Tag: pubmed

JAMA Neurol. 2023 Nov 6. doi: 10.1001/jamaneurol.2023.3599. Online ahead of print.

ABSTRACT

IMPORTANCE: Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields.

OBJECTIVE: To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry.

DESIGN, SETTING, PARTICIPANTS: This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies.

MAIN OUTCOMES AND MEASURES: The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses.

RESULTS: Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94).

CONCLUSION AND RELEVANCE: Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

PMID:37930705 | DOI:10.1001/jamaneurol.2023.3599

JAMA Netw Open. 2023 Nov 1;6(11):e2341422. doi: 10.1001/jamanetworkopen.2023.41422.

ABSTRACT

IMPORTANCE: Although hospice care has been covered by health insurance for the purpose of improving the quality of life of patients with terminal cancer as well as their caregivers, few studies have evaluated the outcomes of the policy to cover home-based hospice care services.

OBJECTIVE: To investigate the changes in the place of death of patients with cancer after the introduction of insurance-covered, home-based hospice care services in Korea.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from February 1, 2018, to December 31, 2021, from the Causes of Death Statistics database, released annually by Statistics Korea, which contains information on all deaths in the country. Individuals who died of cancer, a representative hospice-eligible disease, were assigned to the case group, and those who died of dementia, a non-hospice-eligible disease, were assigned to the control group. A total of 218 522 individuals constituted the study population.

EXPOSURE: Because the Korean Health Insurance Service had begun covering home-based hospice care services on September 1, 2020, and the last follow-up date was December 31, 2021, the follow-up periods for before and after intervention were 31 months and 16 months, respectively (preintervention period: February 1, 2018, to August 31, 2020; postintervention period: September 1, 2020 to December 31, 2021).

MAIN OUTCOMES AND MEASURES: The place of death was categorized as a binary variable according to whether it was the person’s own home or not. Comparative interrupted time-series models with segmented regression were applied to analyze the time trend and its change in outcomes.

RESULTS: Of the 218 522 deaths eligible for the analysis (mean [SD] age at death, 78.6 [8.8] years; 130 435 men [59.7%]), 207 459 were due to cancer, and 11 063 were due to dementia. Immediately after the introduction of home-based hospice care, the rate of home deaths was 24.5% higher for patients with cancer than for those with dementia (estimate, 1.245 [95% CI, 1.030-1.504]; P = .02). The difference in the level change between cancer deaths and dementia deaths, on intervention, was more pronounced for those living in rural areas (estimate, 1.320 [95% CI, 1.118-1.558]; P = .001). In addition, a higher educational level was associated with a larger difference in the immediate effect size due to home-based hospice care (low educational level: estimate, 1.205 [95% CI, 1.025-1.416]; P = .02; middle educational level: estimate, 1.307 [95% CI, 0.987-1.730], P = .06; high educational level: estimate, 1.716 [95% CI, 0.932-3.159]; P = .08).

CONCLUSIONS AND RELEVANCE: In this cohort study exploring the changes in the place of death for patients with cancer after the insurance mandates for home-based hospice care in Korea, the probability of patients with cancer dying in their own homes increased after the intervention. This finding suggests the need to broaden the extent of home-based hospice care to honor the autonomy of individuals with terminal illness and improve their quality of death.

PMID:37930703 | DOI:10.1001/jamanetworkopen.2023.41422

JAMA Netw Open. 2023 Nov 1;6(11):e2341516. doi: 10.1001/jamanetworkopen.2023.41516.

ABSTRACT

IMPORTANCE: To date, the diagnostic test completion rate and the time to diagnostic endoscopy or colonoscopy among adults with iron-deficiency anemia (IDA) and/or hematochezia have not been well characterized.

OBJECTIVE: To evaluate the diagnostic test completion rate and the time to diagnostic testing among veterans younger than 50 years with IDA and/or hematochezia.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted within the Veterans Health Administration between October 1, 1999, and December 31, 2019, among US veterans aged 18 to 49 years from 2 separate cohorts: those with a diagnosis of IDA (n = 59 169) and those with a diagnosis of hematochezia (n = 189 185). Statistical analysis was conducted from August 2021 to August 2023.

EXPOSURES: Diagnostic testing factors included age, sex, race and ethnicity, Veterans Health Administration geographic region, and hemoglobin test value (IDA cohort only).

MAIN OUTCOMES AND MEASURES: Primary outcomes of diagnostic testing were (1) bidirectional endoscopy after diagnosis of IDA and (2) colonoscopy or sigmoidoscopy after diagnosis of hematochezia. The association between diagnostic testing factors and diagnostic test completion was examined using Poisson models.

