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Abstract Background The analysis of the nonstructural (NS) gene of the highly pathogenic (HP) H5N1 avian influenza viruses (AIV) isolated in Sweden early 2006 indicated the co-circulation of two sub-lineages of these viruses at that time. In order to complete the information on their genetic features and relation to other HP H5N1 AIVs the seven additional genes of twelve Swedish isolates were amplified in full length, sequenced, and characterized. Results The presence of two sub-lineages of HP H5N1 AIVs in Sweden in 2006 was further confirmed by the phylogenetic analysis of approximately the 95% of the genome of twelve isolates that were selected on the base of differences in geographic location, timing and animal species of origin. Ten of the analyzed viruses belonged to sub-clade 2.2.2. and grouped together with German and Danish isolates, while two 2.2.1. sub-clade viruses formed a cluster with isolates of Egyptian, Italian, Slovenian, and Nigerian origin. The revealed amino acid differences between the two sub-groups of Swedish viruses affected the predicted antigenicity of the surface glycoproteins, haemagglutinin and neuraminidase, rather than the nucleoprotein, polymerase basic protein 2, and polymerase acidic protein, the main targets of the cellular immune responses. The distinctive characteristics between members of the two subgroups were identified and described. Conclusion The comprehensive genetic characterization of HP H5N1 AIVs isolated in Sweden during the spring of 2006 is reported. Our data support previous findings on the coincidental spread of multiple sub-lineage H5N1 HPAIVs via migrating aquatic birds to large distance from their origin. The detection of 2.2.1. sub-clade viruses in Sweden adds further data regarding their spread in the North of Europe in 2006. The close genetic relationship of Swedish isolates sub-clade 2.2.2. to the contemporary German and Danish isolates supports the proposition of the introduction and spread of a single variant of 2.2.2. sub-clade H5N1 avian influenza viruses in the Baltic region. The presented findings underline the importance of whole genome analysis.

Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinson's disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex ( PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter ( VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1+/− mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinson's disease. Thus, it appears likely that VGluT1-expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1+/− mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1+/− mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia. [ABSTRACT FROM AUTHOR]

Recurrent inhibition of the bladder C fibre reflex was studied in adult female cats anaesthetized with α-chloralose. Test reflexes were evoked by electrical stimulation of bladder Aδ and C afferents in the right pelvic nerve and were recorded from the proximal end of a small ipsilateral pelvic nerve branch, transected close to the bladder. Such test reflexes were consistently depressed by repetitive electrical stimulation of the contralateral bladder pelvic nerve (20 Hz, 20 s) at intensities sufficient to recruit axons of bladder preganglionic neurones. The inhibition could be evoked after transection of the left dorsal roots S1–S4 and the sympathetic supply to the bladder but was abolished by transection of the pelvic nerve central to the site of stimulation. Hence, it most likely involved central recurrent collaterals of antidromically activated bladder preganglionic neurones. The reflex suppression was quite considerable – maximal C fibre reflexes were reduced to a group mean of 25% (± 9% confidence interval) of their control size. The effect had a slow onset, requiring a few seconds of conditioning stimulation to be revealed, and was very long lasting (minutes). Naloxone (0.01–0.5 mg kg−1i.v.) abolished the recurrent inhibition of both the C fibre and Aδ bladder reflexes, while inhibition from afferents in the dorsal clitoris nerve remained unchanged. It is concluded that the segmental bladder C fibre reflex and the spino-ponto-spinal Aδ micturition reflex are both targets of recurrent inhibition from bladder parasympathetic preganglionic neurones and that the effect involves an enkephalinergic mechanism. [ABSTRACT FROM AUTHOR]

Presents a study comparing the risk of nerve injury for monopolar, bipolar electrosurgery (ES) and ultrasonically activated dissection instruments. Dissection of the biceps femoris muscles adjacent to the sciatic nerve using monopolar ES; Determination of the extent of heat damage in four nerves that were divided with ES bipolar scissors; Frequency of the reduction in the electromyographic potential in the monopolar ES.

