Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis.

Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.

Socioeconomic inequalities in physical, psychological, and cognitive multimorbidity in middle-aged and older adults in 33 countries: a cross-sectional study.

BACKGROUND: Many physical, psychological, and cognitive disorders are highly clustered among populations with low socioeconomic status. However, the extent to which socioeconomic status is associated with different combinations of these disorders is unclear, particularly outside high-income countries. We aimed to evaluate these associations in 33 countries including high-income countries, upper-middle-income countries, and one lower-middle-income country. METHODS: This cross-sectional multi-region study pooled individual-level data from seven studies on ageing between 2017 and 2020. Education and total household wealth were used to measure socioeconomic status. Physical disorder was defined as having one or more of the self-reported chronic conditions. Psychological and cognitive disorders were measured by study-specific instruments. The outcome included eight categories: no disorders, physical disorder, psychological disorder, cognitive disorder, and their four combinations. Multivariable-adjusted logistic regression models were used to estimate odds ratios (ORs) and 95% CIs for the associations of socioeconomic status with these outcomes separately for high-income countries, upper-middle-income countries, and the lower-middle-income country. FINDINGS: Among 167 376 individuals aged 45 years and older, the prevalence of multimorbidity was 24·5% in high-income countries, 33·9% in upper-middle-income countries, and 8·1% in the lower-middle-income country (India). Lower levels of education, household wealth, and a combined socioeconomic status score were strongly associated with physical, psychological, and cognitive multimorbidity in high-income countries and upper-middle-income countries, with ORs (low vs high socioeconomic status) for physical-psychological-cognitive multimorbidity of 12·36 (95% CI 10·29-14·85; p<0·0001) in high-income countries and of 23·84 (18·85-30·14; p<0·0001) in upper-middle-income countries. The associations in the lower-middle-income country were mixed. Participants with both a low level of education and low household wealth had the highest odds of multimorbidity (eg, OR for physical-psychological-cognitive multimorbidity 21·21 [15·95-28·19; p<0·0001] in high-income countries, 37·07 [25·66-53·56; p<0·0001] in upper-middle-income countries, and 54·96 [7·66-394·38; p<0·0001] in the lower-middle-income country). INTERPRETATION: In study populations from high-income countries, upper-middle-income countries, and the lower-middle-income country, the odds of multimorbidity, which included physical, psychological, and cognitive disorders, were more than ten times greater in individuals with low socioeconomic status. Equity-oriented policies and programmes that reduce social inequalities in multimorbidity are urgently needed to achieve Sustainable Development Goals. FUNDING: Zhejiang University, Fundamental Research Funds for the Central Universities, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Wellcome Trust, Medical Research Council, National Institute on Aging, and Academy of Finland. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Sleep Behaviors and Progression of Multimorbidity in Middle-Aged and Older Adults: A Prospective Cohort Study From China.

BACKGROUND: Sleep behavior (eg, sleep duration, sleep quality, and nap) is closely related to many chronic conditions. However, less is known about its association with multiple chronic conditions (multimorbidity), particularly evidence from cohort studies. METHODS: Data were collected from a cohort of 8 937 individuals aged 45 and older from the China Health and Retirement Longitudinal Study (2011-2018). Sleep duration, sleep quality, and nap duration were collected in 2011 and 2013. Progression of multimorbidity was defined as the first report of 2 or more chronic conditions for participants without multimorbidity or the new report of 1 or more conditions for those with multimorbidity. Cox regression models were performed to calculate the hazard ratios and 95% confidence intervals (CIs) of the associations between sleep behaviors and the progression of multimorbidity. RESULTS: Short sleep duration and poor sleep quality were associated with the progression of multimorbidity independently and jointly, especially in those less than 65 years and females. The U-shaped dose-response relationships were observed between nighttime and total sleep duration and the progression of multimorbidity. Persistent short and unsteadily changed sleep behaviors increased the risk of multimorbidity progression. Individuals sleeping ≤5 h/night with 5-7 restless days/week had 1.53 times higher risk of multimorbidity progression (95% CI: 1.37-1.71), compared to those sleeping 7-8 h/night with <1 restless day/week. CONCLUSIONS: Short sleep duration and poor sleep quality were independently and jointly associated with a higher risk of multimorbidity progression in a mid-to-older population. Optimal sleep duration and sleep quality should be emphasized in multimorbidity prevention and control.