RESULTS: There were 59 169 veterans with a diagnosis of IDA (mean [SD] age, 40.7 [7.1] years; 30 502 men [51.6%]), 189 185 veterans with a diagnosis of hematochezia (mean [SD] age, 39.4 [7.6] years; 163 690 men [86.5%]), and 2287 veterans with IDA and hematochezia (mean [SD] age, 41.6 [6.9] years; 1856 men [81.2%]). The cumulative 2-year diagnostic workup completion rate was 22% (95% CI, 22%-22%) among veterans with IDA and 40% (95% CI, 40%-40%) among veterans with hematochezia. Veterans with IDA were mostly aged 40 to 49 years (37 719 [63.7%]) and disproportionately Black (24 480 [41.4%]). Women with IDA (rate ratio [RR], 0.42; 95% CI, 0.40-0.43) had a lower likelihood of diagnostic test completion compared with men with IDA. Black (RR, 0.65; 95% CI, 0.62-0.68) and Hispanic (RR, 0.88; 95% CI, 0.82-0.94) veterans with IDA were less likely to receive diagnostic testing compared with White veterans with IDA. Veterans with hematochezia were mostly White (105 341 [55.7%]). Among veterans with hematochezia, those aged 30 to 49 years were more likely to receive diagnostic testing than adults younger than 30 years of age (age 30-39 years: RR, 1.15; 95% CI, 1.12-1.18; age 40-49 years: RR, 1.36; 95% CI, 1.33-1.40). Hispanic veterans with hematochezia were less likely to receive diagnostic testing compared with White veterans with hematochezia (RR, 0.96; 95% CI, 0.93-0.98).

CONCLUSIONS AND RELEVANCE: In the cohorts of veterans younger than 50 years with IDA and/or hematochezia, the diagnostic test completion rate was low. Follow-up was less likely among female, Black, and Hispanic veterans with IDA and Hispanic veterans with hematochezia. Optimizing timely follow-up across social and demographic groups may contribute to improving colorectal cancer outcomes and mitigate disparities.

PMID:37930701 | DOI:10.1001/jamanetworkopen.2023.41516

J Womens Health (Larchmt). 2023 Nov 6. doi: 10.1089/jwh.2023.0307. Online ahead of print.

ABSTRACT

Background: We previously examined National Institutes of Health (NIH)-funded randomized controlled trials (RCTs) published in 2004, 2009, and 2015 and found low compliance with NIH policies on inclusion, analysis, and reporting results for female and minoritized subgroups, with no improvement over time. We conducted a fourth wave of data collection using RCTs published in 2021, comparing current results with previous years. Materials and Methods: The authors used PubMed to find 657 RCTs published in print in 14 leading US medical journals in 2021. Of those, 93 (14.2%) were eligible for analysis. We reviewed all parts of eligible studies and any published commentary. Fisher’s exact statistics compared proportions of studies analyzing or reporting results for subgroups in 2021 compared with RCTs studied in previous waves. Posthoc analysis compared eligible RCTs about the Covid-19 pandemic to eligible RCTs on other topics. Results: Twenty-five of 93 studies (26.9%) analyzed or reported outcomes by race or ethnicity, an increase over previous years (p < 0.01). Among 79 RCTs with participants of both sexes, the median proportion of female participants was 43%. Moreover, 34 (43.0%) reported an outcome by sex, included sex as a covariate in statistical analysis, or reported results by sex, also an increase over previous waves (p < 0.01). Eleven eligible studies (11.8%) were on a SARS-CoV-2 topic; there was no difference between SARS-CoV-2 RCTs and RCTs on other topics. Conclusions: Analysis and reporting by sex, race, and ethnicity for NIH-funded RCTs published in 2021 significantly increased from previous waves, despite no corresponding increase in enrollment.

PMID:37930690 | DOI:10.1089/jwh.2023.0307

Chaos. 2023 Nov 1;33(11):113111. doi: 10.1063/5.0136673.