Objectives To evaluate retrospectively the result of anogenital afferent stimulation (AGAS) in neurological healthy children with therapy-resistant urge incontinence. Patients and method The study included 48 children (24 girls and 24 boys, 5–14 years old) with a diagnosis of bladder instability verified by cystometry in all. Anogenital afferent stimulations were applied using a battery-powered dual constant-current stimulator. The children were stimulated continuously at 10 Hz for 20 min once or twice daily and if required the children and/or the parents continued to apply the treatment at home. For home stimulation a single (anal) channel stimulator was used. The patients were instructed to stimulate for 20 min at maximum intensity two to three times a week until the effects were optimal. The outcome was evaluated retrospectively by comparing voiding/incontinence diaries obtained before and at the follow-up 6–12 months after the end of treatment. Results AGAS was applied at the clinic for a median (range) of 9 (4–20) times. Thirty-one children continued with home stimulation for another 25 (5–96) sessions. At the follow-up, 18 children were cured and another seven improved, with a leakage score of less than half that before treatment. The treatment was well tolerated by most children. Conclusions Anogenital afferent stimulation is an effective, potentially curative treatment in children with severe urge incontinence. Home stimulation is a well accepted adjuvant to treatment at the clinic and improves the outcome. [ABSTRACT FROM AUTHOR]

The Puchezh‐Katunki impact structure, 40–80 km in diameter, located ~400 km northeast of Moscow (Russia), has a poorly constrained age between ~164 and 203 Ma (most commonly quoted as 167 ± 3 Ma). Due to its relatively large size, the Puchezh‐Katunki structure has been a prime candidate for discussions on the link between hypervelocity impacts and extinction events. Here, we present new 40Ar/39Ar data from step‐heating analysis of five impact melt rock samples that allow us to significantly improve the age range for the formation of the Puchezh‐Katunki impact structure to 192–196 Ma. Our results also show that there is not necessarily a simple relationship between the observed petrographic features of an impact melt rock sample and the obtained 40Ar/39Ar age spectra and inverse isochrons. Furthermore, a new palynological investigation of the postimpact crater lake sediments supports an age significantly older than quoted in the literature, i.e., in the interval late Sinemurian to early Pliensbachian, in accordance with the new radioisotopic age estimate presented here. The new age range of the structure is currently the most reliable age estimate of the Puchezh‐Katunki impact event. [ABSTRACT FROM AUTHOR]

Soils are a crucial link between the atmosphere, biosphere, and geosphere. Any disturbance to the health of soils will severely impact plants as well as a multitude of organisms living in or on soils, such as fungi, bacteria, and insects. Catastrophic soil loss is thought to have played a pivotal role during mass-extinction events as a result of major deforestation, but the exact feedbacks remain elusive. Here, we assess the role of soil loss during the end-Triassic mass-extinction event based on proxy data obtained from four sediment sections recovered from France, Germany, and Denmark. Clay mineral and palynological data indicate a strong increase in erosion during the latest Rhaetian with the influx of kaolinite and abundantly reworked Palaeozoic and Neoproterozoic organic matter. Based on a new timeline, these changes were coeval with intense volcanic activity in the Central Atlantic Magmatic Province (CAMP). In addition to vegetation dieback, repeated forest fires, as well as widespread seismic activity related to CAMP emplacement led to landscape destruction triggering removal of soils. The biological degradation of fern spore walls by fungi and bacteria, a process coupled to organic matter decay in soils, strongly decreased across the T/J boundary. We interpret this counter-intuitive result as evidence for rapid and widespread removal of soils. Taken together, CAMP induced environmental changes led to profound changes in erosion and removal of soils, while soil resilience during the Hettangian appears to have proceeded hand in hand with recovery in Jurassic seas. [ABSTRACT FROM AUTHOR]

Background: Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear., Methods: We analyzed a prospective cohort of 66 308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs)., Results: In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI = 1.83, 1.49 to 2.26) and males (2.03, 1.51 to 2.73) as well as early-onset breast cancer in females (3.06, 2.20 to 4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12 to 2.14) and 1.69 (1.11 to 2.57) in the highest genetic risk category and 1.03 (0.64 to 1.67) and 0.81 (0.36 to 1.85) in the lowest., Conclusions: Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer., (Published by Oxford University Press 2024.)