Interventions and management on multimorbidity: An overview of systematic reviews.

BACKGROUND: Multimorbidity poses an immense burden on the healthcare systems globally, whereas the management strategies and guidelines for multimorbidity are poorly established. We aim to synthesize current evidence on interventions and management of multimorbidity. METHODS: We searched four electronic databases (PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews). Systematic reviews (SRs) on interventions or management of multimorbidity were included and evaluated. The methodological quality of each SR was assessed by the AMSTAR-2 tool, and the quality of evidence on the effectiveness of interventions was assessed by the grading of recommendations assessment, development and evaluation (GRADE) system. RESULTS: A total of 30 SRs (464 unique underlying studies) were included, including 20 SRs of interventions and 10 SRs summarizing evidence on management of multimorbidity. Four categories of interventions were identified: patient-level interventions, provider-level interventions, organization-level interventions, and combined interventions (combining the aforementioned two or three- level components). The outcomes were categorized into six types: physical conditions/outcomes, mental conditions/outcomes, psychosocial outcomes/general health, healthcare utilization and costs, patients' behaviors, and care process outcomes. Combined interventions (with patient-level and provider-level components) were more effective in promoting physical conditions/outcomes, while patient-level interventions were more effective in promoting mental conditions/outcomes and psychosocial outcomes/general health. As for healthcare utilization and care process outcomes, organization-level and combined interventions (with organization-level components) were more effective. The challenges in the management of multimorbidity at the patient, provider and organizational levels were also summarized. CONCLUSION: Combined interventions for multimorbidity at different levels would be favored to promote different types of health outcomes. Challenges exist in the management at the patient, provider, and organization levels. Therefore, a holistic and integrated approach of patient-, provider- and organization- level interventions is required to address the challenges and optimize care of patients with multimorbidity.

Change of serum uric acid and progression of cardiometabolic multimorbidity among middle aged and older adults: A prospective cohort study.

Background: Hyperuricemia is prevalent and associated with individual cardiometabolic diseases, highlighting the potential role of serum uric acid (SUA) in the development and progression of cardiometabolic multimorbidity (CMM, the coexistence of diabetes, heart disease, or stroke). This study aimed to examine the role of SUA change in the progression of CMM. Methods: This prospective cohort study used data from the China Health and Retirement Longitudinal Study, included 4,820 participants aged 45 years or above with three complete surveys at 2011 (baseline), 2015, and 2018. SUA level at survey 2011 and 2015 was used to measure SUA change as keeping or rising to hyperuricemia, and keeping or declining to non-hyperuricemia. CMM progression was defined as the first report of CMM or additional report of cardiometabolic diseases during survey 2015 and 2018. We used logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) of SUA change on CMM progression. Results: During the follow-up of around 7 years, 519 (10.8%) of the participants kept or rose to hyperuricemia from survey 2011 to 2015, and 311 (6.5%) experienced CMM progression from survey 2015 to 2018. Participants who kept or rose to hyperuricemia had 1.86 (95% CI, 1.29, 2.68) increased odds of CMM progression compared with those who kept or declined to non-hyperuricemia. Specifically, keeping or rising to hyperuricemia (vs. keeping or declining to non-hyperuricemia) was associated with 2.01 times higher odds (95% CI, 1.18, 3.43) of incident diabetes and 1.67 times higher odds (OR:1.67; 95% CI, 1.15, 2.43) of incident cardiovascular diseases following diabetes. Conclusion: Keeping or rising to hyperuricemia was associated with CMM progression, particularly with incident cardiovascular diseases following diabetes. These findings suggest that monitoring SUA change may provide innovative insights into the prevention of CMM, especially in the secondary prevention of CMM (i.e., preventing further progression to cardiovascular diseases among patients with diabetes).