1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Control in relation to suicidal ideation and nonfatal suicidal behavior among older adults: a systematic review.

OBJECTIVES: This review aims to evaluate and synthesize quantitative and qualitative findings on perceived control and value placed on control within the context of suicidal ideation or nonfatal suicidal behaviors in older adults. METHOD: A comprehensive literature search was completed in June 2022, October 2022, and November 2023. Included studies focused on perceived control or value placed on control and on suicidal ideation or nonfatal suicidal behavior. Studies were published in English and included older adults (≥ 60 years) in separate analyses. Studies focusing on self-efficacy were excluded. RESULTS: Twelve studies with 10 unique samples of 1487 total participants from eight countries were assessed. Quantitative studies indicated that perceived control and value placed on control are significant correlates of suicidal ideation and nonfatal suicidal behaviors, while qualitative studies highlighted that individuals who survive suicide attempts often specify decreased perceived control as a reason for their attempts. CONCLUSION: Results of this review indicate that perceived control and value placed on control are relevant variables when studying suicidal ideation and nonfatal suicidal behavior. This conclusion should be considered preliminary. Future research should examine heterogeneous samples, adopt gold standard assessments, and assess covariates in the associations.

Assessing age invariance of the Male Depression Risk Scale-22 in younger and older adult males.

OBJECTIVES: Women are twice as likely to be diagnosed with major depressive disorder as men. Yet suicide rates are four times higher in men than women, increasing to six times when comparing older men to older women. Investigators have begun researching if depression presents differently in individuals who adhere to masculine norms, leading to the conceptualization of masculine depression. Despite validity evidence for the Male Depression Risk Scale-22 (MDRS-22) in mixed-age samples, few studies have investigated the possibility of age-related differences in masculine depression. The present study aimed to test for age invariance of the MDRS-22. METHOD: Age invariance for the MDRS-22 was tested via a multi-group confirmatory factor analysis with groups of younger (18-64 years) and older (65+ years) males (N = 469). RESULTS: Age invariance for the MDRS-22 was not established, ΔX2 = 451.47, Δdf = 16, p < 0.001. CONCLUSION: Results of the study indicate that masculine depression may present differently between younger and older men. To fully understand the construct of masculine depression, it is important to investigate how symptoms may present in individuals of all ages. Overall, the study highlights the importance of investigating how masculine depression may present differently in older men.

Trauma re-engagement and PTSD in older medically ill veterans: implications for trauma-informed care.

OBJECTIVES: We characterize rates and correlates of PTSD and of trauma re-engagement without PTSD in medically ill older Veterans, as well as supportive strategies, with the goal of advancing trauma-informed care. METHODS: We interviewed medically ill older Veterans (N = 88, M age 75.13, SD = 6.14) with primary care screening measures for PTSD and trauma re-engagement, and open-ended questions to assess supportive strategies. RESULTS: One-fifth (20.5%) presented with probable PTSD, associated with greater trauma exposures (r=.57, p<.001), whereas two-fifths (43.2%) reported re-engagement with military memories without PTSD, associated with having a spouse/partner (t = 2.27, p=.028). Of those who experienced trauma, half reported thinking more about the trauma recently and becoming more emotional on certain days. In response to the question 'What gives you strength as you think about the future with your illness' Veterans described support of family, healthcare, worldview, personal control, acceptance, and health behaviors. CONCLUSION: Memories of trauma are common with medical illness. Age-friendly trauma-informed care could consider factors that patients describe as sources of strength with illness.

Burnout and Depression Among Sandwich Generation Caregivers: A Brief Report.

Twenty-nine percent of adults in the U.S. care for children, and 12% to 24.3% of those adults are multigenerational caregivers who also provide unpaid care for one or more adults. These adults are considered members of the "sandwich generation," which is a term for multigenerational caregivers who provide care, financial support, and emotional support for both their children and parents. The present study characterized the sandwich generation and examined how sandwich generation caregivers differed from caregivers of children, caregivers of parents, and non-caregivers regarding burnout and depression. We found that sandwich generation caregivers and caregivers of parents reported significantly higher levels of informal caregiving burnout than caregivers of children. Compared to non-caregivers, all caregivers reported significantly higher levels of personal burnout. Burnout is higher in sandwich generation caregivers and those who care for parents than burnout among those who care only for children. Future studies should investigate additional variables that affect burnout.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Stereoretentive Olefin Metathesis: An Avenue to Kinetic Selectivity.