Suicide among children and young adults is a leading cause of mortality, highlighting the importance of the development of life-saving interventions. This study is part of the nationwide study Retrospective investigation of health care utilization of individuals who died by suicide in Sweden in 2015, Lund University, Sweden. The aim was to gain a better understanding of verbal suicidal communication and suicidal behaviour in children and young adults who die by suicide, to analyse gender and age differences, and to discuss the findings in relation to the prevailing psychological theories of suicidality. The study sample consisted of medical records from final health care consultations of 114 individuals up to 25 years, who died by suicide in Sweden a single year. Suicidal plans were documented in 13 percent of children and young adults. Females were more likely to have a notation of suicidal communication than males. Twenty-seven percent had made previous suicide attempts. Approximately 90 percent of the study cohort had contact with health care settings within 24 months prior to suicide. Questioning about suicidal plans appears to be an insufficient tool to assess suicidality in children and young adults. Clinical implications regarding alternative assessment methods and preventive measures are discussed.

In Sweden, approximately 1,200 individuals die by suicide annually. Inpatient suicide is considered rare, but death by suicide still occurs when admitted to a psychiatric hospital. This study was part of a national retrospective project covering data from all patients' medical records for the 2 years before death by suicide in 2015. In this study, 41 patients who died by suicide while being admitted to psychiatric care were identified. The aim was to retrospectively identify documentation of suicide risk, safety measures, and comparisons between those with and without suicide attempts for patients who died by suicide during psychiatric inpatient care. There was documentation of suicidal variables in 80% of the patients; 59% had a previous known suicide attempt, 63% were diagnosed with mood disorders, and 41% were assessed for elevated suicide risk. The most common suicide method was hanging, suffocation (68%), and 22% had died by suicide within 24 h after admission. Almost three-quarters were on voluntary care. No patients had constant professional supervision on a one-to-one basis, and 17% had 15-minute checks. One-third were on agreed leave at the time of the suicide. These results emphasise the lifesaving role of high-level supervision in the early stages of inpatient care.

New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.L., S.L.M., T.A.J, E.L., D.H., E.Z. and A.K. are authors on a patent application related to this work (publication no. WO 2022/220725, application no. PCT/SE2022/050360, filed on October 20, 2022). The authors declare no other competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Integrating genome-wide association study (GWAS) and transcriptomic datasets can help identify potential mediators for germline genetic risk of cancer. However, traditional methods have been largely unsuccessful because of an overreliance on total gene expression. These approaches overlook alternative splicing, which can produce multiple isoforms from the same gene, each with potentially different effects on cancer risk. Here, we integrate genetic and multi-tissue isoform-level gene expression data from the Genotype Tissue-Expression Project (GTEx, N = 108-574) with publicly available European-ancestry GWAS summary statistics (all N > 20,000 cases) to identify both isoform- and gene-level risk associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total). Compared to traditional methods leveraging total gene expression, directly modeling isoform expression through transcriptome-wide association studies (isoTWAS) substantially increases discovery of transcriptomic mechanisms underlying genetic associations. Using the same RNA-seq datasets, isoTWAS identified 164% more significant unique gene associations compared to TWAS (6,163 and 2,336, respectively), with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes (P = 6.1 × 10 -13 ). isoTWAS tags transcriptomic associations at 52% more independent GWAS loci compared to TWAS across the six cancers. Additionally, isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression when evaluating cis-genetic influence on isoform expression. We highlight several notable isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including, CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast). These results underscore the critical importance of modeling isoform-level expression to maximize discovery of genetic risk mechanisms for cancers.

