Context-Specific Stress Causes Compartmentalized SARM1 Activation and Local Degeneration in Cortical Neurons.

Sterile alpha and TIR motif containing 1 (SARM1) is an inducible NADase that localizes to mitochondria throughout neurons and senses metabolic changes that occur after injury. Minimal proteomic changes are observed upon either SARM1 depletion or activation, suggesting that SARM1 does not exert broad effects on neuronal protein homeostasis. However, whether SARM1 activation occurs throughout the neuron in response to injury and cell stress remains largely unknown. Using a semiautomated imaging pipeline and a custom-built deep learning scoring algorithm, we studied degeneration in both mixed-sex mouse primary cortical neurons and male human-induced pluripotent stem cell-derived cortical neurons in response to a number of different stressors. We show that SARM1 activation is differentially restricted to specific neuronal compartments depending on the stressor. Cortical neurons undergo SARM1-dependent axon degeneration after mechanical transection, and SARM1 activation is limited to the axonal compartment distal to the injury site. However, global SARM1 activation following vacor treatment causes both cell body and axon degeneration. Context-specific stressors, such as microtubule dysfunction and mitochondrial stress, induce axonal SARM1 activation leading to SARM1-dependent axon degeneration and SARM1-independent cell body death. Our data reveal that compartment-specific SARM1-mediated death signaling is dependent on the type of injury and cellular stressor.

Climate-conscious inhaler prescribing for family physicians.

OBJECTIVE: To provide family physicians with prescribing and diagnostic strategies that can reduce carbon emissions associated with inhalers. SOURCES OF INFORMATION: This review is based on the authors' experience developing the climate-conscious inhaler prescribing playbooks and courses for CASCADES (Creating a Sustainable Canadian Health System in a Climate Crisis). The approach was refined through patient and provider feedback since the first playbook was published in 2021. PubMed was also searched for relevant publications on inhaler use, asthma management, and chronic obstructive pulmonary disease (COPD) management. Current asthma and COPD guidelines were also reviewed. MAIN MESSAGE: There is growing acknowledgment of the substantial impact that inhalers have on climate emissions generated by the health sector. Recent surveys indicate that most Canadian patients care about climate change and would be willing to opt for less carbon-intensive treatment and care delivery options where available. Beyond inhaler choice, there are many opportunities to address the climate impacts of respiratory care and enhance quality of care. Working with patients to ensure they are using the right medications in the right ways will produce both carbon savings and better health outcomes. The climate crisis can therefore serve as a catalyst for improving treatment of patients with respiratory conditions. Family physicians may reduce carbon emissions associated with inhalers by reducing unnecessary inhaler prescribing; ensuring patients' control of asthma and COPD is optimized; considering whether a more sustainable inhaler may be appropriate; optimizing dosing technique to reduce emissions and waste; and disposing of inhalers appropriately if possible. CONCLUSION: Family physicians may reduce carbon emissions associated with inhalers through the following strategies: confirming diagnosis, controlling disease, considering inhaler type, optimizing dosing technique, and encouraging appropriate disposal.

Iron-Catalyzed Hydrobenzylation: Stereoselective Synthesis of (-)-Eugenial C.

Metal-hydride hydrogen atom transfer (MHAT) has emerged as a useful tool to form quaternary carbons from alkenes via hydrofunctionalization. Methods to date that cross-couple alkenes with sp3 partners rely on heterobimetallic catalysis to merge the two cycles. Here, we report an iron-only cross-coupling via putative MHAT/SH2 steps that solves a key stereochemical problem in the synthesis of meroterpenoid eugenial C and obviates the need for nickel. The concise synthesis benefits from a conformationally locked o,o'-disubstituted benzyl bromide and a locally sourced chiral pool terpene coupling partner.

Ocular abnormalities at diagnosis and after the completion of treatment in children and adolescents with newly diagnosed acute lymphoblastic leukemia.

