Recovery Dynamics and Prognosis After Dialysis for Acute Kidney Injury.

Importance: The interplay among baseline kidney function, severity of acute kidney disease (AKD), and post-AKD kidney function has significant associations with patient outcomes. However, a comprehensive understanding of how these factors are collectively associated with mortality, major adverse cardiac events (MACEs), and end-stage kidney disease (ESKD) in patients with dialysis-requiring acute kidney injury (AKI-D) is yet to be fully explored. Objective: To investigate the associations of baseline kidney function, AKD severity, and post-AKD kidney function with mortality, MACEs, and ESKD in patients with AKI-D. Design, Setting, and Participants: This nationwide, population-based cohort study of patients with AKI-D was conducted between January 1, 2015, and December 31, 2018, using data from various health care settings included in the Taiwan nationwide population-based cohort database. Data analysis was conducted from April 28, 2022, to June 30, 2023. Exposure: Exposure to severe AKI and baseline and post-AKD kidney function. Main Outcomes and Measures: The primary outcomes were all-cause mortality and incident MACEs, and secondary outcomes were risks of permanent dialysis and readmission. Results: A total of 6703 of 22 232 patients (mean [SD] age, 68.0 [14.7] years; 3846 [57.4%] male) with AKI-D with post-AKD kidney function follow-up and AKD stage data were enrolled. During a mean (SD) 1.2 (0.9) years of follow-up, the all-cause mortality rate was 28.3% (n = 1899), while the incidence rates of MACEs and ESKD were 11.1% (n = 746) and 16.7% (n = 1119), respectively. After adjusting for known covariates, both post-AKD kidney function and baseline kidney function, but not AKD severity, were independently associated with all-cause mortality, MACEs, ESKD, and readmission. Moreover, worse post-AKD kidney function correlated with progressive and significant increases in the risk of adverse outcomes. Conclusions and Relevance: In this cohort study of patients with AKI-D, more than one-quarter of patients died after 1.2 years of follow-up. Baseline and post-AKD kidney functions serve as important factors associated with the long-term prognosis of patients with AKI-D. Therefore, concerted efforts to understand the transition from post-AKD to chronic kidney disease are crucial.

Sodium-Glucose Cotransport Protein 2 Inhibitors in Patients With Type 2 Diabetes and Acute Kidney Disease.

Importance: Sodium-glucose cotransport protein 2 inhibitors (SGLT-2is) have demonstrated associations with positive kidney-related and cardiovascular outcomes in patients with type 2 diabetes. However, the association of SGLT-2is with outcomes among patients with type 2 diabetes and acute kidney disease (AKD) remains unclear. Objective: To examine the long-term associations of SGLT-2is with mortality, major adverse kidney events (MAKEs), and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes and AKD. Design, Setting, and Participants: This cohort study used global health care data (the TriNetX database) spanning from September 30, 2002, to September 30, 2022. Propensity score matching was used to select a cohort of patients, and follow-up was conducted with a maximum duration of 5 years (completed on September 30, 2022) or until the occurrence of an outcome or death. Intervention: The use of SGLT-2is. Main Outcomes and Measures: The primary outcomes measured were mortality, MAKEs, and MACEs. Adjusted hazard ratios (AHR) with 95% CIs were calculated to compare the risks between SGLT-2i users and nonusers, representing the mean treatment effect among the treated patients. Results: A total of 230 366 patients with AKD (mean [SD] age, 67.1 [16.4] years; 51.8% men and 48.2% women) were enrolled in the study, which had a median follow-up duration of 2.3 (IQR, 1.2-3.5) years. Among these, 5319 individuals (2.3%) were identified as SGLT-2i users. Among nonusers, the incidence of mortality was 18.7%, the incidence of MAKEs was 21.0%, and the incidence of MACEs was 25.8%. After propensity score matching, the absolute differences between SGLT-2i users and nonusers for incidence of mortality, MAKEs, and MACEs were 9.7%, 11.5%, and 12.3%, respectively. Based on the treated population, SGLT-2i use was associated with a significantly lower risk of mortality (AHR, 0.69 [95% CI, 0.62-0.77]), MAKEs (AHR, 0.62 [95% CI, 0.56-0.69]), and MACEs (AHR, 0.75 [95% CI, 0.65-0.88]) compared with nonuse. External validation using a multicenter cohort data set of 1233 patients with AKD patients who were SGLT-2i users confirmed the observed beneficial outcomes. Notably, the risk reduction associated with SGLT-2is remained significant even among patients without hypertension, those with advanced chronic kidney disease, and those not receiving other hypoglycemic agents. Conclusions and Relevance: In this cohort study of patients with type 2 diabetes and AKD, administration of SGLT-2is was associated with a significant reduction in all-cause mortality, MAKEs, and MACEs when compared with nonuse, underscoring the importance of SGLT-2is in care after acute kidney injury. These findings emphasize the potential benefits of SGLT-2is in managing AKD and mitigating the risks of major cardiovascular and kidney diseases.