Olefin metathesis is an incredibly valuable transformation that has gained widespread use in both academic and industrial settings. Lately, stereoretentive olefin metathesis has garnered much attention as a method for the selective generation of both E- and Z-olefins. Early studies employing ill-defined catalysts showed evidence for retention of the stereochemistry of the starting olefins at low conversion. However, thermodynamic ratios E/Z were reached as the reaction proceeded to equilibrium. Recent studies in olefin metathesis have focused on the synthesis of catalysts that can overcome the inherent thermodynamic preference of an olefin, providing synthetically useful quantities of a kinetically favored olefin isomer. These reports have led to the development of stereoretentive catalysts that not only generate Z-olefins selectively, but also kinetically produce E-olefins, a previously unmet challenge in olefin metathesis. Advancements in stereoretentive olefin metathesis using tungsten, ruthenium, and molybdenum catalysts are presented.

Ruthenium-catalyzed C-C coupling of amino alcohols with dienes via transfer hydrogenation: redox-triggered imine addition and related hydroaminoalkylations.

Ruthenium-catalyzed hydrogen transfer from 4-aminobutanol to butadiene results in the pairwise generation of 3,4-dihydro-2H-pyrrole and an allylruthenium complex, which combine to form products of imine anti-crotylation. In couplings of 1-substituted-1,3-dienes, novel C2 regioselectivity is observed. As corroborated by deuterium labeling studies, kinetically preferred hydrometalation of the terminal olefin of the 1-substituted-1,3-diene delivers a 1,1-disubstituted π-allylruthenium complex that isomerizes to a thermodynamically more stable monosubstituted π-allylruthenium complex, which undergoes imine addition with allylic inversion through a closed transition structure. Direct ruthenium-catalyzed diene hydroaminoalkylations with pyrrolidine also are described.

Comparison of reproductive performance of primiparous dairy cattle following revaccination with either modified-live or killed multivalent viral vaccines in early lactation.

The objective of this randomized clinical trial was to compare the effect of revaccination in primiparous dairy cows with modified live viral (MLV) or killed viral (KV) vaccines containing bovine viral diarrhea virus (BVDV) and bovine herpesvirus-1 (BoHV-1) on (1) pregnancy rate following estrus synchronization-timed artificial insemination (TAI), (2) serum progesterone concentrations, and (3) serum neutralizing antibody titers at revaccination and at TAI. Primiparous dairy cows (n=692) that had been previously vaccinated with 4 doses of MLV vaccine as calves or heifers were randomized to receive either an MLV or a KV vaccine between 21 and 28 d in milk and 17 d before initiation of a double-Ovsynch-TAI protocol. Serum was collected within the double-Ovsynch protocol for determination of progesterone concentrations, and at vaccination and TAI for serum neutralizing antibody titers. Ultrasound pregnancy determinations were made at 30 and 60 d after TAI. No differences in pregnancy rates were observed between cows receiving MLV vaccine (44%; n=326) or KV vaccine (43%; n=336). No differences were observed in serum progesterone concentrations during a double-Ovsynch-TAI protocol between cows receiving MLV and KV vaccines. No differences were observed in BVDV 1 or BVDV 2 antibody titers at vaccination and TAI between cows receiving MLV or KV vaccine; however, BoHV-1 antibody titers were greater at TAI in cows receiving KV vaccine. Overall response to vaccination-defined as the percent of all individual cows that had any detectable increase in antibody titer from vaccination to TAI-was 39% for BVDV 1, 45% for BVDV 2, and 61% for BoHV-1. In this research, use of an MLV vaccine did not impede reproduction when revaccination was performed between 21 and 28 DIM and just before enrollment in an estrus synchronization-TAI program in primiparous dairy cows; however, response to vaccination as defined by increases in virus-specific antibody titers could be considered less than ideal for this population of cattle.