Background: Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development. However, they may not be suitable for large-scale studies. The aim of this study was to investigate if a zebrafish-based xenograft model can recapitulate MB growth and enable rapid drug testing., Methods: Nine different MB cell lines or patient-derived cells were transplanted into blastula-stage zebrafish embryos. Tumor development and migration were then monitored using live imaging. RNA sequencing was performed to investigate transcriptome changes after conditioning cells in neural stem cell-like medium. Furthermore, drug treatments were tested in a 96-well format., Results: We demonstrate here that transplantation of MB cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing., Conclusion: Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Given the limited research focusing on psychotherapeutic interventions for suicide attempters, it is noteworthy that the Attempted Suicide Short Intervention Program (ASSIP) has demonstrated promising results in previous studies. In this investigation, we aim to evaluate the effectiveness of ASSIP across diverse healthcare settings, outlining the study design and planned evaluation., Methods: Using a Randomized Controlled Trial (RCT) design with four assessment points (baseline, 3, 12- and 24-month follow-up), we aim to assess the effect of the 3-session psychotherapeutic intervention and hereafter brief contact via structured letters during 2 years in a clinical sample of recent suicide attempters (suicide attempts within three months before inclusion). Participants are randomly assigned to one of two groups; treatment as usual plus ASSIP or the control condition, treatment as usual. Assessments include measures of suicidal intent, coping, symptoms of depression, quality of life, self-stigma, and sick leave. The primary outcome is suicide attempt(s) within 3, 12, and 24 months and the secondary outcome is suicidal ideation within the same time frames after study inclusion., Discussion: Findings from this study will provide novel insights regarding the effects of ASSIP on not only subsequent suicidal behavior but also other outcomes including self-stigma, quality of life, social network, sick leave, and symptoms of depression., Trial Registration: The trial was registered at ClinicalTrial.gov NCT04746261 on 2020-10-15., (© 2024. The Author(s).)

Background: Contribution of dominance effects to cancer heritability is unknown. We leveraged existing genome-wide association data for seven cancers to estimate the contribution of dominance effects to the heritability of individual cancer types., Methods: We estimated the proportion of phenotypic variation caused by dominance genetic effects using genome-wide association data for seven cancers (breast, colorectal, lung, melanoma, nonmelanoma skin, ovarian, and prostate) in a total of 166,772 cases and 284,824 controls., Results: We observed no evidence of a meaningful contribution of dominance effects to cancer heritability. By contrast, additive effects ranged between 0.11 and 0.34., Conclusions: In line with studies of other human traits, the dominance effects of common genetic variants play a minimal role in cancer etiology., Impact: These results support the assumption of an additive inheritance model when conducting cancer association studies with common genetic variants., (©2024 American Association for Cancer Research.)

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Purpose: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR)., Methods: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status., Results: Genetically predicted BMI was positively associated with non-dense area (IVW: β = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10 -63 ) and inversely associated with dense area (IVW: β = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10 -7 ). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (β = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (β =  - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches., Conclusion: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The Attempted Suicude Short Intervention Program (ASSIP) provides an effective and cost-effective treatment option for people who have attempted suicide. Studies suggest that longer treatment latency is associated with poorer response to therapy, more severe symptomatology, and more suicide attempts This study examined the influence of treatment latency (time between suicide attempt and initiation of therapy) on the number of suicide attempts over the long-term course of ASSIP and the influence of treatment relationship on the extent of suicidal ideation., Method: Survival and regression analyses were performed on 60 participants who had recently attempted suicide and received ASSIP at an outpatient psychiatric clinic. 60% were women and 40% were men., Results: The results found no significant association between treatment outcome in ASSIP and treatment latency (HR = 1.06; 95% CI: 0.92- 1.21, p = .44). Treatment relationship significantly influenced suicidal ideation at time t 4 (B = - .35, t(55) = -3.21, p = .002), but treatment latency was not significantly associated with suicidal ideation (B = .02, t(55) = 0.87, p = .39)., Conclusion: No relationship between treatment latency and treatment outcome could be found, suggesting that ASSIP can be implemented at any time after the last suicide attempt. In contrast, the treatment relationship plays a central role in ASSIP.

