Hepatorenal Syndrome in Cirrhosis.

Hepatorenal syndrome (HRS) is a form of kidney dysfunction that characteristically occurs in liver cirrhosis. It is characterized by a marked impairment of kidney function in response to circulatory and hemodynamic alterations that occur in advanced stages of liver cirrhosis, aggravated by systemic inflammation and bacterial translocation. The classical definitions of the types of HRS have been recently revisited and 2 forms of HRS have been redefined: the acute form, referred to as acute kidney injury (HRS-AKI), and the chronic form, referred to as chronic kidney disease. HRS-AKI is one of the most severe forms of AKI in patients with cirrhosis and it consists of an abrupt impairment of kidney function, frequently triggered by an infection, appearing in the setting of advanced decompensated cirrhosis. Differential diagnosis with other causes of AKI is crucial because HRS-AKI requires a specific treatment. Differential diagnosis with AKI-acute tubular necrosis may be challenging and kidney biomarkers may be useful in this setting. Treatment of HRS-AKI is based on the administration of vasoconstrictor drugs in combination with volume expansion with albumin. Prognosis of HRS-AKI is poor, and the ideal definitive treatment consists of liver transplantation or simultaneous liver-kidney transplantation. HRS-AKI has a big impact on patients' quality of life. Management of HRS-AKI remains challenging in specific situations such as alcohol-associated hepatitis or metabolic-associated steatotic liver disease cirrhosis. Developing preventive measures for HRS-AKI, improving its early identification, discovering new biomarkers for differential diagnosis, and improving the response to therapy are some of the unmet needs in the field of HRS-AKI.

Safety, tolerability, and pharmacokinetics of HRS9432(A) injection in healthy Chinese subjects: a phase-I randomized, double-blind, dose escalation, placebo-controlled study.

HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered. Safety was continually monitored, including adverse events, clinical laboratory examinations, vital signs, 12-lead electrocardiograms, and physical examinations, while the pharmacokinetic profile within the body was evaluated. The results indicated that concentrations of HRS9432 peaked immediately after infusion, demonstrating essentially linear pharmacokinetic characteristics within the dosage range of 200-1,200 mg. It exhibited a low clearance rate and an extended half-life, with a clearance of approximately 0.2 L/h, a volume of distribution of around 40 L, and a half-life of approximately 140h following a single dose. The accumulation index for AUC0-τ after multiple doses ranged from 1.41 to 1.75. No severe adverse events occurred during the study, and the severity of all adverse events was mild or moderate. Therefore, the intravenous administration of HRS9432(A) in healthy Chinese adult subjects, either as multiple infusions of 200 to 600 mg (once a week, four doses) or as a single infusion of 900-1,200 mg, demonstrated overall good safety and tolerability. The pharmacokinetic exhibited essentially linear characteristics in the body, supporting a weekly dosing frequency for clinical applications and providing additional options for the treatment or prevention of invasive fungal infections. CLINICAL TRIALS: This study is registered with the International Clinical Trials Registry Platform as ChiCTR2300073525.

Three-dimensional representation of the pure electric-dipole and the mixed first hyperpolarizabilities: The modified unit sphere representation.

In this work, the theory of the modified unit sphere representation (mUSR) has been proposed as a computational tool suitable for the three-dimensional representation of the pure electric-dipole [ ß λ µ ν ( - 2 ω ; ω , ω ) ] as well as of the mixed electric-dipole/magnetic-dipole [ α J λ µ ν ( - 2 ω ; ω , ω ) and ß J λ µ ν ( - 2 ω ; ω , ω ) ] or electric-dipole/electric-quadrupole [ α K λ µ ν o ( - 2 ω ; ω , ω ) and ß K λ µ ν o ( - 2 ω ; ω , ω ) ] first hyperpolarizabilities. These five quantities are Cartesian tensors and they are responsible for the chiral signal in the chiroptical version of the hyper-Rayleigh scattering (HRS) spectroscopy, namely the HRS optical activity (HRS-OA) spectroscopy. For the first time, for each hyperpolarizability, alongside with the three-dimensional representation of the whole (i.e., reducible) Cartesian tensors, the mUSRs are developed for each of the irreducible Cartesian tensors (ICTs) that constitute them. This scheme has been applied to a series of three (chiral) hexahelicene molecules containing different degrees of electron-withdrawing (quinone) groups and characterized by the same (positive) handedness. For these molecules, the mUSR shows that, upon substitution, the most remarkable qualitative and semi-quantitative (enhancement of the molecular responses) effects are obtained for the pure electric-dipole and for the mixed electric-dipole/magnetic-dipole hyperpolarizabilities.

