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In response to a surge of drug overdoses involving polysubstance use among Atlanta service industry workers that resulted in the deaths of five people in the Atlanta area in the summer of 2021, a local community of harm reductionists and nurses organized opioid education and naloxone distribution (OEND) training sessions specifically customized for service industry workers in Atlanta. After the sessions, the nurses and harm reductionists asked attendants to participate in a study concerning their response to overdoses. The reason nurses and harm reductionists conducted the study was to determine the efficacy of OEND training adapted for those working in the service industries as well as to evaluate and possibly modify the training sessions for future use. This pre-post study examined if and how participants' knowledge and attitudes toward an opioid-involved overdose changed after engaging with the OEND training. If the study determined that the sessions were successful in teaching service industry workers how to mitigate the immediate and devastating effects of overdose, we recommend expanding and implementing both adaptable training sessions like the OEND training referenced, as well as accompanying studies to improve the training sessions' effectiveness.The pre-post study used convenience sampling to recruit participants in emergent OEND training. Participants completed an abbreviated version the Opioid Overdose Attitudes Scale (OOAS) which measured how, and to what degree, they changed their attitudes towards overdoses and their responses to them. Participants also completed an abbreviated version of the Opioid Overdose Knowledge Scale (OOKS) which measured how effectively the OEND increased their knowledge when it came to properly responding to an overdose, which included implementing naloxone as part of immediate rehabilitation treatment. Paired nonparametric tests assessed changes in participants' OOAS/OOKS scores.A total of 161 individuals attended, and 72 consented to be in the study. The sample predominately consisted of white (76.4%) and female (66.7%) adults whose age averaged 34.3 years. Attitude and knowledge score improvements were statistically significant: approximately 11 points (p .001) and 3 points (p .001), respectively.This rapidly implemented training was associated with improving attitudes and knowledge about responding to an opioid-involved overdose. We recommend expanding the scope of studies like these in order to develop and examine effective, dynamic, and targeted OEND training tailored towards specific community groups and situations, such as polysubstance overdose among service industry workers. As the opioid epidemic worsens, it is critical to equip community members themselves with the skills and tools to recognize and respond to opioid overdoses as a frontline prevention to overdose deaths.

Background: Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation: Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding: Vertex Pharmaceuticals.

AimsPsychotropic medication may be associated with adverse effects, including among people with diabetes. We conducted a systematic review of observational studies investigating the association between antidepressant or antipsychotic drug prescribing and type 2 diabetes outcomes.Methods We systematically searched PubMed, EMBASE, and PsycINFO to 15th August 2022 to identify eligible studies. We used the Newcastle-Ottawa scale to assess study quality and performed a narrative synthesis.Results We included 18 studies, 14 reporting on antidepressants and four on antipsychotics. There were 11 cohort studies, one self-controlled before and after study, two case-control studies, and four cross-sectional studies, of variable quality with highly heterogeneous study populations, exposure definitions, and outcomes analysed. Antidepressant prescribing may be associated with increased risk of macrovascular disease, whilst evidence on antidepressant and antipsychotic prescribing and glycaemic control was mixed. Few studies reported microvascular outcomes and risk factors other than glycaemic control.ConclusionsStudies of antidepressant and antipsychotic drug prescribing in relation to diabetes outcomes are scarce, with shortcomings and mixed findings. Until further evidence is available, people with diabetes prescribed antidepressants and antipsychotics should receive monitoring and appropriate treatment of risk factors and screening for complications as recommended in general diabetes guidelines.

