Win Ratio Analyses of Piperacillin-Tazobactam Versus Meropenem for Ceftriaxone-Nonsusceptible Escherichia coli or Klebsiella pneumoniae Bloodstream Infections: Post Hoc Insights From the MERINO Trial.

BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Are Changes in Somatic Health Reflected Differently in Updated Self-Ratings by Big-Five Personality Traits?

Objectives: This longitudinal study tests whether the Big-Five personality traits influence the changes individuals make in self-rated health (SRH) as they adjust their initial level to account for information on concurrent changes in disease burden, activities of daily living (ADLs), and pain. Methods: A bi-variate Latent Growth Curve model was fitted to data to estimate longitudinal associations between SRH and each health measure across up-to-five repeated observations, collected from the year 2006 to 2018 from 13,096 participants in the Health and Retirement Study. Results: Negative longitudinal associations between SRH and all three health reports were significantly stronger for those who are more conscientious. No significant moderation was found for the other four personality traits. Discussion: Compared to the less conscientious, highly conscientious people may assign greater importance to specific health reports when rating and revising their assessments of SRH. This moderating effect was previously tested but not supported.

Unified Synthesis of 2-Isocyanoallopupukeanane and 9-Isocyanopupukeanane through a "Contra-biosynthetic" Rearrangement.

Herein, we describe our synthetic efforts toward the pupukeanane natural products, in which we have completed the first enantiospecific route to 2-isocyanoallopupukeanane in 10 steps (formal synthesis), enabled by a key Pd-mediated cyclization cascade. This subsequently facilitated an unprecedented bio-inspired "contra-biosynthetic" rearrangement, providing divergent access to 9-isocyanopupukeanane in 15 steps (formal synthesis). Computational studies provide insight into the nature of this rearrangement.

Trends in sleep duration in the U.S. from 2004 to 2018: A decomposition analysis.

Average sleep duration in the United States declined in recent years, and the decline may be linked with many biopsychosocial factors. We examine how a set of biopsychosocial factors have differentially contributed to the temporal trends in self-reported sleep duration across racial groups between 2004-2005 and 2017-2018. Using repeated nationally representative cross-sections from the National Health Interview Survey, we decompose the influence of biopsychosocial factors on sleep duration trends into two components. One component corresponds to coefficient changes (i.e., changes in the associations between behaviors or exposures and sleep duration) of key biopsychosocial factors, and the other part accounts for the compositional changes (i.e., changes in the distributions of exposures) in these biopsychosocial factors during the study period. We reveal that changes in the coefficients of some biopsychosocial factors are more important than compositional changes in explaining the decline in sleep duration within each racial/ethnic group. Our findings highlight racial differences manifest across multiple biopsychosocial domains that are shifting in terms of association and composition. Methodologically, we note that the standard regression approach for analyzing temporal trends neglects the role of coefficient changes over time and is thus insufficient for fully capturing how biopsychosocial factors may have influenced the temporal patterns in sleep duration and related health outcomes.

An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization.

A first-of-its-kind enantioselective aromatic Finkelstein reaction is disclosed for the remote desymmetrization of diarylmethanes. The reaction operates through a copper-catalyzed C-I bond-forming event, and high levels of enantioselectivity are achieved through the deployment of a tailored guanidinylated peptide ligand. Strategic use of transition-metal-mediated reactions enables the chemoselective modification of the aryl iodide products; thus, the synthesis of a diverse set of otherwise difficult-to-access diarylmethanes with excellent levels of selectivity is realized from a common intermediate. A mixed experimental/computational analysis of steric parameters and substrate conformations identifies the importance of remote conformational effects as a key to achieving high enantioselectivity in this desymmetrization reaction.

Generality-oriented optimization of enantioselective aminoxyl radical catalysis.

Catalytic enantioselective methods that are generally applicable to a broad range of substrates are rare. We report a strategy for the oxidative desymmetrization of meso-diols predicated on a nontraditional catalyst optimization protocol by using a panel of screening substrates rather than a singular model substrate. Critical to this approach was rational modulation of a peptide sequence in the catalyst incorporating a distinct aminoxyl-based active residue. A general catalyst emerged, providing high selectivity in the delivery of enantioenriched lactones across a broad range of diols, while also achieving up to ~100,000 turnovers.

Cost-Savings of Do Not Resuscitate Orders Among Elderly Patients With Heart Failure in the United States.

Do-not-resuscitate (DNR) orders should preclude the use of cardiopulmonary resuscitation and may be associated with patient outcomes for patients hospitalized with heart failure (HF). This study examined the association between DNR and costs, mortality, and length of stay. The study cohort was a national sample of 700 922 hospital admissions of patients aged >65 with a primary diagnosis of HF. Elderly HF patients who died with a DNR had cost-savings of $5640 ( P < 0.001). Patients with a DNR order were 8.9% points more likely to die before discharge than patients without ( P < 0.001), and patients who died with a DNR had a significantly shorter hospital stay by 1.51 days ( P < 0.001). DNR orders among elderly patients with HF are associated with cost-savings, as well as a higher mortality and shorter length of stay. In addition to primary benefits, advance care planning may aid in containing costs of care at end of life for HF.