Natural Selection Across Three Generations of Americans.

We investigate natural selection on polygenic scores in the contemporary US, using the Health and Retirement Study. Across three generations, scores which correlate negatively (positively) with education are selected for (against). However, results only partially support the economic theory of fertility as an explanation for natural selection. The theory predicts that selection coefficients should be stronger among low-income, less educated, unmarried and younger parents, but these predictions are only half borne out: coefficients are larger only among low-income parents and unmarried parents. We also estimate effect sizes corrected for noise in the polygenic scores. Selection for some health traits is similar in magnitude to that for cognitive traits.

Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

AIM: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. MATERIALS AND METHODS: This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. RESULTS: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. CONCLUSIONS: HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.

Ultra-processed foods consumption among a USA representative sample of middle-older adults: a cross-sectional analysis.

The study evaluated the association between ultra-processed foods (UPF) and nutrient intake and identified the socio-demographic characteristics associated with UPF consumption among a nationally representative sample of middle-older adults. Dietary assessment was collected in 2013 using a validated FFQ. The Nova system was used to classify food and drinks into UPF. The percentage of dietary energy from UPF was calculated and used throughout the analyses, and average nutrient intake across quintiles of UPF was evaluated. The determinants associated with the dietary caloric contribution of UPF intake were investigated using linear regression models. A cross-sectional analysis of a nationally representative study of Americans over the age of 50, the Health and Retirement Study, was conducted. The analysis included 6220 participants. The mean age was 65 (se 0·28) years, with 55 % being female. UPF intake accounted for 51 % (se 0·25) of total intake. An increase in the percentage of (%UPF) consumption was correlated with an increase in calories, carbohydrates, saturated fat and sugar, and a decrease in fibre, vitamins and minerals. %UPF intake was inversely associated with being Hispanic, higher income, physical activity, vegetarian diet and Mediterranean diet but positively associated with very low food insecurity. UPF represented half of the calories consumed. A higher %UPF intake was associated with a lower nutrient profile, suggesting decreasing %UPF intake as a strategy to improve the nutritional quality of middle-older adults. A few socio-demographic factors were associated with %UPF, which would help in planning strategies to reduce UPF consumption.

Evaluating the health outcomes of aging in place: the role of medicaid aging waiver program on U.S. older adults.

The Medicaid Aging Waiver program (MAW) subsidizes the cost of long-term care (LTC) at home or in communities to satisfy older people's increasing desire to age in place. The MAW program might be health improving for older people by allowing them to age at home. However, less quality and quantity of home-based care comparing to nursing home care could offset some of the potential benefits. I use policy expenditure across states over time linked with detailed health information from the Health and Retirement Study (HRS) to identify the associated effects of MAWs on health outcomes of older adults who are at risk of needing LTC and who are resources constrained to be potentially eligible for Medicaid. Overall, the findings suggest that the MAW program is beneficial to health: a $1,000 increase in MAW spending for each older person results is associated with a 1.4 percent improvement in self-reported health status, a 1.5 percent reduction in functional mobility limitations, a 1.6 percent decrease in Instrumental Activities of Daily Living (IADL) limitations, and a 1.7 percent improvement in negative psychological feelings. For older people who are most likely not eligible for MAWs, such as those who are wealthy or in good health and do not require LTC, these health-improving effects have not been observed.