BACKGROUND: Ocular abnormalities (OA) in pediatric patients with acute lymphoblastic leukemia (ALL) are common findings both at diagnosis and later in follow-up. The frequency, predictors, and prognostic impact of OA in the context of recent ALL protocols are not well characterized. PROCEDURE: Single-center retrospective analysis of the medical records of 224 patients with ALL enrolled on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. RESULTS: Overall, 217 (98%) patients had at least one ophthalmic exam. Retinal hemorrhages were the most frequent abnormalities at diagnosis (11%) and cataracts at later time points (13%). OA at diagnosis were associated with age ≥10 years and with the severity of anemia and thrombocytopenia; they were also univariately associated with lower 5-year event-free survival (EFS) (high risk [HR] = 3.09 [95% CI: 1.38-6.94]; p = .006), but not in a disease-free survival (DFS) model adjusted for end-induction minimal residual disease (p = .82). The cumulative incidence of cataract was 13.1% ± 2.8% at 43 months from diagnosis; its development was associated with high presenting white blood cell count (≥50,000/µl) (p = .010), male sex (p = .036), higher risk group (p = .025), and cranial radiation (p = .004). Cataract was associated with decreased visual acuity. CONCLUSIONS: OA at diagnosis, present in 12% of patients, were associated with older age, anemia, and thrombocytopenia and did not carry a significant prognostic impact. Cataracts were detected in over 10% of patients and were associated with decreased visual acuity, thus supporting routine screening after completion of therapy, especially for those treated with high-risk protocols.

Cycling for health: Improving health and mitigating the climate crisis.

OBJECTIVE: To review the literature about cycling and health, and to provide an overview and discussion of the available evidence. SOURCES OF INFORMATION: The MeSH terms bicycle and transportation were searched in PubMed. Clinical trials, practice reviews, and systematic reviews were included. All reference lists were reviewed for additional articles. MAIN MESSAGE: Climate change is a threat to health. In Canada alone, transportation is the second largest source of greenhouse gas emissions. Active transportation, which is any form of human-powered transportation, can mitigate the health effects of the climate crisis while simultaneously improving the health of people. Physical activity improves overall well-being, as well as physical and mental health. Active transportation, particularly cycling, is a convenient way to meet physical activity targets, reduce risk of disease and all-cause mortality, and derive mental health and social benefits. Family physician advocacy for active transportation has been shown to increase cycling levels in patients compared with no physician advocacy. CONCLUSION: Family physicians can help to increase the level of active transportation at the individual patient level through patient education and behaviour change counseling; at the community level through community education and political advocacy; and at the policy level through partnerships with larger organizations.

Integrating social justice advocacy into a family health team: Successes and lessons learned.

PROBLEM ADDRESSED: Health is largely determined by socioeconomic factors. Health care providers can potentially address these factors through social justice advocacy. However, many individual providers and teams have not taken on this role in Canada. OBJECTIVE OF PROGRAM: To address identified barriers in integrating social justice advocacy into the practice of individual health care providers and interdisciplinary teams. PROGRAM DESCRIPTION: An Advocacy Tool Kit was created in 2017 to build individual capacity for social justice advocacy. An advocacy framework was adopted in 2018 that reiterated the commitment of the Department of Family and Community Medicine at St Michael's Hospital in Toronto, Ont, to social justice advocacy and outlined 2 new processes: to adopt and implement specific departmentwide campaigns to advocate for social justice; and to respond to inquiries about social justice issues and external advocacy campaigns. CONCLUSION: The initiatives have helped integrate social justice advocacy into the core activities of the interdisciplinary primary care team and can likely be replicated by other interested groups across the country.

Addressing financial strain through a peer-to-peer intervention in primary care.

BACKGROUND: Financial strain is a key social determinant of health. As primary care organizations begin to explore ways to address social determinants, peer-to-peer interventions hold promise. OBJECTIVE: Our objective was to evaluate a peer-to-peer intervention focussed on financial empowerment delivered in primary care, in partnership with a social enterprise. METHODS: This intervention was hosted by a large primary care organization in Toronto, Canada. Participants were recruited within the organization and from local services. We organized three separate groups who met over 10 weekly in-person, facilitated sessions: millennials (age 19-29) no longer in school, precariously employed adults (age 30-55) and older adults near retirement (age 55-64). We applied principles of adult education and peer-to-peer learning. We administered surveys at intake, at exit and at 3 months after the intervention, and conducted three focus groups. RESULTS: Fifty-nine people took part. At 3 months, participants had sustained higher rates of optimism about their financial situation (54% improved from baseline), their degree of control (55% improved) and stress around finances (50% improved). In focus groups, participants reported greater understanding of their finances, that they were not alone in struggling with finances, and that it was useful to meet with others. One group continued to meet for several months after the intervention. CONCLUSIONS: In this study, a peer-to-peer intervention helped address a key social determinant of health, likely through reducing stigma, providing group support and creating a space to discuss solutions. Primary care can host these interventions and help engage potential participants.

