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Due to insufficient emission reductions in recent years, it is increasingly likely that global warming will exceed the 1.5 °C temperature limit in the late 2020s or 2030s. As a result, several Earth system tipping elements could, at least temporarily, have their tipping points surpassed, posing risks of large-scale and profound structural change. Tipping does not always occur immediately upon crossing such a critical threshold. If the length of time the driver is beyond the critical level is short enough, tipping could still be avoided for some slow-responding elements of the climate system. An improved understanding is therefore needed of whether tipping remains avoidable, for which systems, and under what conditions. Here, we review how minimising the magnitude and duration of any temperature overshoot beyond 1.5 °C could decrease tipping risks. Tipping elements with fast response times, such as warm-water coral reefs, are especially vulnerable to overshoot. In contrast, those with slow response times, such as polar ice sheets, may be less sensitive to temporary overshoot. Potential interactions between tipping elements and additional human pressures, such as deforestation in the Amazon or pollution and overfishing of coral reef habitats, may further lower tipping points, narrowing the range of overshoot trajectories that can still avoid it. The vulnerability of many tipping elements, even under shorter overshoot conditions, underscores that global warming must peak below 2 °C above pre-industrial levels, return to below 1.5 °C as quickly as possible (i.e. within this century), and to around 1 °C thereafter to limit tipping point risks.

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Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN–BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein–protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.

To compare a Posttraumatic Stress Disorder (PTSD) treatment (Cognitive Processing Therapy; CPT), an Alcohol Use Disorder (AUD) treatment (Relapse Prevention; RP), and assessment-only (AO) for those meeting diagnostic criteria for both PTSD and AUD. Participants with current PTSD/AUD (N = 101; mean age = 42.10; 56% female) were initially randomized to CPT, RP, or AO and assessed post-treatment or 6-weeks post-randomization (AO). AO participants were then re-randomized to CPT or RP. Follow-ups were at immediate post-treatment, 3-, and 12-months. Mixed effects intent-to-treat models compared conditions on changes in PTSD symptom severity, drinking days, and heavy drinking days. At post-treatment, participants assigned to CPT showed significantly greater improvement than those in AO on PTSD symptom severity (b = -9.72, 95% CI [-16.20, -3.23], d = 1.22); the RP and AO groups did not differ significantly on PTSD. Both active treatment conditions significantly decreased heavy drinking days relative to AO (CPT vs. AO: Count Ratio [CR] = 0.51, 95% CI [0.30, 0.88]; RP vs. AO: CR = 0.34, 95% CI [0.19, 0.59]). After re-randomization both treatment conditions showed substantial improvements in PTSD symptoms and drinking between pre-treatment and post-treatment over the 12-month follow-up period, with RP showing an advantage on heavy drinking days. Treatments targeting one or the other aspects of the PTSD/AUD comorbidity may have salutary effects on both PTSD and drinking outcomes. These preliminary results suggest that people with this comorbidity may have viable treatment options whether they present for mental health or addiction care. The trial is registered at clinicaltrials.gov (NCT01663337).

Steps to facilitate inter-jurisdictional collaboration nationally and continentally have been critical for implementing and conducting coordinated wildlife rabies management programs that rely heavily on oral rabies vaccination (ORV). Formation of a national rabies management team has been pivotal for coordinated ORV programs in the United States of America. The signing of the North American Rabies Management Plan extended a collaborative framework for coordination of surveillance, control, and research in border areas among Canada, Mexico, and the US. Advances in enhanced surveillance have facilitated sampling of greater scope and intensity near ORV zones for improved rabies management decision-making in real time. The value of enhanced surveillance as a complement to public health surveillance was best illustrated in Ohio during 2007, where 19 rabies cases were detected that were critical for the formulation of focused contingency actions for controlling rabies in this strategically key area. Diverse complexities and challenges are commonplace when applying ORV to control rabies in wild meso-carnivores. Nevertheless, intervention has resulted in notable successes, including the elimination of an arctic fox (Vulpes lagopus) rabies virus variant in most of southern Ontario, Canada, with ancillary benefits of elimination extending into Quebec and the northeastern US. Progress continues with ORV toward preventing the spread and working toward elimination of a unique variant of gray fox (Urocyon cinereoargenteus) rabies in west central Texas. Elimination of rabies in coyotes (Canis latrans) through ORV contributed to the US being declared free of canine rabies in 2007. Raccoon (Procyon lotor) rabies control continues to present the greatest challenges among meso-carnivore rabies reservoirs, yet to date intervention has prevented this variant from gaining a broad geographic foothold beyond ORV zones designed to prevent its spread from the eastern US. Progress continues toward the development and testing of new bait-vaccine combinations that increase the chance for improved delivery and performance in the diverse meso-carnivore rabies reservoir complex in the US.

ObjectiveChronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear.DesignUsing an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation.ResultsFMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes.ConclusionThe gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.

BackgroundOpioid overdose is a major and increasing cause of injury and death. There is an urgent need for interventions to reduce overdose events among high-risk persons.MethodsAdults at elevated risk for opioid overdose involving heroin or pharmaceutical opioids who had been cared for in an emergency department (ED) were randomised to overdose education combined with a brief behavioural intervention and take-home naloxone or usual care. Outcomes included: (1) time to first opioid overdose-related event resulting in medical attention or death using competing risks survival analysis; and (2) ED visit and hospitalisation rates, using negative binomial regression and adjusting for time at risk.ResultsDuring the follow-up period, 24% of the 241 participants had at least one overdose event, 85% had one or more ED visits and 55% had at least one hospitalisation, with no significant differences between intervention and comparison groups. The instantaneous risk of an overdose event was not significantly lower for the intervention group (sub-HR: 0.83; 95% CI 0.49 to 1.40).DiscussionThese null findings may be due in part to the severity of the population in terms of housing insecurity (70% impermanently housed), drug use, unemployment and acute healthcare issues. Given the high overdose and healthcare utilisation rates, more intensive interventions, such as direct referral and provision of housing and opioid agonist treatment medications, may be necessary to have a substantial impact on opioid overdoses for this high-acuity population in acute care settings.Trial registration numberNCT0178830; Results.