Rural-urban differences in personality traits and well-being in adulthood.

OBJECTIVE: One large focus of personality psychology is to understand the biopsychosocial factors responsible for adult personality development and well-being change. However, little is known about how macro-level contextual factors, such as rurality-urbanicity, are related to personality development and well-being change. METHOD: The present study uses data from two large longitudinal studies of U.S. Americans (MIDUS, HRS) to examine whether there are rural-urban differences in levels and changes in the Big Five personality traits and well-being (i.e., psychological well-being, and life satisfaction) in adulthood. RESULTS: Multilevel models showed that Americans who lived in more rural areas tended to have lower levels of openness, conscientiousness, and psychological well-being, and higher levels of neuroticism. With the exception of psychological well-being (which replicated across MIDUS and HRS), rural-urban differences in personality traits were only evident in the HRS sample. The effect of neuroticism was fully robust to the inclusion of socio-demographic and social network covariates, but other effects were partially robust (i.e., conscientiousness and openness) or were not robust at all (i.e., psychological well-being). In both samples, there were no rural-urban differences in Big Five or well-being change. CONCLUSIONS: We discuss the implications of these findings for personality and rural health research.

Association between longest-held occupation and mortality risk.

BACKGROUND: Occupation is associated with a large part of daily activities, affecting lifestyle and social status. However, limited research exists on the association between longest-held occupation (LHO) and early mortality. We examine if LHO is associated with mortality risk among US adults 51 years of age and older. METHODS: Using Health and Retirement Study data from 1992 to 2020, we followed 26,758 respondents 51 years of age and older for up to 29 years. We used competing-risks analysis methodology to estimate the risk of mortality. RESULTS: Across the average 20.5 follow-up years, women with LHO in the categories of machine operators (subhazard ratio [SHR]: 1.42), food preparation (SHR: 1.39), handlers and helpers (SHR: 1.35), and sales (SHR: 1.15), were more likely to die earlier than women with the LHO in the professional and technical support occupation, the reference occupation. Men with LHO in the categories of food preparation (SHR: 1.43), machine operators (SHR: 1.36), personal services (SHR: 1.34), handlers and helpers (SHR: 1.32), protective services (SHR: 1.31), clerical (SHR: 1.27), farming and fishing (SHR: 1.26), sales (SHR: 1.23), and precision production (SHR: 1.20) had elevated risks of mortality compared to men whose LHO was in the referent professional and technical support occupation. CONCLUSIONS: Findings from this study provide comprehensive and current evidence that occupation can be one of the risk factors for adverse health outcomes and ultimately for early mortality.

The dynamic and reciprocal relationship between perceived everyday discrimination and cognitive function in later life.

OBJECTIVES: This study, based on socioemotional selectivity theory and cognitive theory, investigates the dynamic and reciprocal relationship between perceived discrimination and cognitive function in later life. METHODS: Data were drawn from four waves of the Health and Retirement Study (HRS 2006, 2010, 2014, and 2018). A total of 4,125 people who were 51 and older were included. Cognitive function was measured by the telephone interview for cognitive status (TICS-27). Perceived discrimination was measured using scores of the perceived everyday discrimination scale. Random intercept cross-lagged panel model (RI-CLPM) was utilized. The model was adjusted for a range of covariates. Subgroup analysis by ethnoracial groups was conducted. RESULTS: Cross-sectionally, while lower cognitive function was associated with higher perceived discrimination, this relationship was unidirectional. Longitudinally, higher perceived discrimination predicted lower cognitive function in later waves only among non-Hispanic White individuals. CONCLUSION: Results suggested that a decline in cognitive function may precede and contribute to the worsening of perceived discrimination, which may result in further decline in cognitive function. Lifetime experience of discrimination was discussed as a possible source of the racial/ethnic variations in the relationship. Further study is needed to examine whether this relationship holds among people with cognitive impairment and dementia.