Background: The literature on the relationship between anxiety and suicidal behaviors is limited and findings are mixed. This study sought to determine whether physicians noted anxiety symptoms and suicidality in their patients in the weeks and months before suicide., Methods: Data were derived from a nationwide medical record review of confirmed suicides in Sweden in 2015. Individuals with at least one documented physician consultation in any health care setting during 12 months before suicide (N = 956) were included. Clinical characteristics were compared between decedents with and without a notation of anxiety symptoms. Odds ratios were calculated to estimate associations between anxiety symptoms and suicidality in relation to suicide proximity., Results: Anxiety symptoms were noted in half of individuals 1 week before suicide. Patients with anxiety were characterized by high rates of depressive symptoms, ongoing substance use issues, sleeping difficulties, and fatigue. After adjustment for mood disorders, the odds of having a notation of elevated suicide risk 1 week before death were doubled in persons with anxiety symptoms. Associations were similar across time periods (12 months - 1 week). Two-thirds had been prescribed antidepressants at time of death., Limitations: Data were based on physicians' notations which likely resulted in underreporting of anxiety depending on medical specialty. Records were not available for all decedents., Conclusions: Anxiety symptoms were common in the final week before suicide and were accompanied by increases in documented elevated suicide risk. Our findings can inform psychiatrists, non-psychiatric specialists, and GPs who meet and assess persons with anxiety symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The long-term effects of the Central Atlantic Magmatic Province, a large igneous province connected to the end-Triassic mass-extinction (201.5 Ma), remain largely elusive. Here, we document the persistence of volcanic-induced mercury (Hg) pollution and its effects on the biosphere for ~1.3 million years after the extinction event. In sediments recovered in Germany (Schandelah-1 core), we record not only high abundances of malformed fern spores at the Triassic-Jurassic boundary, but also during the lower Jurassic Hettangian, indicating repeated vegetation disturbance and stress that was eccentricity-forced. Crucially, these abundances correspond to increases in sedimentary Hg-concentrations. Hg-isotope ratios (δ 202 Hg, Δ 199 Hg) suggest a volcanic source of Hg-enrichment at the Triassic-Jurassic boundary but a terrestrial source for the early Jurassic peaks. We conclude that volcanically injected Hg across the extinction was repeatedly remobilized from coastal wetlands and hinterland areas during eccentricity-forced phases of severe hydrological upheaval and erosion, focusing Hg-pollution in the Central European Basin., (© 2024. The Author(s).)

Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli . We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae . Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-β-lactamase, metallo-β-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance., Competing Interests: Competing interests statement:E.Z., D.A., V.R.K., S.L., G.O., P. Brandt, T.A.J., S.L.M., D.H., and A.K. have secured a patent [WO 2022/220725 (PCT/SE2022/050360)] for the compounds presented in this publication.

Importance: Early-onset cancer (diagnosed under 50 years of age) is associated with aggressive disease characteristics and its rising incidence is a global concern. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants is unknown., Objective: To examine the associations between genetic risk, lifestyle, and risk of early-onset cancers., Design Setting and Participants: We analyzed a prospective cohort of 66,308 white British participants who were under age 50 and free of cancer at baseline in the UK Biobank., Exposures: Sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs, which summarize smoking status, body mass index [males only], physical activity, alcohol consumption, and diet)., Main Outcomes and Measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer., Results: A total of 1,247 incident invasive early-onset cancer cases (female: 820, male: 427, breast: 386) were documented. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.85, 1.50-2.29) and males (1.94, 1.45-2.59) as well as early-onset breast cancer in females (3.06, 2.20-4.25). An unfavorable lifestyle (highest vs. lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer was stronger in the highest genetic risk category than the lowest: HRs in females and men were 1.85 (1.02, 3.36), 3.27 (0.78, 13.72) in the highest genetic risk category and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40) in the lowest., Conclusions and Relevance: Both genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer., Competing Interests: Conflict of Interest Disclosures The authors declare no potential conflicts of interest.

Introduction: Prior reviews synthesized findings of studies on long-term cardiac complications of COVID-19. However, the reporting and methodological quality of these studies has not been systematically evaluated. Here, we conducted a systematic review and meta-analysis on long-term cardiac complications of COVID-19 and examined patterns of reported findings by study quality and characteristics., Methods: We searched for studies examining long-term cardiac complications of COVID-19 that persisted for 4 weeks and over. A customized Newcastle-Ottawa scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed to generate prevalence estimates of long-term cardiac complications across studies. Stratified analyses were further conducted to examine the prevalence of each complication by study quality and characteristics. The GRADE approach was used to determine the level of evidence for complications included in the meta-analysis., Results: A total number of 150 studies describing 57 long-term cardiac complications were included in this review, and 137 studies reporting 17 complications were included in the meta-analysis. Only 25.3% (n = 38) of studies were of high quality based on the NOS quality assessment. Chest pain and arrhythmia were the most widely examined long-term complications. When disregarding study quality and characteristics, summary prevalence estimates for chest and arrhythmia were 9.79% (95% CI 7.24-13.11) and 8.22% (95% CI 6.46-10.40), respectively. However, stratified analyses showed that studies with low-quality scores, small sample sizes, unsystematic sampling methods, and cross-sectional design were more likely to report a higher prevalence of complications. For example, the prevalence of chest pain was 22.17% (95% CI 14.40-32.55), 11.08% (95% CI 8.65-14.09), and 3.89% (95% CI 2.49-6.03) in studies of low, medium, and high quality, respectively. Similar patterns were observed for arrhythmia and other less examined long-term cardiac complications., Conclusion: There is a wide spectrum of long-term cardiac complications of COVID-19. Reported findings from previous studies are strongly related to study quality, sample sizes, sampling methods, and designs, underscoring the need for high-quality epidemiologic studies to characterize these complications and understand their etiology., (© 2023. The Author(s).)