A Qualitative Exploration of Perceived Medication Adherence Determinants Conducted Among Older Adults with HIV and Type 2 Diabetes Mellitus.

Background: People living with HIV (PLWH) are at higher risk of developing type 2 diabetes (T2DM). Both chronic conditions require individuals to adhere to medication regimens, yet few studies have sought to explore medication-taking behaviors among individuals with comorbid HIV and T2DM (HIV+T2DM). Objective: This qualitative study sought to: 1) identify and compare perceived determinants of medication adherence for HIV and, separately, for T2DM, and 2) explore how participants prioritize conditions. Methods: Between October 2022 and January 2023, we conducted in-depth interviews with individuals aged 50 or older, living with comorbid HIV+T2DM. Participants were prescribed oral medications to treat their conditions and had recent clinical measures indicating probable challenges with medication adherence. Interviews with consented participants from a large academic health center in the Midwest were conducted remotely. Questions largely drew from the Theoretical Domains Framework (TDF), a widely used implementation science framework. Additional questions explored the prioritization of conditions. Analysis employed the Framework Method and a side-by-side comparison of key determinants of medication adherence by condition. Results: A total of 19 interviews were audio recorded, transcribed, and analyzed. Participants were an average age of 61, mostly male (89.5%), and Non-Hispanic White (47.4%). Although results revealed many commonalities between perceived determinants of medication adherence for HIV and for T2DM, differences relating to two TDF domains were noted: nature of the behavior (taking medications as prescribed), and motivations and goals. Many participants viewed their conditions as equally important, though they suggested T2DM was more difficult to manage, largely due to lifestyle modifications. Conclusion: As individuals with HIV develop chronic conditions, such as T2DM, they may require additional medication adherence support. Attention should be paid to offering support early. Disease perceptions may differ by condition, and as such, one's motivations to take medication as prescribed may also differ by condition.

A Simple and Affordable Method to Create Nonsense Mutation Clones of p53 for Studying the Premature Termination Codon Readthrough Activity of PTC124.

(1) Background: A premature termination codon (PTC) can be induced by a type of point mutation known as a nonsense mutation, which occurs within the coding region. Approximately 3.8% of human cancer patients have nonsense mutations of p53. However, the non-aminoglycoside drug PTC124 has shown potential to promote PTC readthrough and rescue full-length proteins. The COSMIC database contains 201 types of p53 nonsense mutations in cancers. We built a simple and affordable method to create different nonsense mutation clones of p53 for the study of the PTC readthrough activity of PTC124. (2) Methods: A modified inverse PCR-based site-directed mutagenesis method was used to clone the four nonsense mutations of p53, including W91X, S94X, R306X, and R342X. Each clone was transfected into p53 null H1299 cells and then treated with 50 µM of PTC124. (3) Results: PTC124 induced p53 re-expression in H1299-R306X and H1299-R342X clones but not in H1299-W91X and H1299-S94X clones. (4) Conclusions: Our data showed that PTC124 more effectively rescued the C-terminal of p53 nonsense mutations than the N-terminal of p53 nonsense mutations. We introduced a fast and low-cost site-directed mutagenesis method to clone the different nonsense mutations of p53 for drug screening.

