be contributing to the differences in disease outcomes. Further studies using larger datasets from different populations will expand on these findings.
Topics: Humans; COVID-19; Ghana; SARS-CoV-2; Gene Expression Profiling; Epithelium; Antiviral Agents; Transcriptome
PubMed: 38375062
DOI: 10.1155/2024/6668017 -
Journal of Medical Genetics May 2024Pogo transposable element-derived protein with ZNF domain () gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum...
Pogo transposable element-derived protein with ZNF domain () gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the -associated syndrome remain unclear. We screened for sleep implications among individuals with causative variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the regulatory targets, aiming to uncover the molecular pathways that, when disrupted by loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to and its regulatory targets.
Topics: Humans; Neurodevelopmental Disorders; Phenotype; Sleep Wake Disorders; Male; Female; Sleep; Child; Child, Preschool; Circadian Rhythm; DNA-Binding Proteins; Cell Cycle Proteins
PubMed: 38350721
DOI: 10.1136/jmg-2023-109508 -
Histology and Histopathology Jul 2024Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent... (Review)
Review
Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in or . Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to mutations. mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.
Topics: Humans; Congenital Hyperinsulinism; Phenotype; Mutation; Pancreatic Neoplasms; Hyperinsulinism; Insulinoma; Hypoglycemia; Genotype; Genetic Association Studies
PubMed: 38305063
DOI: 10.14670/HH-18-709 -
Research Report (Health Effects... Nov 2023Early ecological studies have suggested a link between air pollution and Coronavirus Diseases 2019 (COVID-19); however, the evidence from individual-level prospective...
INTRODUCTION
Early ecological studies have suggested a link between air pollution and Coronavirus Diseases 2019 (COVID-19); however, the evidence from individual-level prospective cohort studies is still sparse. Here, we have examined, in a general population, whether long-term exposure to air pollution is associated with the risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19, resulting in hospitalization or death and who is most susceptible. We also examined whether long-term exposure to air pollution is associated with hospitalization or death due to COVID-19 in those who have tested positive for SARS-CoV-2.
METHODS
We included all Danish residents 30 years or older who resided in Denmark on March 1, 2020. and followed them in the National COVID-19 Surveillance System until first positive test (incidence), COVID-19 hospitalization, or death until April 26, 2021. We estimated mean levels of nitrogen dioxide (NO), particulate matter with an aerodynamic diameter <2.5 μm (PM), black carbon (BC), and ozone (O) at cohort participants' residence in 2019 by the Danish Eulerian Hemispheric Model/Urban Background Model. We used Cox proportional hazard models to estimate the associations of air pollutants with COVID-19 incidence, hospitalization, and mortality adjusting for age, sex, and socioeconomic status (SES) at the individual and area levels. We examined effect modification by age, sex, SES (education, income, wealth, employment), and comorbidities with cardiovascular disease, respiratory disease, acute lower respiratory infections, diabetes, lung cancer, and dementia. We used logistic regression to examine association of air pollutants with COVID-19-related hospitalization or death among SARS-CoV-2 positive patients, adjusting for age, sex, individual- and area-level SES.
RESULTS
Of 3,721,810 people, 138,742 were infected, 11,270 hospitalized, and 2,557 died from COVID-19 during 14 months of follow-up. We detected strong positive associations with COVID-19 incidence, with hazard ratio (HR) and 95% confidence interval (CI) of 1.10 (CI: 1.05-1.14) per 0.5-μg/m increase in PM and 1.18 (CI: 1.14-1.23) per 3.6-μg/m increase in NO. For COVID-19 hospitalizations and for COVID-19 deaths, corresponding HRs and 95% CIs were 1.09 (CI: 1.01-1.17) and 1.19 (CI: 1.12-1.27), respectively for PM, and 1.23 (CI: 1.04-1.44) and 1.18 (CI: 1.03-1.34), respectively for NO. We also found strong positive and statistically significant associations with BC and negative associations with O. Associations were strongest in those aged 65 years old or older, participants with the lowest SES, and patients with chronic cardiovascular, respiratory, metabolic, lung cancer, and neurodegenerative disease. Among 138,742 individuals who have tested positive for SARS-Cov-2, we detected positive association with COVID-19 hospitalizations (N = 11,270) with odds ratio and 95% CI of 1.04 (CI: 1.01- 1.08) per 0.5-μg/m increase in PM and 1.06 (CI: 1.01-1.12) per 3.6-μg/m increase in NO, but no association with PM with an aerodynamic diameter <10 μm (PM), BC, or O and no association between any of the pollutants and COVID-19 mortality (N = 2,557).
CONCLUSIONS
This large nationwide study provides strong new evidence in support of association between long-term exposure to air pollution and COVID-19.
Topics: Humans; Aged; Nitrogen Dioxide; Prospective Studies; Neurodegenerative Diseases; Environmental Exposure; COVID-19; SARS-CoV-2; Air Pollution; Air Pollutants; Particulate Matter; Cardiovascular Diseases; Incidence; Lung Neoplasms; Denmark
PubMed: 38286761
DOI: No ID Found