ImportanceCognitive impairment in depression is poorly understood. Family history of depression is a potentially useful risk marker for cognitive impairment, facilitating early identification and targeted intervention in those at highest risk, even if they do not themselves have depression. Several research cohorts have emerged recently that enable findings to be compared according to varying depths of family history phenotyping, in some cases also with genetic data, across the life span.ObjectiveTo investigate associations between familial risk of depression and cognitive performance in 4 independent cohorts with varied depth of assessment, using both family history and genetic risk measures.Design, Setting, and ParticipantsThis study used data from the Three Generations at High and Low Risk of Depression Followed Longitudinally (TGS) family study (data collected from 1982 to 2015) and 3 large population cohorts, including the Adolescent Brain Cognitive Development (ABCD) study (data collected from 2016 to 2021), National Longitudinal Study of Adolescent to Adult Health (Add Health; data collected from 1994 to 2018), and UK Biobank (data collected from 2006 to 2022). Children and adults with or without familial risk of depression were included. Cross-sectional analyses were conducted from March to June 2022.ExposuresFamily history (across 1 or 2 prior generations) and polygenic risk of depression.Main Outcomes and MeasuresNeurocognitive tests at follow-up. Regression models were adjusted for confounders and corrected for multiple comparisons.ResultsA total of 57 308 participants were studied, including 87 from TGS (42 [48%] female; mean [SD] age, 19.7 [6.6] years), 10 258 from ABCD (4899 [48%] female; mean [SD] age, 12.0 [0.7] years), 1064 from Add Health (584 [49%] female; mean [SD] age, 37.8 [1.9] years), and 45 899 from UK Biobank (23 605 [51%] female; mean [SD] age, 64.0 [7.7] years). In the younger cohorts (TGS, ABCD, and Add Health), family history of depression was primarily associated with lower performance in the memory domain, and there were indications that this may be partly associated with educational and socioeconomic factors. In the older UK Biobank cohort, there were associations with processing speed, attention, and executive function, with little evidence of education or socioeconomic influences. These associations were evident even in participants who had never been depressed themselves. Effect sizes between familial risk of depression and neurocognitive test performance were largest in TGS; the largest standardized mean differences in primary analyses were −0.55 (95% CI, −1.49 to 0.38) in TGS, −0.09 (95% CI, −0.15 to −0.03) in ABCD, −0.16 (95% CI, −0.31 to −0.01) in Add Health, and −0.10 (95% CI, −0.13 to −0.06) in UK Biobank. Results were generally similar in the polygenic risk score analyses. In UK Biobank, several tasks showed statistically significant associations in the polygenic risk score analysis that were not evident in the family history models.Conclusions and RelevanceIn this study, whether assessed by family history or genetic data, depression in prior generations was associated with lower cognitive performance in offspring. There are opportunities to generate hypotheses about how this arises through genetic and environmental determinants, moderators of brain development and brain aging, and potentially modifiable social and lifestyle factors across the life span.

Background Tackling Scotland's drug-related deaths and improving outcomes from substance misuse treatments, including residential rehabilitation, is a national priority. Aims To analyse and report outcomes up to 4 years after attendance at a substance misuse residential rehabilitation programme (Lothians and Edinburgh Abstinence Programme). Method In total, 145 participants were recruited to this longitudinal quantitative cohort study of an abstinence-based residential rehabilitation programme based on the therapeutic community model; 87 of these participants were followed up at 4 years. Outcomes are reported for seven subsections of the Addiction Severity Index-X (ASI-X), together with frequency of alcohol use, heroin use, injecting drug use and rates of abstinence from substances of misuse. Results Significant improvement in most outcomes at 4 years compared with admission scores were found. Completing the programme was associated with greater rates of abstinence, reduced alcohol use and improvements in alcohol status score (Mann–Whitney U = 626, P = 0.013), work satisfaction score (U = 596, P = 0.016) and psychiatric status score (U = 562, P = 0.007) on the ASI-X, in comparison with non-completion. Abstinence rates improved from 12% at baseline to 48% at 4 years, with the rate for those completing the programme increasing from 14.5% to 60.7% (χ2(2, 87) = 9.738, P = 0.002). Remaining abstinent from substances at follow-up was associated with better outcomes in the medical (U = 540, P < 0.001), psychiatric (U = 273.5, P < 0.001) and alcohol (U = 322.5, P < 0.001) subsections of the ASI-X. Conclusions Attending this abstinence-based rehabilitation programme was associated with positive changes in psychological and social well-being and harm reduction from substance use at 4-year follow-up, with stability of change from years 1 to 4.