ABSTRACT

We study a two-layer energy balance model that allows for vertical exchanges between a surface layer and the atmosphere. The evolution equations of the surface temperature and the atmospheric temperature are coupled by the emission of infrared radiation by one level, that emission being partly captured by the other layer, and the effect of all non-radiative vertical exchanges of energy. Therefore, an essential parameter is the absorptivity of the atmosphere, denoted εa. The value of εa depends critically on greenhouse gases: increasing concentrations of CO2 and CH4 lead to a more opaque atmosphere with higher values of ϵa. First, we prove that global existence of solutions of the system holds if and only if εa∈(0,2) and blow up in finite time occurs if εa>2. (Note that the physical range of values for εa is (0,1].) Next, we explain the long time dynamics for εa∈(0,2), and we prove that all solutions converge to some equilibrium point. Finally, motivated by the physical context, we study the dependence of the equilibrium points with respect to the involved parameters, and we prove, in particular, that the surface temperature increases monotonically with respect to εa. This is the key mathematical manifestation of the greenhouse effect.

PMID:37930684 | DOI:10.1063/5.0136673

Clin J Am Soc Nephrol. 2023 Nov 6. doi: 10.2215/CJN.0000000000000354. Online ahead of print.

ABSTRACT

BACKGROUND: Use of eGFR to determine preemptive waitlisting eligibility may contribute to racial/ethnic disparities in access to waitlisting, which can only occur when the eGFR falls to <20 mL/min1.73m2. Use of an alternate risk-based strategy for waitlisting (e.g.,a Kidney Failure Risk Equation [KFRE] estimated two-year risk of kidney failure) rather than the standard eGFR threshold for determining waitlist eligibility may reduce these inequities. Our objective was to model the amount of preemptive waittime that could be accrued by race and ethnicity, applying two different strategies to determine waitlist eligibility.

METHODS: Using electronic health record data, linear mixed models were used to compare racial/ethnic differences in preemptive waittime that could be accrued using two strategies: estimating the time between an eGFR<20 and 5 mL/min/1.73 m2 versus time between a 25% 2-year predicted risk of kidney failure (using the KFRE, which incorporates age, sex, albuminuria, and eGFR to provide kidney failure risk estimation) and eGFR of 5 mL/min/1.73 m2.

RESULTS: Among 1,290 adults with CKD stage 4-5, using the CKD-EPI equation yielded shorter preemptive waittime between an eGFR of 20 and 5 mL/min/1.732 in Black (-6.8 months;95%CI -11.7, -1.9), Hispanic (-10.2 months;-15.3,-5.1) and Asian/Pacific Islander patients (-10.3; 95%CI -15.3,-5.4) compared with non-Hispanic White patients. Use of a KFRE threshold to determine waittime yielded smaller differences by race and ethnicity than observed when using a single eGFR threshold, with shorter time still noted for Black (-2.5 months;95%CI-7.8,2.7), Hispanic (-4.8 months; 95% CI -10.3,0.6) and Asian/Pacific Islander individuals (-5.4 months;-10.7,-0.1) compared to non-Hispanic White individuals, but findings only met statistical significance criteria in Asian/Pacific Islander individuals. When we compared potential waittime availability using a KFRE versus eGFR threshold, use of the KFRE yielded more equity in waittime for Black (p=0.02), Hispanic (p=0.002) and Asian/Pacific Islander (p=0.002) patients.

CONCLUSIONS: Use of a risk-based strategy was associated with greater racial equity in waittime accrual compared with use of a standard single eGFR threshold to determine eligibility for preemptive waitlisting.

PMID:37930674 | DOI:10.2215/CJN.0000000000000354

JAMA Neurol. 2023 Nov 6. doi: 10.1001/jamaneurol.2023.3810. Online ahead of print.

ABSTRACT

IMPORTANCE: Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.

OBJECTIVE: To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.

INTERVENTIONS: In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.

MAIN OUTCOMES AND MEASURES: The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.

RESULTS: A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.

CONCLUSIONS AND RELEVANCE: In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03548584.

PMID:37930669 | DOI:10.1001/jamaneurol.2023.3810

Monaldi Arch Chest Dis. 2023 Nov 3. doi: 10.4081/monaldi.2023.2778. Online ahead of print.