MidCog study: a prospective, observational cohort study investigating health literacy, self-management skills and cognitive function in middle-aged adults.

INTRODUCTION: The lack of definitive means to prevent or treat cognitive impairment or dementia is driving intense efforts to identify causal mechanisms. Recent evidence suggests clinically meaningful declines in cognition might present as early as middle age. Studying cognitive changes in middle adulthood could elucidate modifiable factors affecting later cognitive and health outcomes, yet few cognitive ageing studies include this age group. The purpose of the MidCog study is to begin investigations of less-studied and potentially modifiable midlife determinants of later life cognitive outcomes. METHODS AND ANALYSIS: MidCog is a prospective cohort study of adults ages 35-64, with two in-person interviews 2.5 years apart. Data will be collected from interviews, electronic health records and pharmacy fill data. Measurements will include health literacy, self-management skills, cognitive function, lifestyle and health behaviours, healthcare use, health status and chronic disease outcomes. Associations of health literacy and self-management skills with health behaviours and cognitive/health outcomes will be examined in a series of regression models, and moderating effects of modifiable psychosocial factors.Finally, MidCog data will be linked to an ongoing, parallel cohort study of older adults recruited at ages 55-74 in 2008 ('LitCog'; ages 70-90 in 2023), to explore associations between age, health literacy, self-management skills, chronic diseases, health status and cognitive function among adults ages 35-90. ETHICS AND DISSEMINATION: The Institutional Review Board at Northwestern University has approved the MidCog study protocol (STU00214736). Results will be published in peer-reviewed journals and summaries will be provided to the funders of the study as well as patients.

New-onset diabetes mellitus risk associated with concurrent autonomous cortisol secretion in patients with primary aldosteronism.

Concurrent autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA patients) is not uncommon. This work aimed to determine the effect of cortisol levels on incident new-onset type 2 diabetes mellitus (NODM) in PA patients. Using the prospectively designed observational TAIPAI cohort, the PA patients were grouped by cortisol level after an overnight low-dose dexamethasone suppression test (1-mg DST). Of the 476 PA patients, 387 (43.7% men; mean age 52.8 years) did not have baseline DM. After a mean follow-up of 4.3 ± 2.9 years, 32 patients (8.3%) developed NODM. The cutoff value obtained via a generalized additive model showed that a serum cortisol level ≥ 2.65 µg/dL after 1-mg DST was a risk factor for developing NODM (HR, 3.5, p = 0.031) by Cox proportional- hazards model.. In PA patients with a higher body mass index (>25 kg/m2; HR, 3.16), lower estimated glomerular filtration rate (<90 ml/min/1.73 m2; HR, 3.18), longer hypertension duration (>7 years; HR, 3.34), and higher waist-to-hip ratio (>0.9; HR, 3.07), a concomitant cortisol level ≥ 2.65 µg/dL after 1-mg DST were more likely to develop NODM. The high-cortisol group of patients with aldosterone-producing adenoma (APA) using mineralocorticoid receptor antagonist (MRA) was associated with an increased risk of NODM (HR, 5.72). Our results showed that PA patients with a concomitant cortisol level ≥ 2.65 µg/dL after 1-mg DST, independent of the aldosterone level, had a higher incidence of NODM. Such PA patients should be carefully evaluated and managed to achieve better glucose control and prevent metabolic syndrome.

P63 and P73 Activation in Cancers with p53 Mutation.

The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.

Predialysis serum lactate levels could predict dialysis withdrawal in Type 1 cardiorenal syndrome patients.