To study the characteristics and genetic constraints on alkalic-type epithermal Au mineralisation, here we use the example of the Tuvatu Au-Ag deposit in Fiji, with an emphasis on detailed, quantitative mineralogy. Tuvatu mineralisation is hosted in a weakly altered potassic monzonite in parallel sided-veins of K-feldspar, biotite, sericite, calcite, and quartz, with epidote-bearing propylitic or sericite-rich selvages. Petrographic study of core and automated SEM-based mineralogical mapping of thin sections have been utilised to update previous parageneses of the deposit. Automated SEM techniques enable identification of small amounts of obscure minerals that form minuscule grains, which would otherwise be very difficult to identify and measure. As a result, our data show that gold fineness is extremely high, with the mean and median Au content of native-Au and Au-Ag alloy being 96.7% and 100% respectively, yet precious-metal tellurides make up the majority of the Au deportment. Tellurides show evidence of multiple phases and zoning with depth. For the first time at Tuvatu, Pt- and Pd-tellurides have been identified. Tuvatu has a number of features in common with alkalic systems elsewhere, including quartz-poor, carbonate-rich veins and alteration, abundant and varied telluride minerals, high gold grades, and Pt-Pd occurrences. We suggest these characteristics are a result of relatively high temperature (250–300 °C) fluids and immiscible semi-metal melts fluxing into the shallow epithermal environment. High pH fluids lead to quartz-poor alteration, but mildly acidic conditions dominate in areas of high fluid flux, where the lower pH causes precipitation of tellurides with quartz. Boiling of the fluids produces zonation of tellurides with depth but leaves relatively subtle textural evidence compared to boiling in most epithermal systems, in common with other quartz poor, carbonate-rich alkalic epithermal deposits around the world.

Background: Lithium, a mood stabilizer, is known to exhibit neuroprotective effects in animal models and may have anti-dementia effects. Aims: We used data from Scottish Mental Survey 1932, a population-based cohort study, to investigate the association between lithium in drinking water and dementia rate in humans. Method: Lithium levels in drinking water from 285 sampling sites across Scotland dating from 2014 were obtained from the sole public water provider (Scottish Water). Dementia and non dementia cases were identified from cohort data by electronic health records until 2012, and linked to postcode. Results: The mean lithium level at all sampling sites was 1.45 μg/L (SD 1.83, range 0.5–18.2) and was 1.26 (SD 0.63, range 0.55–9.19) for sites matched to participant data. Of 37,597 study members, 3605 developed dementia until June 2012. Lithium levels were positively associated with the risk of dementia in women (highest in second quartile, HR 1.17, 95%CI 1.04–1.32), but there was no relationship in men (highest in second quartile, HR 0.95, 95% CI 0.81–1.12). The pattern of association was explored further by decile, and in females there was an association between lithium level and increased dementia risk compared to the lowest decile (0.55–0.68 μg/L) in all deciles except the highest, corresponding with lithium levels 0.68–2.1 μg/L. Conclusions: Lithium levels in drinking water are very low across Scotland which limited detection of potential effect. Our results do not support an association between extremely low levels of lithium and later dementia risk. We found a trend to increased risk in females at lithium levels below but not above 2.1 μg/L.

Background: Immigrants often work in jobs that are known as dirty, demanding, and dangerous. Globally, the agricultural occupations have been associated with the emergence of chronic kidney disease of unknown etiology (CKDu) primarily in outdoor worker populations. The disease has also been reported in immigrants in the United States who work in agricultural occupations, but little research has been done outside of agricultural workers to determine whether immigrants who work other occupations are at risk for developing CKDu. Methods: This study assessed the self-reported occupational histories of undocumented immigrants receiving frequent, emergent-only dialysis in Atlanta, GA. We assessed demographics, employment status, and work history, using the Grady Dialysis Questionnaire and the Occupational/Environmental Health History Form. Results: Fifty undocumented immigrants receiving frequent, emergent-only hemodialysis were recruited for this study. The average age was 49.5 years ( SD ± 11.5), and the majority (52%) were female and originated from Mexico (66%). A majority (74%) reported having worked in the past 5 years and 28% reported currently working. A total of 68 unique jobs were reported. In decreasing order of frequency, our sample worked in occupations with documented renal toxicant exposures, such as applying pesticides in landscaping, heat exposure in agriculture, construction, landscaping, and dry cleaning, and lead paint fumes in construction. Discussion: Occupational histories provide a greater understanding of the exposures and working conditions of those receiving frequent, emergent-only hemodialysis. This exploratory study suggests that further research is needed to investigate and assess whether renal toxicants are associated with occupations with high numbers of undocumented workers. Application to Practice: A detailed and thorough occupational history should be conducted from those receiving frequent, emergent-only hemodialysis. Developing continuing education for nursing and medical staff in dialysis centers on taking an occupational history, mandatory State reporting requirements, and hazard communication training for workers should be considered. Collaborations between occupational health professionals, public health authorities, employers, dialysis providers, and clinicians who see undocumented workers is required to understand and develop appropriate prevention measures for this population.

