Sense of purpose in life and extending the cognitive healthspan: evidence from multistate survival modeling.

Having a sense of purpose in life predicts better maintenance of cognitive function in older adulthood and reduced risk of mild cognitive impairment (MCI) and dementia. However, little research has examined its influence on the rate of cognitive decline and length of cognitive healthspan. This study evaluated the role of sense of purpose on the risk and timing of transitions between normal cognition, MCI, and dementia. Older adults from the Memory and Aging Project (MAP; n = 1821) and the Health and Retirement Study (HRS; n = 10,542) were followed annually for 19 years and biennially for 12 years, respectively. Multistate survival models assessed whether sense of purpose predicted transitions across normal cognition, MCI, dementia, and death. More purposeful older adults had lower risk of developing MCI (HR = 0.82 in MAP; HR = 0.93 in HRS), higher likelihood of cognitive improvement, and longer cognitively healthy life expectancies. Results suggest sense of purpose may extend the cognitive healthspan.

Opportunities for Insight into the Mechanism of Efficient CO2/CO Interconversion at a Nickel-Iron Cluster in CO Dehydrogenase.

The reduction of CO2 with low overpotential and high selectivity is a crucial challenge in catalysis. Fortunately, natural systems have evolved enzymes that achieve this catalytic reaction very efficiently at a complex nickel-iron-sulfur cluster within carbon monoxide dehydrogenase (CODH). Extensive biochemical, crystallographic, and spectroscopic work has been done to understand the structures and mechanism involved in the catalytic cycle, which are summarized here from the perspective of mechanistic organometallic chemistry. We highlight the ambiguities in the data and suggest experiments that could lead to clearer understanding of the mechanism and structures of intermediates at the active-site cluster. These include parallel crystallography and spectroscopy, as well as the preparation of synthetic analogues that help to interpret structural and spectroscopic signatures.

COVID-19 Vaccine Uptake and Effectiveness by Time since Vaccination in the Western Cape Province, South Africa: An Observational Cohort Study during 2020-2022.

There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced widespread SARS-CoV-2 infection before vaccine availability. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa, in an observational cohort study of >2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalization and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies, and healthcare utilization. We found that by the end of 2022, 41% of surviving adults had completed vaccination and 8% had received a booster dose. Recent vaccination was associated with notable reductions in severe COVID-19 during periods dominated by Delta, and Omicron BA.1/2 and BA.4/5 (sub)lineages. During the latest Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, distinct reductions of effectiveness occurred at longer times post completing or boosting vaccination. Results highlight the importance of continued emphasis on COVID-19 vaccination and boosting for those at high risk of severe COVID-19, even in settings with widespread infection-induced immunity.

Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis.

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

Portable Air Cleaner Usage and Particulate Matter Exposure Reduction in an Environmental Justice Community: A Pilot Study.

Particulate matter (PM) exposure is associated with adverse health outcomes, including respiratory illness. A large fraction of exposure to airborne contaminants occurs in the home. This study, conducted over 5 months in a community with high asthma rates (Chelsea, MA, USA), investigated the use of portable air cleaners (PACs) to reduce indoor PM. Seven asthma-affected households participated, receiving a PAC (Austin Air Health Mate HEPA filter), a QuantAQ sensor to measure PM1, PM2.5, PM10 (µg/m3), and a HOBO plug-load data logger to track PAC usage. Results describe hourly and daily PM concentrations and PAC usage for each household. Hourly average PM concentrations decreased when PACs were turned on (vs. when they were turned off) across households during the study period: PM1 decreased by 0.46 µg/m3, PM2.5 decreased by 0.69 µg/m3, and PM10 decreased by 3.22 µg/m3. PAC usage varied for each household, including constant usage in one household and only usage at certain times of day in others. Higher filtration settings led to lower PM, with significant reductions in some, but not all, homes. Our findings highlight some difficulties in implementing household PAC interventions, yet also provide evidence to support household-level interventions to reduce PM and other indoor sources of air pollution. We also highlight academic-community partnerships as contributing to evidence-based solutions.

Perceptions of a good life: Associations with culture, age, wellbeing, and health.

What does a good life look like? The present research investigated individual differences in people's perceptions of the factors that are most important for living a good life using two waves of data in probability samples from the U.S. (MIDUS; N = 4,041) and Japan (MIDJA; N = 381). We examined country- and age-related similarities and differences in perceptions of a good life and associations of perceptions of a good life with experiences of wellbeing and physical health. Some factors were considered important for living a good life in both countries and across age (e.g., positive relationships with family), whereas other factors varied between countries (e.g., U.S. participants were more likely to perceive faith as important) and by age (e.g., younger adults were more likely to perceive having a good job as important). Further, perceptions of a good life were related to experiences of wellbeing and physical health concurrently and prospectively. This research informs our understanding of how people differ from one another in their perceptions of a good life, and how these differences may matter for individuals' experiences of a good life.