BACKGROUND: Renal replacement therapy (RRT) is an effective rescue therapy for Type 1 cardiorenal syndrome (CRS). Previous studies have demonstrated that type 1 CRS patients with severe renal dysfunction were susceptible to sepsis, and that serum lactate has been correlated with the risk of mortality in patients with sepsis. However, the association between serum lactate level and the prognosis of type 1 CRS patients requiring RRT is unknown. METHODS: An inception cohort of 500 type 1 CRS patients who received RRT in a tertiary-care referral hospital in Taiwan from August 2011 to January 2018 were enrolled. The outcomes of interest were dialysis withdrawal and 90-day mortality. The results were further externally validated using sampling data of type 1 CRS patients requiring dialysis from multiple tertiary-care centers. FINDINGS: The 90-day mortality rate was 52.8% and the incidence rate of dialysis withdrawal was 34.8%. Lower pre-dialysis lactate was correlated with a higher rate of dialysis withdrawal and lower rate of mortality. Generalized additive model showed that 4.2 mmol/L was an adequate cut-off value of lactate to predict mortality. Taking mortality as a competing risk, Fine-Gray subdistribution hazard analysis further indicated that a low lactate level (≦ 4.2 mmol/L) was an independent predictor for the possibility of dialysis withdrawal, as also shown in external validation. The interaction of quick Sequential Organ Failure Assessment score and lactate was associated with dialysis dependence in a disease severity-dependent manner. Furthermore, the associations between hyperlactatemia and dialysis dependence were consistent in the patients with and without sepsis. INTERPRETATION: Serum lactate level is accurate and capable of forecasting the prognosis along with qSOFA severity for clinical decision-making for treating type 1 CRS patients. Further studies are needed to validate our results. FUNDING: This study was supported by grants from Taiwan National Science Council [104-2314-B-002-125-MY3,106-2314-B-002-166-MY3,107-2314-B-002-026-MY3], National Taiwan University Hospital [106-FTN20,106-P02,UN106-014,106-S3582,107-S3809,107-T02,PC1246,VN109-09,109-S4634,UN109-041], Ministry of Science and Technology of the Republic of China [MOST106-2321-B-182-002,106-2314-B-182A-064,MOST107-2321-B-182-004,MOST107-2314-B-182A-138, MOST108-2321-B-182-003,MOST109-2321-B-182-001, MOST108-2314-B-182A-027], Chang Gung Memorial Hospital [CMRPG-2G0361,CMRPG-2H0161,CMRPG-2J0261, CMRPG-2K0091], and Ministry of Health and Welfare of the Republic of China [PMRPG-2L0011].

Cigarette Smoking, Alcohol Consumption, and Risk of Alopecia Areata: A Population-Based Cohort Study in Taiwan.

BACKGROUND: The effects of cigarette smoking and alcohol consumption on the risk of alopecia areata (AA) are unclear. OBJECTIVE: The aim was to examine the association of cigarette smoking and alcohol consumption with AA. METHODS: We collected participants from four rounds (2001, 2005, 2009, and 2013) of the Taiwan National Health Interview Survey. Incident AA cases were identified from the National Health Insurance database. RESULTS: Of the 60,055 participants, 154 developed AA during the 647,902 person-years of follow-up. After controlling for confounders, current smokers had a higher risk of incident AA than never smokers [adjusted hazard ratio (aHR) 1.88; 95% confidence interval (CI) 1.22-2.88]. There was a trend toward an increased risk of AA with increasing numbers of years of smoking and cumulative pack-years of smoking among current smokers. The aHRs (95% CIs) of current smokers of > 5 and ≤ 15 cigarettes per day, > 10 and ≤ 20 years of smoking, ≤ 10, and > 10 and ≤ 20 pack-years of smoking were 2.03 (1.17-3.51), 2.25 (1.21-4.18), 1.86 (1.12-3.09), and 2.04 (1.04-4.01), respectively. Conversely, social and regular drinkers had significantly lower risks of AA than never drinkers [aHRs (95% CIs) 0.65 (0.43-0.98) and 0.49 (0.26-0.93), respectively]. CONCLUSION: Current smokers had an increased risk of developing AA, while alcohol consumption was associated with a decreased risk of AA.