ABSTRACT

In cancer treatment, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors are thriving. Activated T lymphocytes expressed PD-1, it works with its ligand PD-L1 to limit T lymphocyte activation and prevent autoimmune disease. The expression of molecular biomarkers and PD-L1 in lung cancer determines the appropriate treatment strategy for patients with lung cancer. The purpose of this study was to look at the prevalence of molecular biomarkers and PD-L1 expression in a large group of Tunisian patients with advanced non-small cell lung cancer. We conducted an observational retrospective study in which medical/treatment history data were extracted retrospectively from medical records and archived tissue samples between January 1st 2019 and December 31st 2021. We gathered 157 patients who had recently been diagnosed with non-small cell lung carcinoma. In 36.9%of the cases, there was no molecular genotyping. EGFR (28.6%), KRAS (5.73%), and ALK gene rearrangement were the most common genotyping mutations (3.8%). ROS1 rearrangement was not present. There was a link between EGFR and gender, HER and age, and KRAS and biopsy tissue origin. Six of the tested cases with PD-L1 met the cut-off (³50%). PD-L1 positivity was more common in solid type adenocarcinoma (1.9%) than in acinar or papillary adenocarcinoma. There were no significant differences in PD-L1 expression across clinical and demographic parameters. High PD-L1 expression and molecular abnormalities were found in 1 case of EGFR, 1 case of BRAF, and 1 case of KRAS (3 cases). All of the other specimens with abnormalities had a PD-L1 <50%. ALK, ROS1, BRAF, KRAS, and MET were found to be significantly associated with PD-L1 expression. Our study is one of the country’s largest, describing a large panel of biomarkers and their clinicopathologic/histopathologic associations in Tunisian lung cancer patients. We have the same molecular profile as European patients with an EGFR mutation, which is not the most common genotype abnormality in Tunisian patients. There is only one mutation at any given time. The expression of PD-L1 is determined by the histologic type and the origin of the biopsy tissue.

PMID:37930659 | DOI:10.4081/monaldi.2023.2778

Clin Rheumatol. 2023 Nov 6. doi: 10.1007/s10067-023-06804-4. Online ahead of print.

ABSTRACT

BACKGROUND: It has been proved that rheumatoid arthritis (RA) patients have high incidence of atrial fibrillation (AF). Nevertheless, whether they have causal relevance is uncertain. This study aimed to explore and verify the authenticity of causal relationship between RA and AF using Mendelian randomization (MR).

METHODS: The genome-wide association study (GWAS) summary data from Biobank Japan Project (BBJ) (RA, 4199 cases and 208,254 controls) were regarded as exposure data and the GWAS data from European Bio-informatics Institute database (EBI) (AF, 15,979 cases and 102,776 controls) as outcome data. The causal effect was appraised by the inverse variance weighted (IVW) method, MR-Egger regression, and weighted median estimator. MR-robust adjusted profile score (MR-RAPS) method was delivered to examine the robustness of causal relationship and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) method to control horizontal (directional) pleiotropy.

RESULTS: The results indicated that RA increased the risk of AF (IVW, the odds ratio (OR) = 1.060; 95% confidence interval (CI), 1.028 to 1.092; p = 1.411 × 10^-4; weighted median, OR = 1.046, 95% CI, 1.002 to 1.093, p = 0.047). The MR analysis also showed this causal effect through all four IVW methods with various statistical algorithms. Both MR-RAPS and MR-PRESSO supported the causality of RA and AF. Also, the MR-PRESSO result indicated the absence of apparent pleiotropy.

CONCLUSION: There is a causal association between RA and AF. RA patients are genetically more vulnerable to AF. This study may contribute to further exploring early clinical prevention and fundamental mechanism of AF in patients with RA. Key Points • We provided some genetic evidence for the causal link between rheumatoid arthritis (RA) and atrial fibrillation (AF) with multiple Mendelian randomization (MR) methods. • RA patients were genetically more vulnerable to AF. • This study partly shed light on latent fundamental mechanisms underlying RA-induced AF and inspired future studies on RA-AF relationship.

PMID:37930596 | DOI:10.1007/s10067-023-06804-4

Psychometrika. 2023 Nov 6. doi: 10.1007/s11336-023-09935-4. Online ahead of print.

ABSTRACT

The key assumption of conditional independence of item responses given latent ability in item response theory (IRT) models is addressed for multistage adaptive testing (MST) designs. Routing decisions in MST designs can cause patterns in the data that are not accounted for by the IRT model. This phenomenon relates to quasi-independence in log-linear models for incomplete contingency tables and impacts certain types of statistical inference based on assumptions on observed and missing data. We demonstrate that generalized residuals for item pair frequencies under IRT models as discussed by Haberman and Sinharay (J Am Stat Assoc 108:1435-1444, 2013. https://doi.org/10.1080/01621459.2013.835660 ) are inappropriate for MST data without adjustments. The adjustments are dependent on the MST design, and can quickly become nontrivial as the complexity of the routing increases. However, the adjusted residuals are found to have satisfactory Type I errors in a simulation and illustrated by an application to real MST data from the Programme for International Student Assessment (PISA). Implications and suggestions for statistical inference with MST designs are discussed.

PMID:37930558 | DOI:10.1007/s11336-023-09935-4