Benzannulation via ruthenium-catalyzed diol-diene [4+2] cycloaddition: one- and two-directional syntheses of fluoranthenes and acenes.

A new benzannulation protocol is described and applied to the synthesis of polycyclic aromatic hydrocarbons. Ruthenium(0)-catalyzed diol-diene [4+2] cycloaddition delivers cyclohex-1-ene-4,5-diols, which are subject to aromatization upon dehydration or Nicholas diol deoxydehydration. Employing diol and tetraol reactants, benzannulation can be conducted efficiently in one- and two-directional modes, respectively, as illustrated in the construction of substituted fluoranthenes and acenes.

Catalytic enantioselective C-H functionalization of alcohols by redox-triggered carbonyl addition: borrowing hydrogen, returning carbon.

The use of alcohols and unsaturated reactants for the redox-triggered generation of nucleophile-electrophile pairs represents a broad, new approach to carbonyl addition chemistry. Discrete redox manipulations that are often required for the generation of carbonyl electrophiles and premetalated carbon-centered nucleophiles are thus avoided. Based on this concept, a broad, new family of enantioselective C-C coupling reactions that are catalyzed by iridium or ruthenium complexes have been developed, which are summarized in this Minireview.

An update on lipophilic efficiency as an important metric in drug design.

INTRODUCTION: Lipophilic efficiency (LipE) and lipophilic metabolic efficiency (LipMetE) are valuable tools that can be utilized as part of a multiparameter optimization process to advance a hit to a clinical quality compound. AREAS COVERED: This review covers recent, effective use cases of LipE and LipMetE that have been published in the literature over the past 5 years. These use cases resulted in the delivery of high-quality molecules that were brought forward to in vivo work and/or to clinical studies. The authors discuss best-practices for using LipE and LipMetE analysis, combined with lipophilicity-focused compound design strategies, to increase the speed and effectiveness of the hit to clinical quality compound optimization process. EXPERT OPINION: It has become well established that increasing LipE and LipMetE within a series of analogs facilitates the improvement of broad selectivity, clearance, solubility, and permeability and, through this optimization, also facilitates the achievement of desired pharmacokinetic properties, efficacy, and tolerability. Within this article, we discuss lipophilic efficiency-focused optimization as a tool to yield high-quality potential clinical candidates. It is suggested that LipE/LipMetE-focused optimization can facilitate and accelerate the drug-discovery process.

Ruthenium catalyzed hydrohydroxyalkylation of isoprene with heteroaromatic secondary alcohols: isolation and reversible formation of the putative metallacycle intermediate.

Heteroaromatic secondary alcohols react with isoprene to form products of hydrohydroxyalkylation in the presence of ruthenium(0) catalysts generated from Ru3(CO)12 and tricyclohexylphosphine, enabling direct conversion of secondary to tertiary alcohols in the absence of premetalated reagents or stoichiometric byproducts. The putative oxaruthenacycle intermediate has been isolated and characterized, and reversible metallacycle formation has been demonstrated.

Spin Josephson vortices in two tunnel-coupled spinor Bose gases.

We study topological excitations in spin-one Bose-Einstein condensates trapped in an elongated double-well optical potential. This system hosts a new topological defect, the spin Josephson vortex (SJV), which forms due to the competition between the interwell atomic tunneling and short-range ferromagnetic two-body interaction. We identify the spin structure and formation dynamics of the SJV and determine the phase diagram of the system. By exploiting the intrinsic stability of the SJV, we propose a dynamical method to create SJVs under realistic experimental conditions.

Enantioselective conversion of primary alcohols to α-exo-methylene γ-butyrolactones via iridium-catalyzed C-C bond-forming transfer hydrogenation: 2-(alkoxycarbonyl)allylation.

Upon exposure of acrylic ester 1 to alcohols 2a-i in the presence of a cyclometalated iridium catalyst modified by (-)-TMBTP, catalytic C-C coupling occurs, providing enantiomerically enriched 5-substituted α-exo-methylene γ-butyrolactones 3a-i. Bromination of the methylene butyrolactone products followed by zinc-mediated reductive aldehyde addition provides the disubstituted α-exo-methylene γ-butyrolactones 6a and 6b with good to excellent levels of diastereoselectivity.