The Foundational Science of Endogenous Opioids and Their Receptors.

The function of endogenous opioids spans from initiating behaviors that are critical for survival, to responding to rapidly changing environmental conditions. A network of interconnected systems throughout the body characterizes the endogenous opioid system (EOS). EOS receptors for beta-endorphin, enkephalin, dynorphin, and endomorphin underpin the diverse functions of the EOS across biological systems. This chapter presents a succinct yet comprehensive summary of the structure of the EOS, EOS receptors, and their relationship to other biological systems.

Physical Exercise as an Intervention for Depression: Evidence for Efficacy and Mu-Opioid Receptors as a Mechanism of Action.

Physical exercise is often cited as an important part of an intervention for depression, and there is empirical evidence to support this. However, the mechanism of action through which any potential antidepressant effects are produced is not widely understood. Recent evidence points toward the involvement of endogenous opioids, and especially the mu-opioid system, as a partial mediator of these effects. In this chapter, we discuss the current level of empirical support for physical exercise as either an adjunctive or standalone intervention for depression. We then review the extant evidence for involvement of endogenous opioids in the proposed antidepressant effects of exercise, with a focus specifically on evidence for mu-opioid system involvement.

The Roles of Endogenous Opioids in Placebo and Nocebo Effects: From Pain to Performance to Prozac.

Placebo and nocebo effects have been well documented for nearly two centuries. However, research has only relatively recently begun to explicate the neurobiological underpinnings of these phenomena. Similarly, research on the broader social implications of placebo/nocebo effects, especially within healthcare delivery settings, is in a nascent stage. Biological and psychosocial outcomes of placebo/nocebo effects are of equal relevance. A common pathway for such outcomes is the endogenous opioid system. This chapter describes the history of placebo/nocebo in medicine; delineates the current state of the literature related to placebo/nocebo in relation to pain modulation; summarizes research findings related to human performance in sports and exercise; discusses the implications of placebo/nocebo effects among diverse patient populations; and describes placebo/nocebo influences in research related to psychopharmacology, including the relevance of endogenous opioids to new lines of research on antidepressant pharmacotherapies.

Endogenous Opioid Activity as the Mechanism of Action for Mitragyna speciosa (Kratom): The Current State of the Evidence.

Kratom (Mitragyna speciosa) is a substance derived from botanical compounds native to Southeast Asia. This substance has been cultivated predominantly in Thailand, Malaysia, Vietnam, and Myanmar, where it has historically been used in traditional medicine as a near panacea for several health problems. Such ritualistic use of kratom has been present for centuries; however, recreational use appears to have increased globally, especially in the United States. Pharmacodynamic and pharmacokinetic studies have found that kratom demonstrates a unique parabolic, dose-dependent pattern of effects ranging from stimulation to opioid and analgesic effects. Pharmacological research indicates that kratom is both a mu opioid receptor (µ-OR; MOR) and a kappa opioid receptor (κ-OR; KOR) agonist, which mediates its analgesic effects. Other research suggests that kratom may simultaneously act on dopaminergic and serotonergic receptors, which mediate its stimulant effects. This chapter reviews the literature related to the structural, functional, and cultural characteristics of kratom use. We begin with an overview of current and historical patterns of kratom, followed by a review of data on the pharmacodynamics and pharmacokinetics of kratom thus far.

Depression, Cancer, Inflammation, and Endogenous Opioids: Pathogenic Relationships and Therapeutic Options.

Endogenous opioids and their associated receptors form a system that maintains survival by positively reinforcing behaviors that are vital to life. Cancer and cancer treatment side effects capitalize on this system pathogenically, leading to maladaptive biological responses (e.g., inflammation), as well as cognitive and emotional consequences, most notably depression. Psychologists who treat people with cancer frequently find depression to be a primary target for intervention. However, in people with cancer, the etiology of depression is unique and complex. This complexity necessitates that psycho-oncologists have a fundamental working knowledge of the biological substrates that underlie depression/cancer comorbidity. Building on other chapters in this volume pertaining to cancer and endogenous opioids, this chapter focuses on the clinical applications of basic scientific findings.

Introduction to the Volume: The Journey Ahead.

The endogenous opioid system (EOS) is complex. The line of research contributing to our current body of knowledge about this system is diverse, as are the ways in which endogenous opioids affect human health and behavior. This chapter serves as an introduction to the edited volume. It includes commentary about the current public discourse related to opioids, the rationale for this book, and the unique contributions of each chapter within this volume.

Congested C(sp3)-rich architectures enabled by iron-catalysed conjunctive alkylation.