Chimpanzee ranging responses to fruit availability in a high-elevation environment.

Most primates experience seasonal fluctuations in the availability of food resources and face the challenge of balancing energy expenditure with energy gain during periods of resource scarcity. This is likely to be particularly challenging in rugged, montane environments, where available energy is relatively low and travel costs are high. Chimpanzees (Pan troglodytes) show extensive behavioral diversity across study sites. Yet, as most research has focused on low- and mid-elevation sites, little is known on how chimpanzees respond to periods of low fruit availability in harsh montane environments. We use focal follow and phenology data to investigate how fruit availability influences daily path length and monthly home range in chimpanzees living in Nyungwe National Park, a montane forest in Rwanda. Nyungwe chimpanzees decreased their daily travel distances during periods of fruit scarcity. However, this decrease in travel effort did not correspond with a decrease in foraging area. Instead, monthly homes ranges shifted location across the study period. Nyungwe chimpanzees occupy a relatively wide altitudinal range and the shifts in monthly home range location may reflect differences in the altitudinal distribution of food resources. Chimpanzee monthly diet was often dominated by one or two species and each of these species were confined to different elevation zones. One important species, Podocarpus latifolius, grew only at high elevations (2,600-2,950 m) and chimpanzees ranged at the altitudinal peak of their range for 2 consecutive months while feeding on this species. Thus, while high elevations are often thought to be harsh environments for primates, they can be an important part of a species' home range when they provide a refugium for densely distributed, important food species.

Cycloisomerization of Olefins in Water.

Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel-Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.

Hydroalkylation of Olefins To Form Quaternary Carbons.

Metal-hydride hydrogen atom transfer (MHAT) functionalizes alkenes with predictable branched (Markovnikov) selectivity. The breadth of these transformations has been confined to π-radical traps; no sp3 electrophiles have been reported. Here we describe a Mn/Ni dual catalytic system that hydroalkylates unactivated olefins with unactivated alkyl halides, yielding aliphatic quaternary carbons.

Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support.

DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, noncovalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp2)-C(sp3) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. The utility of these reactions was demonstrated through a DEL-rehearsal in which all newly developed chemistries were orchestrated to afford a compound rich in diverse skeletal linkages. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.

The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer.

The implementation of any chemical reaction in a structurally complex setting ( King , S. M. J. Org. Chem. 2014 , 79 , 8937 ) confronts structurally defined barriers: steric environment, functional group reactivity, product instability, and through-bond electronics. However, there are also practical barriers. Late-stage reactions conducted on small quantities of material are run inevitably at lower than optimal concentrations. Access to late-stage material limits extensive optimization. Impurities from past reactions can interfere, especially with catalytic reactions. Therefore, chemical reactions on which one can rely at the front lines of a complex synthesis campaign emerge from the crucible of total synthesis as robust, dependable, and widely applied. Trost conceptualized "chemoselectivity" as a reagent's selective reaction of one functional group or reactive site in preference to others ( Trost , B. M. Science 1983 , 219 , 245 ). Chemoselectivity and functional group tolerance can be evaluated quickly using robustness screens ( Collins , K. D. Nat. Chem. 2013 , 5 , 597 ). A reaction may also be characterized by its "chemofidelity", that is, its reliable reaction with a functional group in any molecular context. For example, ketone reduction by an electride (dissolving metal conditions) exhibits high chemofidelity but low chemoselectivity: it usually works, but many other functional groups are reduced at similar rates. Conversely, alkene coordination chemistry effected by π Lewis acids can exhibit high chemoselectivity ( Trost , B. M. Science 1983 , 219 , 245 ) but low chemofidelity: it can be highly selective for alkenes but sensitive to the substitution pattern ( Larionov , E. Chem. Commun. 2014 , 50 , 9816 ). In contrast, alkenes undergo reliable, robust, and diverse hydrogen atom transfer reactions from metal hydrides to generate carbon-centered radicals. Although there are many potential applications of this chemistry, its functional group tolerance, high rates, and ease of execution have led to its rapid deployment in complex synthesis campaigns. Its success derives from high chemofidelity, that is, its dependable reactivity in many molecular environments and with many alkene substitution patterns. Metal hydride H atom transfer (MHAT) reactions convert diverse, simple building blocks to more stereochemically and functionally dense products ( Crossley , S. W. M. Chem. Rev. 2016 , 116 , 8912 ). When hydrogen is returned to the metal, MHAT can be considered the radical equivalent of Brønsted acid catalysis-itself a broad reactivity paradigm. This Account summarizes our group's contributions to method development, reagent discovery, and mechanistic interrogation. Our earliest contribution to this area-a stepwise hydrogenation with high chemoselectivity and high chemofidelity-has found application to many problems. More recently, we reported the first examples of dual-catalytic cross-couplings that rely on the merger of MHAT cycles and nickel catalysis. With time, we anticipate that MHAT will become a staple of chemical synthesis.

