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.

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.

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.

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.

How health conditions translate into self-ratings: a comparative study of older adults across Europe.

Using data from the Survey of Health, Ageing and Retirement in Europe, we examine how respondents translate morbidity and disability into self-rated health (SRH), how national populations differ in SRH, and how normative and person-specific reporting styles shape SRH. We construct proxy variables that allow us to specify cultural differences in reporting styles and individual differences in relative rating behavior. Using generalized logistic regression, we find that both of these dimensions of subjectivity are related to SRH; however, their inclusion does not significantly alter the connection between SRH and the set of disease and disability indicators. Further, country differences in SRH persist after controlling for all these factors. Our findings suggest that observed country differences in SRH reflect compositional differences, cultural differences in reporting styles, and perceptions of how health restricts typical activities. SRH also seems to capture underlying but unmeasured health differences across populations.

The Retirement Life Course in America at the Dawn of the Twenty-First Century.

As the baby boom cohorts expand the number of U.S. retirees, population estimates of the employment, withdrawal and reentry behaviors of older Americans' remain scarce. How long do people work? How frequently is retirement reversed? How many years are people retired? What is the modal age of retirement? And, how do the patterns for women compare to those for men? Using the 1992-2004 Health and Retirement Study, we estimate multistate working life tables to update information on the age-graded regularities of the retirement life course of men and women in the United States. We find that at age 50 men can expect to spend half of their remaining lives working for pay, while women can expect to spend just one-third. Half of all men and women have left the labor force by ages 63 and 61, respectively. Although the majority of retirement exits are final, variation in the nature and duration of the retirement process is substantial, as about a third of men's and women's exits are reversed. By quantifying these patterns for men and women, we provide a sound empirical basis for evaluating policy designed to address the financial pressures population aging places on public and private pension systems.

Women's retirement expectations: how stable are they?

OBJECTIVE: Using the National Longitudinal Survey of Mature Women, we examine between- and within-person differences in expected retirement age as a key element of the retirement planning process. The expectation typologies of 1,626 women born between 1923 and 1937 were classified jointly on the basis of specificity and consistency. METHODS: Latent class analysis was used to determine retirement expectation patterns over a 7-year span. Multinomial logistic regression analyses were employed to estimate the effects of demographic and status characteristics on the likelihood of reporting 4 distinct longitudinal patterns of retirement expectations. RESULTS: Substantial heterogeneity in reports of expected retirement age between and within individuals over the 7-year span was found. Demographic and status characteristics, specifically age, race, marital status, job tenure, and recent job change, sorted respondents into different retirement expectation patterns. CONCLUSIONS: The frequent within-person fluctuations and substantial between-person heterogeneity in retirement expectations indicate uncertainty and variability in both expectations and process of expectation formation. Variability in respondents' reports suggests that studying retirement expectations at multiple time points better captures the dynamics of preretirement planning.