Catalytic cross-coupling by transition metals has revolutionized the formation of C-C bonds in organic synthesis. However, the challenge of forming multiple alkyl-alkyl bonds in crowded environments remains largely unresolved. Here, we report the regioselective functionalization of olefins with sp3-hybridized organohalides and organozinc reagents using a simple (terpyridine)iron catalyst. Aliphatic groups of various sizes are successfully installed on either olefinic carbon, furnishing a diverse array of products with congested cores featuring C- or heteroatom-substituted stereocenters. The method enables access to valuable but synthetically challenging C(sp3)-rich molecules, including alicyclic compounds bearing multiple contiguous stereocenters through annulation cascades. Mechanistic and theoretical studies suggest a stepwise iron-mediated radical carbometallation pathway followed by outer-sphere C-C bond formation, which potentially opens the door to a broader scope of transformations and new chemical space.

Ice formation and its elimination in cryopreservation of oocytes.

Damage from ice and potential toxicity of ice-inhibiting cryoprotective agents (CPAs) are key issues in assisted reproduction of humans, domestic and research animals, and endangered species using cryopreserved oocytes and embryos. The nature of ice formed in bovine oocytes (similar in size to oocytes of humans and most other mammals) after rapid cooling and during rapid warming were examined using synchrotron-based time-resolved x-ray diffraction. Using cooling rates, warming rates and CPA concentrations of current practice, oocytes show no ice after cooling but always develop large ice fractions - consistent with crystallization of most free water - during warming, so most ice-related damage must occur during warming. The detailed behavior of ice at warming depended on the nature of ice formed during cooling. Increasing cooling rates allows oocytes soaked as in current practice to remain essentially ice free during both cooling and warming. Much larger convective warming rates are demonstrated and will allow routine ice-free cryopreservation with smaller CPA concentrations. These results clarify the roles of cooling, warming, and CPA concentration in generating ice in oocytes and establish the structure and grain size of ice formed. Ice formation can be eliminated as a factor affecting post-thaw oocyte viability and development in many species, improving outcomes and allowing other deleterious effects of the cryopreservation cycle to be independently studied.

Time-Resolved X-ray Emission Spectroscopy and Synthetic High-Spin Model Complexes Resolve Ambiguities in Excited-State Assignments of Transition-Metal Chromophores: A Case Study of Fe-Amido Complexes.

To fully harness the potential of abundant metal coordination complex photosensitizers, a detailed understanding of the molecular properties that dictate and control the electronic excited-state population dynamics initiated by light absorption is critical. In the absence of detectable luminescence, optical transient absorption (TA) spectroscopy is the most widely employed method for interpreting electron redistribution in such excited states, particularly for those with a charge-transfer character. The assignment of excited-state TA spectral features often relies on spectroelectrochemical measurements, where the transient absorption spectrum generated by a metal-to-ligand charge-transfer (MLCT) electronic excited state, for instance, can be approximated using steady-state spectra generated by electrochemical ligand reduction and metal oxidation and accounting for the loss of absorptions by the electronic ground state. However, the reliability of this approach can be clouded when multiple electronic configurations have similar optical signatures. Using a case study of Fe(II) complexes supported by benzannulated diarylamido ligands, we highlight an example of such an ambiguity and show how time-resolved X-ray emission spectroscopy (XES) measurements can reliably assign excited states from the perspective of the metal, particularly in conjunction with accurate synthetic models of ligand-field electronic excited states, leading to a reinterpretation of the long-lived excited state as a ligand-field metal-centered quintet state. A detailed analysis of the XES data on the long-lived excited state is presented, along with a discussion of the ultrafast dynamics following the photoexcitation of low-spin Fe(II)-Namido complexes using a high-spin ground-state analogue as a spectral model for the 5T2 excited state.

Estimated Impacts of Prescribed Fires on Air Quality and Premature Deaths in Georgia and Surrounding Areas in the US, 2015-2020.

Smoke from wildfires poses a substantial threat to health in communities near and far. To mitigate the extent and potential damage of wildfires, prescribed burning techniques are commonly employed as land management tools; however, they introduce their own smoke-related risks. This study investigates the impact of prescribed fires on daily average PM2.5 and maximum daily 8-h averaged O3 (MDA8-O3) concentrations and estimates premature deaths associated with short-term exposure to prescribed fire PM2.5 and MDA8-O3 in Georgia and surrounding areas of the Southeastern US from 2015 to 2020. Our findings indicate that over the study domain, prescribed fire contributes to average daily PM2.5 by 0.94 ± 1.45 µg/m3 (mean ± standard deviation), accounting for 14.0% of year-round ambient PM2.5. Higher average daily contributions were predicted during the extensive burning season (January-April): 1.43 ± 1.97 µg/m3 (20.0% of ambient PM2.5). Additionally, prescribed burning is also responsible for an annual average increase of 0.36 ± 0.61 ppb in MDA8-O3 (approximately 0.8% of ambient MDA8-O3) and 1.3% (0.62 ± 0.88 ppb) during the extensive burning season. We estimate that short-term exposure to prescribed fire PM2.5 and MDA8-O3 could have caused 2665 (95% confidence interval (CI): 2249-3080) and 233 (95% CI: 148-317) excess deaths, respectively. These results suggest that smoke from prescribed burns increases the mortality. However, refraining from such burns may escalate the risk of wildfires; therefore, the trade-offs between the health impacts of wildfires and prescribed fires, including morbidity, need to be taken into consideration in future studies.