Strategic elements in computer-assisted retrosynthesis: A case study of the pupukeanane natural products.

Computer-assisted synthesis planning represents a growing area of research, especially for complex molecule synthesis. Here, we present a case study involving the pupukeanane natural products, which are complex, marine-derived, natural products with unique tricyclic scaffolds. Proposed routes to members of each skeletal class informed by pathways generated using the program Synthia™ are compared to previous syntheses of these molecules. In addition, novel synthesis routes are proposed to pupukeanane congeners that have not been prepared previously.

Treating a Global Health Crisis with a Dose of Synthetic Chemistry.

The SARS-CoV-2 pandemic has prompted scientists from many disciplines to work collaboratively toward an effective response. As academic synthetic chemists, we examine how best to contribute to this ongoing effort.

Midlife Work and Women's Long-Term Health and Mortality.

Although paid work is a well-established predictor of health, several gaps in our knowledge about the relationship between adult work patterns and later health and mortality remain, including whether these benefits persist over long periods and whether they are dependent on subjective experiences with work. We draw on more than three decades of data from the National Longitudinal Survey of Mature Women to assess how labor force participation over a period of 20 years during midlife is related to mental and physical health and mortality over the following 16-25 years. We find that consistent work earlier in life continues to predict improved health and longevity over many years as women enter late life, and this relationship does not differ between women with positive and those with negative subjective work experiences. These findings add to knowledge about how key adult social experiences are related to health as individuals enter later life.

Women's spousal choices and a man's handshake: Evidence from a Norwegian study of cohort differences.

Both high grip strength and being married independently relate to better functional capacity and health at older ages, but the combined effect of marital status and strength have not been investigated. Especially at older ages, declining strength can have adverse health and social consequences, where having a spouse could potentially help with everyday support and alleviate some of the negative effects of sarcopenia. We investigate how grip strength relates to being married among two cohorts of 59-71 year olds (born 1923-35 and 1936-48) in the Norwegian city of Tromsø, controlling for a broad set of health variables and sociodemographic characteristics. The baseline included N = 5009 participants of whom 649 died during follow-up. We find that for men, particularly among younger cohorts, the physically stronger are more likely to be married, but no relation is found for women. This is consistent with a hypothesis that women increasingly have selected male marital partners based on preferred individual traits, whereas men do not emphasize strength when selecting women. We find that both marital status and grip strength independently affect mortality, but there is no significant joint effect. However, the distribution of strength and marital status implies that more men than women and increasing shares of later born cohorts have a "double-burden" of low strength and a lack of support from a spouse.

Integrating Metal-Catalyzed C-H and C-O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation.

One major goal of organometallic chemists is the direct functionalization of the bonds most recurrent in organic molecules: C-H, C-C, C-O, and C-N. An even grander challenge is C-C bond formation when both precursors are of this category. Parallel to this is the synthetic goal of achieving reaction selectivity that contrasts with conventional methods. Electrophilic aromatic substitution (EAS) via Friedel-Crafts acylation is the most renowned method for the synthesis of aryl ketones, a common structural motif of many pharmaceuticals, agrochemicals, fragrances, dyes, and other commodity chemicals. However, an EAS synthetic strategy is only effective if the desired site for acylation is in accordance with the electronic-controlled regioselectivity of the reaction. Herein we report steric-controlled regioselective arene acylation with salicylate esters via iridium catalysis to access distinctly substituted benzophenones. Experimental and computational data indicate a unique reaction mechanism that integrates C-O activation and C-H activation with a single iridium catalyst without an exogenous oxidant or base. We disclose an extensive exploration of the synthetic scope of both the arene and the ester components, culminating in the concise synthesis of the potent anticancer agent hydroxyphenstatin.

Multigenerational Attainments, Race, and Mortality Risk among Silent Generation Women.

This study extends health disparities research by examining racial differences in the relationships between multigenerational attainments and mortality risk among "Silent Generation" women. An emerging literature suggests that the socioeconomic attainments of adjacent generations, one's parents and adult children, provide an array of life-extending resources in old age. Prior research, however, has demonstrated neither how multigenerational resources are implicated in women's longevity nor how racial disparities faced by Silent Generation women may differentially structure the relationships between socioeconomic attainments and mortality. With data from the National Longitudinal Survey of Mature Women, the analysis provided evidence of a three-generation model in which parent occupation, family wealth, and adult child education were independently associated with women's mortality. Although we found evidence of racial differences in the associations between parental, personal, and spousal education and mortality risk, the education of adult children was a robust predictor of survival for black and white women.

Race Differences in Linking Family Formation Transitions to Women's Mortality.