Assessing What Matters Most in Older Adults With Multicomplexity.

BACKGROUND AND OBJECTIVES: Abilities and activities that are often simultaneously valued may not be simultaneously achievable for older adults with multicomplexity. Because of this, the Geriatrics 5Ms framework prioritizes care on "what matters most." This study aimed to evaluate and refine the What Matters Most-Structured Tool (WMM-ST). RESEARCH DESIGN AND METHODS: About 105 older adults with an average of 4 chronic conditions completed the WMM-ST along with open-ended questions from the Serious Illness Conversation Guide. Participants also provided demographic and social information, completed cognitive screening with the Telephone-Montreal Cognitive Assessment-Short and frailty screening with the Frail scale. Quantitative and qualitative analyses aimed to (a) describe values; (b) evaluate the association of patient characteristics with values; and (c) assess validity via the tool's acceptability, educational bias, and content accuracy. RESULTS: Older adults varied in what matters most. Ratings demonstrated modest associations with social support, religiosity, cognition, and frailty, but not with age or education. The WMM-ST was rated as understandable (86%) and applicable to their current situation (61%) independent of education. Qualitative analyses supported the content validity of WMM-ST, while revealing additional content. DISCUSSION AND IMPLICATIONS: It is possible to assess what matters most to older adults with multicomplexity using a structured tool. Such tools may be useful in making an abstract process clearer but require further validation in diverse samples.

Advancing Your Confidence as an Educator (ACE): An Academic-VA Partnership to Enhance Educator Skills and Improve Attitudes About Careers in Aging.

Previous research suggests some psychologists may not consider academic careers because of doubts about their teaching competency, and this is especially true for psychologists interested in aging (i.e., geropsychologists). To enhance competencies in the practice of education, we developed a webinar series, Advancing Your Confidence as an Educator, to bolster skills and attitudes toward teaching and improve attitudes about careers in aging. Seven hour-long webinars addressed key skills in developing and executing courses and professional presentations, and 2 panel sessions addressed attitudes toward teaching by featuring early- and later-career professionals discussing their paths to and satisfaction with jobs as educators. Attendance across the highly interactive sessions was robust (M = 50). Evaluation data suggest the webinar was effective in meeting educational needs. To promote sustainable impact, the webinars are archived and freely available online. Challenges in marketing and evaluation arose, but overall, this effort is one way of cultivating a more vigorous interest and self-confidence in teaching.

Differential Diagnoses and Clinical Implications of Medication Nonadherence in Older Patients with Chronic Kidney Disease: A Review.

Older adults with chronic kidney disease (CKD) often have many comorbidities, which requires them to take multiple medications. As the number of daily medications prescribed increases, the risk for polypharmacy increases. Understanding and improving medication adherence in this patient population is vital to avoiding the drug-related adverse events of polypharmacy. The primary objective of this review is to summarize the existing literature and to understand the factors leading to medication nonadherence in older patients with CKD. In this review, we discuss the prevalence of polypharmacy, the current lack of consensus on the incidence of medication nonadherence, the heterogeneity of assessing medication adherence, and the most common differential diagnoses for medication nonadherence in this population. Specifically, the most common differential diagnoses for medication nonadherence in older adults with CKD are (1) medication complexity; (2) cognitive impairment; (3) low health literacy; and (4) systems-based barriers. We provide tailored strategies to address these differential diagnoses and subsequently improve medication adherence. The clinical implications include deprescribing to decrease medication complexity and polypharmacy, utilizing a team-based approach to identify and support patients with cognitive impairment, enriching communication between health providers and patients with low health literacy, and improving health care access to address systems-based barriers. Further research is needed to determine the effects of addressing these differential diagnoses and medication adherence in older adults with CKD.

Development of a Late-Stage Diversification Strategy for the 4- and 5-Positions of 4,5,6-Trisubstituted Indazoles.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.