Neutrophil-mediated hypoxia drives pathogenic CD8 T cell responses in cutaneous leishmaniasis.

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8 T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8 T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce reactive oxygen species and ultimately increased the hypoxic state and granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.

A review of the literature on wellbeing and modifiable dementia risk factors.

Wellbeing-defined broadly as experiencing one's life as enjoyable and fulfilling-has been associated with lower risk for Alzheimer's disease and related dementias. The mechanisms underlying this association are largely unknown. However, prior research and theory suggest that wellbeing impacts health behaviors and biological systems that are relevant to cognitive and brain health. Several of these factors have also been identified by the 2020 Lancet Commission on Dementia Prevention, Intervention, and Care as modifiable dementia risk factors. In the current review, we summarize and evaluate the evidence for associations between wellbeing and each of the 12 Lancet Commission risk factors. We found relatively consistent evidence for associations between higher wellbeing and lower levels of most of the risk factors: physical inactivity, social isolation, smoking, depression, hypertension, diabetes, hearing loss, traumatic brain injury, and air pollution. By contrast, we found evidence for only modest associations between wellbeing and education and mixed evidence for associations of wellbeing with alcohol use and body weight. Although most of the reviewed evidence was observational, longitudinal and experimental evidence suggests that many of the observed associations are likely bidirectional. These findings suggest that modifiable dementia risk factors may be mediators (i.e., intermediate steps in the causal chain) and/or confounders (i.e., variables that impact both wellbeing and dementia, and thus could induce a spurious association) of the association between wellbeing and dementia. We conclude by discussing next steps to test mediation hypotheses and to account for potential confounding in the relation between wellbeing and dementia.

Association of timing and agent for VTE prophylaxis in patients with severe traumatic brain injury on VTE, mortality, neurosurgical intervention, and discharge disposition.

BACKGROUND: Trauma patients are at increased risk for venous thromboembolism events (VTE). The decision of when to initiate VTE chemoprophylaxis (VTEP) and with what agent remains controversial in patients with severe traumatic brain injury (TBI). METHODS: This comparative effectiveness study evaluated the impact of timing and agent for VTEP on outcomes for patients with severe TBI (AIS Head = 3,4, or 5). Data was collected at 35 Level 1 and 2 trauma centers from January 1, 2017 to June 1, 2022. Patients were placed into analysis cohorts: No VTEP, low-molecular weight heparin (LMWH) ≤ 48 hours, LMWH>48 hours, Heparin≤48 hours, Heparin>48 hours. Propensity score matching accounting for patient factors and injury characteristics was used with logistic regression modeling to evaluate in-hospital mortality, VTE events, and discharge disposition. Neurosurgical intervention after initiation of VTEP was used to evaluate extension of intracranial hemorrhage. RESULTS: Of 12,879 patients, 32% had no VTEP, 36% LMWH, and 32% Heparin. Overall mortality was 8.3% and lowest among patients receiving LMWH≤48 hours (4.1%). VTE rates were lower with use of LMWH (1.6 vs 4.5%, OR 2.98, 95% CI 1.40-6.34, p = 0.005) without increasing mortality or neurosurgical interventions. VTE rates were lower with early prophylaxis (2.0 vs 3.5%, OR 1.76, 95% CI 1.15-2.71, p = 0.01) without increasing mortality (p = 1.0). Early VTEP was associated with more non-fatal intracranial operations (p < 0.001). However, patients undergoing neurosurgical intervention after VTEP initiation had no difference in rates of mortality, withdrawal of care, or unfavorable discharge disposition (p = 0.7, p = 0.1, p = 0.5). CONCLUSIONS: In patients with severe TBI, LMWH usage was associated with lower VTE incidence without increasing mortality or neurosurgical interventions. Initiation of VTEP≤48 hours decreased VTE incidence and increased non-fatal neurosurgical interventions without affecting mortality. LMWH is the preferred VTEP agent for severe TBI, and initiation ≤48 hours should be considered in relation to these risks and benefits. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level III.