Background: The prevalence of substance use in people with HIV (PWH) in the United States is higher than in the general population and is an important driver of HIV-related outcomes. We sought to assess if previously identified genetic associations that contribute to substance use are also observed in a population of PWH., Methods: We performed genome-wide association studies (GWAS) of alcohol, smoking, and cannabis use phenotypes in a multi-ancestry population of 7,542 PWH from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). We conducted multi-ancestry GWAS for individuals of African (n = 3,748), Admixed American (n = 1,334), and European (n = 2,460) ancestry. Phenotype data were self-reported and collected using patient reported outcomes (PROs) and three questions from AUDIT-C, an alcohol screening tool. We analyzed nine phenotypes: 1) frequency of alcohol consumption, 2) typical number of drinks on a day when drinking alcohol, 3) frequency of five or more alcoholic drinks in a 30-day period, 4) smoking initiation, 5) smoking cessation, 6) cigarettes per day, 7) cannabis use initiation, 8) cannabis use cessation, 9) frequency of cannabis use during the previous 30 days. For each phenotype we considered a) variants previously identified as associated with a substance use trait and b) novel associations., Results: We observed evidence for effects of previously reported single nucleotide polymorphisms (SNPs) related to alcohol (rs1229984, p = 0.001), tobacco (rs11783093, p = 2.22E-4), and cannabis use (rs2875907, p = 0.005). We also report two novel loci (19p13.2, p = 1.3E-8; and 20p11.21, p = 2.1E-8) associated with cannabis use cessation., Conclusions: Our analyses contribute to understanding the genetic bases of substance use in a population with relatively higher rates of use compared to the general population., Competing Interests: KMJ was employed by Bristol-Myers Squibb during the drafting of this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors report no conflicts of interest to disclose., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Objective: Associations between debt and suicidal behaviour have been identified, but the research is sparse. Thus, more research is needed to understand the association between economic vulnerability and suicide. The study aimed to generate further knowledge about over-indebted individuals who have attempted suicide at least once., Method: Participants were a Swedish sample comprising 641 over-indebted individuals. The inclusion criteria were that the participants should be indebted and have been subjected to debt collection measures and/or seizure orders by the Swedish Enforcement Authority. Participants answered questionnaires regarding socio-demographic variables, debt size, history of suicide attempt, critical life events, and social contacts, and filled the Hospital Anxiety and Depression Scale (HADS). In the statistical analyses, Chi 2 test for independence and t-test was used, and binary logistic regression to adjust for the confounding effects of the variables on each other., Results: The analysis revealed that nearly one in five (19.3%, N  = 123) had attempted suicide at least once. A larger part of the respondents who had a history of suicide attempts reported that they were living alone (OR 2.30 (95% CI 1.34-3.89, p = .002). Many of those living alone were women ( χ 2 (1, n  = 121) = 4.88, p  = 0.03, ɸ = 0.22)., Conclusions: The results of the current study point to the fact that economic vulnerability is an important psychosocial aspect to take into serious consideration concerning mental health and suicide prevention. Longitudinal research is needed to explain, predict and prevent suicide due to over-indebtedness.