Background Chronic pain is a prevalent and costly problem that often has occupational origins. Home care workers (HCWs) are at high risk for work-related injuries, pain, and disability. Current treatments for chronic pain emphasize medications, which are an inadequate stand-alone treatment and can produce significant adverse effects. Methods In this translational study, we will adapt an established work-based injury prevention and health promotion program (COMmunity of Practice And Safety Support: COMPASS) to address the needs of HCWs experiencing chronic pain. COMPASS employs peer-led, scripted group meetings that include educational content, activities, goal setting, and structured social support. The translated intervention, named COMPASS for Navigating Pain (COMPASS-NP), will be delivered in an online group format. Safety protections will be strengthened through an ergonomic self-assessment and vouchers for purchasing ergonomic tools. Educational content will integrate a self-management approach to chronic pain using proven cognitive-behavioral therapy (CBT) principles. We will use a mixed-methods hybrid type 2 evaluation approach to assess effectiveness and implementation. A cluster-randomized waitlist control design will involve 14 groups of 10 HCWs ( n  = 140) recruited from Washington, Oregon, and Idaho. Half of the groups will be randomly selected to complete the intervention during the first 10 weeks, while the waitlist groups serve as controls. During weeks 10–20, the waitlist groups will complete the intervention while the original intervention groups complete a follow-up period without further intervention. Our primary hypothesis is that COMPASS-NP will reduce pain interference with work and life. Secondary outcomes include injury and pain prevention behaviors, pain severity, changes in medication use, risk for opioid misuse, well-being, physical activity, and sleep. Qualitative data, including phone interviews with group facilitators and organizational partners, will evaluate the implementation and guide dissemination. Discussion The results will advance the use and knowledge of secondary prevention interventions such as ergonomic tools and cognitive behavior therapy, to reduce injury, pain, and disability and to encourage appropriate uses of analgesic medications among HCWs. Trial registration ClinicalTrials.gov NCT05492903. Registered on 08 August 2022

Despite high rates of alcohol abstinence, Alaska Native and American Indian (ANAI) people experience a disproportionate burden of alcohol-related morbidity and mortality. Multiple barriers to treatment exist for this population, including a lack of culturally relevant resources; limited access to or delays in receiving treatment; and privacy concerns. Many ANAI people in the state of Alaska, United States, live in sparsely populated rural areas, where treatment access and privacy concerns regarding peer-support programs may be particularly challenging. In addition, prior research demonstrates that many ANAI people prefer a self-management approach to sobriety, rather than formal treatment. Taken together, these factors suggest a potential role for a culturally adapted smartphone app to support ANAI people interested in changing their behavior regarding alcohol use. This study was the first phase of a feasibility and acceptability study of a culturally tailored version of an off-the-shelf smartphone app to aid ANAI people in managing or reducing their use of alcohol. The aim of this qualitative needs assessment was to gather insights and preferences from ANAI people and health care providers serving ANAI people to guide feature development, content selection, and cultural adaptation before a pilot test of the smartphone app with ANAI people. From October 2018 to September 2019, we conducted semistructured interviews with 24 ANAI patients aged ≥21 years and 8 providers in a tribal health care organization in south-central Alaska. Participants generally endorsed the usefulness of a smartphone app for alcohol self-management. They cited anonymity, 24/7 access, peer support, and patient choice as key attributes of an app. The desired cultural adaptations included ANAI- and land-themed design elements, cultural content (eg, stories from elders), and spiritual resources. Participants considered an app especially useful for rural-dwelling ANAI people, as well as those who lack timely access to treatment services or prefer to work toward managing their alcohol use outside the clinical setting. This needs assessment identified key features, content, and cultural adaptations that are being implemented in the next phase of the study. In future work, we will determine the extent to which these changes can be accommodated in a commercially available app, the feasibility of implementation, and the acceptability of the culturally adapted version of the app among ANAI users.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited multi-system disorder that affects skeletal muscles but also many other organ systems. Molecular targets have been identified and targeted therapies are being developed and tested in first-in-human clinical trials. However, insufficient knowledge of the phenotypic heterogeneity and natural course of the disease, together with a lack of reliable biomarkers, complicate the design of clinical trials. The main objectives of this study are to 1) characterize the phenotypic heterogeneity and disease progression of DM1 in a large cohort; 2) identify baseline characteristics that predict subsequent progression; 3) validate RNA biomarkers of disease severity. This is a prospective, multi-site observational study with a follow-up period of 24 months including approximately 700 adult DM1 patients. Visits will occur at baseline, and months 12 and 24. All patients will undergo strength testing, myotonia assessment, a battery of functional outcome assessments, spirometry, and complete various questionnaires and cognitive tests. Blood and urine samples will be taken at each visit for biomarker studies. A subset of 60 patients will undergo a muscle biopsy at baseline and at an additional 3-month visit. The sensitivity to disease progression and minimally clinically important differences will be determined for the various clinical outcome measures. Associations between baseline patient characteristics and the rate of disease progression will be evaluated. The results of this large international study on DM1 will contribute to optimizing clinical trial design. Both data and biological samples will be collected for future research as well. Clinicaltrials.gov NCT03981575.