This article examines the articulation of praxis and phronēsis in book VI of Aristotle's Nicomachean Ethics. With some help from Vernant, Heidegger, and Agamben, it brings out a dimension of Aristotle's thought that makes it challenging for us to think today, namely its lack of a concept of the will. Instead of seeing this as a deficiency, this paper argues that Aristotle's thinking can be more productively read as carving out a space for an ethics that is not governed by this metaphysical concept, in this way showing it not to be as essential to ethical thought as we often think. Phronēsis appears as the point of in-distinction between many oppositions that govern modern thought such as thinking and doing, being and acting, or theory and practice. In this way, it provides a suggestive example for those interested in developing new forms of ethics beyond those that have been bequeathed to us by the modern European tradition.

This essay re-examines Hegel’s critique of Spinoza’s Ethics, focusing on the question of method. Are the axioms and definitions unmotivated presuppositions that make the attainment of absolute knowledge impossible in principle, as Hegel charges? This essay develops a new reading of the Ethics to defend it from this critique. I argue that Hegel reads Spinoza as if his system were constructed only according to the mathematical second kind of knowledge, ignoring Spinoza’s clear preference for knowledge of the third kind. The Ethics, I argue, is a book with several layers: it is at once a deductive mathematical system, and a handbook to aid the intuitive power of the active philosophical reader. The letter of each text may be identical, but they have little else in common – Pierre Menard’s rewriting of Don Quixote given systematic philosophical form.

BackgroundAnxiety and depressive disorders often co-occur and the order of their emergence may be associated with different clinical outcomes. However, minimal research has been conducted on anxiety-anxiety comorbidity. This study examined factors associated with anxiety comorbidity and anxiety-MDD temporal sequence.MethodsOnline, self-report data were collected from the UK-based GLAD and COPING NBR cohorts (N = 38,775). Logistic regression analyses compared differences in sociodemographic, trauma, and clinical factors between single anxiety, anxiety-anxiety comorbidity, anxiety-MDD (major depressive disorder) comorbidity, and MDD-only. Additionally, anxiety-first and MDD-first anxiety-MDD were compared. Differences in familial risk were assessed in those participants with self-reported family history or genotype data.ResultsAnxiety-anxiety and anxiety-MDD had higher rates of self-reported anxiety or depressive disorder diagnoses, younger age of onset, and higher recurrence than single anxiety. Anxiety-MDD displayed greater clinical severity/complexity than MDD only. Anxiety-anxiety had more severe current anxiety symptoms, less severe current depressive symptoms, and reduced likelihood of self-reporting an anxiety/depressive disorder diagnosis than anxiety-MDD. Anxiety-first anxiety-MDD had a younger age of onset, more severe anxiety symptoms, and less likelihood of self-reporting a diagnosis than MDD-first. Minimal differences in familial risk were found.LimitationsSelf-report, retrospective measures may introduce recall bias. The familial risk analyses were likely underpowered.ConclusionsAnxiety-anxiety comorbidity displayed a similarly severe and complex profile of symptoms as anxiety-MDD but distinct features. For anxiety-MDD, first-onset anxiety had an earlier age of onset and greater severity than MDD-first. Anxiety disorders and comorbidity warrant further investigation and attention in research and practice.

This paper reports on an experimental study of magnetohydrodynamic aerobraking using an expansion tube facility, which can generate the correct electrodynamic boundary conditions for spacecraft atm...