Background: Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services., Methods: CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post-testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines., Results: CHARM participants were followed for an average of 15.4 months (range: 0.4-27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations., Conclusion: Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence-based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer., Methods: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs., Results: Assuming a 1 × 10 -5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (OR int  = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (OR int  = 0.91, 95% CI 0.88-0.94)., Conclusions: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci., Methods: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci., Results: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci., Conclusions: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: A person's ability to tolerate negative emotional states (Distress Tolerance - DT), uncertainty in their everyday lives (Intolerance of Uncertainty - IU), and a tendency to appraise their own feelings of anxiety as harmful (Anxiety Sensitivity - AS) have all been identified as vulnerability factors for anxiety and depressive disorders. However, the relationship between these variables and broader aspects of psychiatric symptom severity in participants recruited from routine care remains unclear., Method: The Distress Tolerance Scale (DTS), Anxiety Sensitivity Scale-3 (ASI-3), and Intolerance of Uncertainty Scale-Short Form (IUS-12) were administered to 91 patients receiving treatment at the Lund Outpatient Psychiatric Clinic. Data was collected from their medical records about their psychiatric history and scores on the Brief Symptom Inventory (BSI). The relationship between total scores on the DTS, ASI-3, IUS-12 and BSI were evaluated via correlations and regression analyses., Results: DTS, ASI-3, and IUS-12 total scores correlated in the moderate to large range, and consistent with previous literature, were moderately to strongly correlated with the severity of self-reported depression, anxiety and overall symptoms (BSI). Regression analyses indicated that together, scores on the DTS, ASI-3 and IUS-12 explained moderate levels of variance in BSI symptom scores, with DTS scores showing the strongest associations. These findings suggest that further studies are needed to examine the construct and criterion validity of the three scales. Further validation of these Swedish-language are also warranted., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Funding was recieved from The Lindhaga Foundation., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The aim was to investigate psychiatric health care utilization two years before death by suicide among individuals with previous suicide attempts (PSA) compared with those without (NSA)., Method: A retrospective population-based cohort study was conducted including 484 individuals who died by suicide in Sweden in 2015 and were in contact with psychiatric services within the two years preceding death, identified through the Cause of Death register. Data on psychiatric health care two years before death, including suicide attempts according to notes in the medical record was used. Associations between having at least one PSA vs. NSA and health care utilization were estimated as odds ratios (OR) with 95% confidence intervals (CI) by logistic regression analyses., Results: Of the 484 individuals included, 51% had PSA. Those with PSA were more likely than NSA to have received a psychiatric diagnosis [OR 1.96 (CI 95% 1.17-3.30)], to have ongoing psychotropic medication [OR 1.96 (CI 95% 1.15-3.36)] and to have been absent from appointments during the last three months [1.97 (1.25-3.13)]. In addition, elevated suicide risk was more often noted in the psychiatric case records of those with a PSA than those without [OR 2.17 (CI 95% 1.24-3.79)]., Conclusion: The results underline the importance of improved suicide risk assessment as well as thorough diagnostic assessment and when indicated, psychiatric treatment as suicide preventive interventions regardless of PSA. Furthermore, the larger proportion of absence from appointments in individuals with PSA may indicate a need of improved alliance between psychiatric care providers and individuals with PSA.HIGHLIGHTSBeing assessed with elevated suicide risk was more common among those with previous attempt/s (PSA).One-fifth of all with no previous attempt (NSA) had no psychiatric diagnosis, compared to one in ten in those with PSA.Receiving psychotropic medication was more common among those with PSA.

Background: There is growing body of literature on the long-term cardiac symptoms following COVID-19. We conducted a systematic review and meta-analysis to synthesize and evaluate related evidence to inform clinical management and future studies., Methods: We searched two preprint and seven peer-reviewed article databases from January 1, 2020 to January 8, 2022 for studies investigating cardiac symptoms that persisted for at least 4 weeks among individuals who survived COVID-19. A customized Newcastle-Ottawa scale was used to evaluate the quality of included studies. Random-effects meta-analyses were performed to estimate the proportion of symptoms with 95% confidence intervals (CI), and stratified analyses were conducted to quantify the proportion of symptoms by study characteristics and quality., Results: A total of 101 studies describing 49 unique long-term cardiac symptoms met the inclusion criteria. Based on quality assessment, only 15.8% of the studies (n=16) were of high quality, and most studies scored poorly on sampling representativeness. The two most examined symptoms were chest pain and arrhythmia. Meta-analysis showed that the proportion of chest pain was 10.1% (95% CI: 6.4-15.5) and arrhythmia was 9.8% (95% CI: 5.4-17.2). Stratified analyses showed that studies with low-quality score, small sample size, unsystematic sampling method, and cross-sectional design were most likely to report high proportions of symptoms. For example, the proportion of chest pain was 21.3% (95% CI: 10.5-38.5), 9.3% (95% CI: 6.0-14.0), and 4.0% (95% CI: 1.3-12.0) in studies with low, medium, and high-quality scores, respectively. Similar patterns were observed for other cardiac symptoms including hypertension, cardiac abnormalities, myocardial injury, thromboembolism, stroke, heart failure, coronary disease, and myocarditis., Discussion: There is a wide spectrum of long-term cardiac symptoms following COVID-19. Findings of existing studies are strongly related to study quality, size and design, underscoring the need for high-quality epidemiologic studies to characterize these symptoms and understand their etiology., Competing Interests: Declaration of interests: All authors report no conflicts of interest.