Development of a high number, high coverage dog rabies vaccination programme in Sri Lanka.

BACKGROUND: Rabies is estimated to cause 59,000 deaths and economic losses of US$8.6 billion every year. Despite several years of rabies surveillance and awareness programmes, increased availability of post-exposure prophylaxis vaccinations and dog population control, the disease still remains prevalent in Sri Lanka. This study reports the roll-out of a high number, high coverage canine rabies vaccination campaign in Sri Lanka, providing estimates for the vaccination coverage achieved, analysing the local dog demographics, and identifying barriers of attendance to static vaccination clinics. METHODS: A mass dog vaccination campaign was undertaken in Negombo, Sri Lanka. The campaign was composed of static point and door-to-door vaccination stages, with a final survey of vaccination coverage. A large volume of data on the distribution, health, and signalment of vaccinated dogs was collected through a mobile phone application. A logistic regression model was developed to investigate which socio-spatial and dog-related factors influenced attendance of owners to static vaccination points. RESULTS: The campaign vaccinated over 7800 dogs achieving a vaccination coverage of 75.8%. A dog:human ratio of 1:17 was estimated. Most dogs were owned, and the dog population was mostly male, adult, and non-sterilized. Unawareness, unavailability and handling problems were the most common reasons given by owners to explain failure to attend a static vaccination point. The regression analysis showed that increasing distance to a static point, in addition to young age and poor health of the dog, were associated with a decrease in the likelihood of attendance to a static vaccination points. CONCLUSION: This study demonstrates the feasibility of high number, high coverage vaccination campaigns in Sri Lanka. The information on dog ecology and barriers of attendance to static point vaccination clinics will facilitate development of future vaccination campaigns.

Attachment to primary care and team-based primary care: Retrospective cohort study of people who experienced imprisonment in Ontario.

OBJECTIVE: To examine attachment to primary care and team-based primary care in the community for people who experienced imprisonment in Ontario, and to compare these attachment data with data for the general population. DESIGN: Population-based retrospective cohort study. SETTING: Ontario. PARTICIPANTS: All persons released from provincial prison in Ontario to the community in 2010 who were linked with provincial health administrative data, and an age- and sex-matched general population group. MAIN OUTCOME MEASURES: Primary care attachment and team-based primary care attachment in the 2 years before admission to provincial prison (baseline) and in the 2 years after release in 2010 (follow-up) for the prison release group, and for the corresponding periods for the general population group. RESULTS: People in the prison release group (n = 48 861) were less likely to be attached to primary care compared with the age- and sex-matched general population group (n = 195 444), at 58.9% versus 84.1% at baseline (P < .001) and 63.0% versus 84.4% during follow-up (P < .001), respectively. The difference in attachment to team-based primary care was small in magnitude but statistically significant, at 14.4% versus 16.1% at baseline (P < .001) and 19.9% versus 21.6% during follow-up (P < .001), respectively. CONCLUSION: People who experience imprisonment have lower primary care attachment compared with the general population. Efforts should be made to understand barriers and to facilitate access to high-quality primary care for this population, including through initiatives to link people while in prison with primary care in the community.

Iron-Nickel Dual-Catalysis: A New Engine for Olefin Functionalization and the Formation of Quaternary Centers.

Alkene hydroarylation forms carbon-carbon bonds between two foundational building blocks of organic chemistry: olefins and aromatic rings. In the absence of electronic bias or directing groups, only the Friedel-Crafts reaction allows arenes to engage alkenes with Markovnikov selectivity to generate quaternary carbons. However, the intermediacy of carbocations precludes the use of electron-deficient arenes, including Lewis basic heterocycles. Here we report a highly Markovnikov-selective, dual-catalytic olefin hydroarylation that tolerates arenes and heteroarenes of any electronic character. Hydrogen atom transfer controls the formation of branched products and arene halogenation specifies attachment points on the aromatic ring. Mono-, di-, tri-, and tetra-substituted alkenes yield Markovnikov products including quaternary carbons within nonstrained rings.