We examine how the timing and sequencing of first marriage and childbirth are related to mortality for a cohort of 4,988 white and black women born between 1922 and 1937 from the National Longitudinal Survey of Mature Women. We use Cox proportional hazard models to estimate race differences in the association between family formation transitions and mortality. Although we find no relationships between marital histories and longevity, we do find that having children, the timing of first birth, and the sequencing of childbirth and marriage are associated with mortality. White women who had children lived longer than those who had none, but the opposite was found for black women. The effects of birth timing also differed by race; delaying first birth to older ages was protective for white women but not black women. These results underscore the importance of social context in the study of life course transitions.

Depression in later life: A closer look at the gender gap.

Gender differences in depressive symptoms have been extensively documented, with women reporting a higher number of depressive symptoms than men. However, studies offer different explanations for why such a gap exists. The goal of the current paper is to analyze how much of the observed gender gap in depression may be attributed to (1) compositional versus (2) reporting differences or (3) differences in reactivity to adversities. We contribute to this literature by testing, net of compositional differences, whether the relationship between reporting behavior and depressive symptoms is gendered and whether accounting for the possibility of gender-specific reactivity alters the structure of the gender gap at older ages. Our results show that the observed gender gap in depression (1) only partially derives from compositional differences; (2) is not an artifact of a gender-specific reporting style; and remarkably (3) men appear more sensitive to adversities.

The Long-Term Effects of Caregiving on Women's Health and Mortality.

Caregivers experience numerous mental and physical health effects from the stress of providing care, but we know little about whether these problems persist in the long term and whether long-term effects differ across caregiving contexts. Using the National Longitudinal Survey of Mature Women, we examine the relationship between caregiving and long-term patterns of depressive symptoms, functional limitations, and mortality. We also explore the health effects of caregiving in-home versus out-of-home and by caregiver/care-recipient relationship. Analyses show that in-home spousal and parental caregiving predict increased depressive symptoms and functional limitations in the long term but are unassociated with mortality, while caregiving out-of-home is unassociated with later depression and functional limitations but predicts lower risk of mortality. This study highlights the usefulness of approaching stressful experiences like caregiving from the life course perspective, viewing them as processes that unfold over time within specific contexts and may carry delayed or cumulative consequences.

The Longevity Legacy of World War II: The Intersection of GI Status and Mortality.

PURPOSE OF THE STUDY: We examine hypotheses involving the potential health advantages of selection into military service and the potential health disadvantages associated with the experience of military service by comparing later-life mortality rates for veterans and nonveterans as well as among veterans based on their cohort of reentry into civilian life. DESIGN AND METHODS: We use data on 3,453 men, including 1,496 veterans from the older men cohort of the National Longitudinal Surveys to estimate Cox proportional hazard mortality models. We distinguish between veterans and nonveterans and further classify veterans by age at exit while incorporating measures associated with military selection, health behaviors, and socioeconomic status. RESULTS: Veterans who were discharged from the military at older ages have a mortality advantage relative to veterans discharged at younger ages. For the 1914-1921 birth cohorts, the mortality advantage for veterans who exited around age 30 is apparent for deaths before age 65, but rates equalize across all groups when deaths at older ages are included. These findings are robust to the inclusion of background characteristics, education, occupation, body mass index, smoking, marital status, and proxies for service deferments. IMPLICATIONS: Rather than focusing on a general health effect of military service, per se, future research should distinguish among individual traits; the nature, timing, and duration of exposures relative to life course stage; and the sociohistorical context of military service to expand our understanding of the differential health consequences of military service.

Clarifying hierarchical age-period-cohort models: A rejoinder to Bell and Jones.

Previously, Reither et al. (2015) demonstrated that hierarchical age-period-cohort (HAPC) models perform well when basic assumptions are satisfied. To contest this finding, Bell and Jones (2015) invent a data generating process (DGP) that borrows age, period and cohort effects from different equations in Reither et al. (2015). When HAPC models applied to data simulated from this DGP fail to recover the patterning of APC effects, B&J reiterate their view that these models provide "misleading evidence dressed up as science." Despite such strong words, B&J show no curiosity about their own simulated data--and therefore once again misapply HAPC models to data that violate important assumptions. In this response, we illustrate how a careful analyst could have used simple descriptive plots and model selection statistics to verify that (a) period effects are not present in these data, and (b) age and cohort effects are conflated. By accounting for the characteristics of B&J's artificial data structure, we successfully recover the "true" DGP through an appropriately specified model. We conclude that B&Js main contribution to science is to remind analysts that APC models will fail in the presence of exact algebraic effects (i.e., effects with no random/stochastic components), and when collinear temporal dimensions are included without taking special care in the modeling process. The expanded list of coauthors on this commentary represents an emerging consensus among APC scholars that B&J's essential strategy--testing HAPC models with data simulated from contrived DGPs that violate important assumptions--is not a productive way to advance the discussion about innovative APC methods in epidemiology and the social sciences.