Objective: This study aimed to determine whether a short-term repeated stimulation of tibial nerve afferents induces a prolonged modulation effect on the micturition reflex in a decorticated rat model., Material and Methods: Fifteen female Sprague-Dawley rats (250-350 g) were fully decorticated and paralyzed in the study. Tibial nerve stimulation (TNS) was delivered by inserting two pairs of needle electrodes close to the nerves at the level of the medial malleolus. Constant flow cystometries (0.07 mL/min) at approximately ten-minute intervals were performed, and the micturition threshold volume (MTV) was recorded and used as a dependent variable. After four to five stable recordings, the tibial nerves of both sides were stimulated continuously for five minutes at 10 Hz and at an intensity of three times the threshold for α-motor axons. Six same stimulations were applied repeatedly, with an interval of five minutes between each stimulation. Mean MTV was calculated on the basis of several cystometries in each half-hour period before, during, and after the six repeated TNS., Results: During the experiment, all the animals survived in good condition with relatively stable micturition reflexes, and a significant increase in MTV was detected after TNS. The strongest effect (mean = 178%) was observed during the first 30 minutes after six repeated stimulations. This obvious threshold increase remained for at least five hours., Conclusions: A prolonged poststimulation modulatory effect on the micturition reflex was induced by short-term repeated TNS in decorticated rats. This study provides a theoretical explanation for the clinical benefit of TNS in patients with overactive bladder and suggests decorticated rats as a promising model for further investigation of the neurophysiological mechanisms underlying the bladder inhibitory response induced by TNS., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The primary aim of the present study was to investigate the putative excess mortality by suicide in suicide attempters. As a secondary aim, we investigate excess mortality in specific, clinically relevant subgroups: individuals with repeated suicide attempts (RA); individuals who used violent method at the attempt (VA); and those who scored high on the Suicide Intent Scale (HS) at the time of the baseline attempt. Finally, we investigate excess mortality in men and women separately and within 5 years and over 5 years after hospital admission for attempted suicide., Design: Prospective register-based follow-up for 21-32 years. Standardised mortality ratio (SMR) was calculated for suicide using national census data. Clinically relevant subgroups were investigated separately., Setting: Medical emergency inpatient unit in the south of Sweden., Participants: 1039 individuals who were psychiatrically assessed at admission to medical inpatient care for attempted suicide between 1987 and 1998., Outcome Measure: Suicide., Results: The overall SMR for suicide was 23.50 (95% CI 18.68 to 29.56); significantly higher (p<0.001) among women (30.49 (95% CI 22.27 to 41.72)) than men (18.61 (95% CI 13.30 to 26.05)). Mortality was highest within the first 5 years after the index suicide attempt (48.79 (95% CI 35.64 to 66.77)) compared with those who died after 5 years (p<0.001) (14.74 (10.53 to 20.63)). The highest independent SMR was found for VA (70.22 (95% CI 38.89 to 126.80)). In a regression model including RA, VA and HS all contributed significantly to excess suicide mortality., Conclusions: An elevated risk of premature death by suicide was found in suicide attempters compared with the general population. Assessment of previous suicide attempts is important, even though the attempt/s may have occurred decades ago. When assessing suicide risk, clinicians should consider repeated attempts and whether the attempts involved high suicidal intent and violent method. Healthcare interventions may benefit from targeting identified subgroups of attempters., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)