Enhanced efficiency nitrogen fertilisers (EENFs) attempt to improve nitrogen use efficiency (NUE) by synchronizing nitrogen (N) supply with crop demand to improve crop productivity/profitability and minimize environmental impacts. This study evaluated the impact of ten EENFs (at 125 and 250 kg N ha−1) compared to urea-N (at 0, 62.5, 125, 175, 250 and 300 kg N ha−1) subsurface banded in a no-till maize (Zea mays L.) production system. Crop growth was examined in both the year of application and in the following year (without fertiliser N) to assess residual impacts. Nitrous oxide emissions from a subset of EENFs applied at 150 kg N ha−1 in an adjacent experiment were monitored in year 1. Grain yield increased with increasing rates of applied urea-N in year 1, with a maximum potential yield of 11.2 t ha−1 achieved at ≥ 175 kg N ha−1. However, grain and biomass yield, agronomic NUE, and N transfer efficiency did not increase with EENFs compared to urea-N, and some controlled release fertilisers (CRFs) decreased yield by 9–16%. Nitrification inhibitors decreased cumulative N2O emissions by 67%, while CRFs had no significant effect. Residual fertiliser N remaining in the soil at the end of the first season was strongly correlated with grain yield in the subsequent cropping year, but EENFs did not have a greater residual impact on crop growth than urea-N. The inability of EENFs to deliver increased crop N uptake or grain yield does not provide a clear case for their use as an alternative to conventional urea.

There are no published data on Australian adult cystic fibrosis (CF) patient outcomes post bronchial arterial embolisation (BAE). We report 20 years of experience of BAE at a major Australian tertiary adult CF centre, where 46 patients underwent 100 BAE during this period. Mortality rate was comparable to previous studies (4% per year) and most who died had repeat BAE requirements. A higher proportion (9 out of 45) of patients were transplanted compared to previous publications. Repeat BAE was common and significantly higher in patients already on tranexamic acid.

Funder: Wellcome Trust, Funder: Medical Research Council, BACKGROUND: Progress towards stratified care for anxiety and depression will require the identification of new predictors. We collected data on retrospectively self-reported therapeutic outcomes in adults who received psychological therapy in the UK in the past ten years. We aimed to replicate factors associated with traditional treatment outcome measures from the literature. METHODS: Participants were from the Genetic Links to Anxiety and Depression (GLAD) Study, a UK-based volunteer cohort study. We investigated associations between retrospectively self-reported outcomes following therapy, on a five-point scale (global rating of change; GRC) and a range of sociodemographic, clinical and therapy-related factors, using ordinal logistic regression models (n = 2890). RESULTS: Four factors were associated with therapy outcomes (adjusted odds ratios, OR). One sociodemographic factor, having university-level education, was associated with favourable outcomes (OR = 1.37, 95%CI: 1.18, 1.59). Two clinical factors, greater number of reported episodes of illness (OR = 0.95, 95%CI: 0.92, 0.97) and higher levels of personality disorder symptoms (OR = 0.89, 95%CI: 0.87, 0.91), were associated with less favourable outcomes. Finally, reported regular use of additional therapeutic activities was associated with favourable outcomes (OR = 1.39, 95%CI: 1.19, 1.63). There were no statistically significant differences between fully adjusted multivariable and unadjusted univariable odds ratios. CONCLUSION: Therapy outcome data can be collected quickly and inexpensively using retrospectively self-reported measures in large observational cohorts. Retrospectively self-reported therapy outcomes were associated with four factors previously reported in the literature. Similar data collected in larger observational cohorts may enable detection of novel associations with therapy outcomes, to generate new hypotheses, which can be followed up in prospective studies.

Background Antidepressants are one of the most widely prescribed drugs in the global north. However, little is known about the health consequences of long-term treatment. Aims This study aimed to investigate the association between antidepressant use and adverse events. Method The study cohort consisted of UK Biobank participants whose data was linked to primary care records (N = 222 121). We assessed the association between antidepressant use by drug class (selective serotonin reuptake inhibitors (SSRIs) and ‘other’) and four morbidity (diabetes, hypertension, coronary heart disease (CHD), cerebrovascular disease (CV)) and two mortality (cardiovascular disease (CVD) and all-cause) outcomes, using Cox's proportional hazards model at 5- and 10-year follow-up. Results SSRI treatment was associated with decreased risk of diabetes at 5 years (hazard ratio 0.64, 95% CI 0.49–0.83) and 10 years (hazard ratio 0.68, 95% CI 0.53–0.87), and hypertension at 10 years (hazard ratio 0.77, 95% CI 0.66–0.89). At 10-year follow-up, SSRI treatment was associated with increased risks of CV (hazard ratio 1.34, 95% CI 1.02–1.77), CVD mortality (hazard ratio 1.87, 95% CI 1.38–2.53) and all-cause mortality (hazard ratio 1.73, 95% CI 1.48–2.03), and ‘other’ class treatment was associated with increased risk of CHD (hazard ratio 1.99, 95% CI 1.31–3.01), CVD (hazard ratio 1.86, 95% CI 1.10–3.15) and all-cause mortality (hazard ratio 2.20, 95% CI 1.71–2.84). Conclusions Our findings indicate an association between long-term antidepressant usage and elevated risks of CHD, CVD mortality and all-cause mortality. Further research is needed to assess whether the observed associations are causal, and elucidate the underlying mechanisms.

Aims Despite reports of an elevated risk of breast cancer associated with antipsychotic use in women, existing evidence remains inconclusive. We aimed to examine existing observational data in the literature and determine this hypothesised association. Methods We searched Embase, PubMed and Web of Science™ databases on 27 January 2022 for articles reporting relevant cohort or case-control studies published since inception, supplemented with hand searches of the reference lists of the included articles. Quality of studies was assessed using the Newcastle-Ottawa Scale. We generated the pooled odds ratio (OR) and pooled hazard ratio (HR) using a random-effects model to quantify the association. This study was registered with PROSPERO (CRD42022307913). Results Nine observational studies, including five cohort and four case-control studies, were eventually included for review (N = 2 031 380) and seven for meta-analysis (N = 1 557 013). All included studies were rated as high-quality (seven to nine stars). Six studies reported a significant association of antipsychotic use with breast cancer, and a stronger association was reported when a greater extent of antipsychotic use, e.g. longer duration, was operationalised as the exposure. Pooled estimates of HRs extracted from cohort studies and ORs from case-control studies were 1.39 [95% confidence interval (CI) 1.11–1.73] and 1.37 (95% CI 0.90–2.09), suggesting a moderate association of antipsychotic use with breast cancer. Conclusions Antipsychotic use is moderately associated with breast cancer, possibly mediated by prolactin-elevating properties of certain medications. This risk should be weighed against the potential treatment effects for a balanced prescription decision.

Globally, there is increasing recognition that agricultural workers are at risk for chronic kidney disease of unknown etiology (CKD u). Recurrent heat exposure, physical exertion, dehydration, muscle damage, and inflammation are hypothesized to contribute to the development of CKD u, but the relative importance of these processes and the interactions among them remain unclear. Moreover, there is a need to identify biomarkers that could distinguish individuals who are at greatest risk for kidney damage to target preventative interventions for CKD u. In this study, we evaluated dehydration and markers of inflammation, muscle damage, and renal function in agricultural workers at a non-workday baseline assessment. Urine specific gravity and kidney function were measured before and after work shifts on three subsequent days, and heat index, core body temperature, and heart rate were monitored during the work shifts. A combination of direct comparisons and machine learning algorithms revealed that reduced levels of uromodulin and sodium in urine and increased levels of interleukin-6 and C-reactive protein in serum were indicative of dehydration at baseline, and that dehydration, high body mass index, reduced urine uromodulin, and increased serum interleukin-6, C-reactive protein, and lipopolysaccharide-binding protein at baseline were predictive of acute kidney injury on subsequent workdays. Our findings suggest a method for identifying agricultural workers at greatest risk for kidney injury and reveal potential mechanisms responsible for this process, including pathways overlapping in dehydration and kidney injury. These results will guide future studies confirming these mechanisms and introducing interventions to protect kidney health in this vulnerable population.