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Peyronie's disease (PD) has detrimental effects on the quality of life, mental health, sexual functioning and several other aspects that increase the risk of relationship problems. However, no study to date has assessed the risk of relationship separation in med with PD. Herein, we utilized data from Swedish national registers to examine the risk of relationship separation in men with PD. We conducted a matched cohort study on men born 1933-1992, followed from 1997 to 2013. PD was defined as a physician-assigned diagnosis according to the International Classification of Diseases, Tenth version. Each man with PD (n = 8020) was matched with 10 comparison men. We defined relationship separation as (1) ever separated, and (2) separation rate. We used log-linear regression to estimate the risk ratio, and rate ratio of relationship separation. We adjusted for matching variables (birth year and country of birth), and an indicator of each follow-up year. We found that men with PD had a 13% increased risk of relationship separation (risk ratio 1.13, 95% confidence interval [CI] 1.08-1.17). The rate of relationship separation events, measured on a yearly basis, was increased by 18% (rate ratio 1.18, CI 1.12-1.24), and remained similar when adjusting for follow-up year and socio-economic status., (© 2024. The Author(s).)

This retrospective study analyzed prognostic factors for neurological improvement and ambulation in 194 adult patients (≥ 15 years) with traumatic cervical spinal cord injuries treated at the neurological SCI unit (SCIU) at the Karolinska University Hospital Stockholm, Sweden, between 2010 and 2020. The primary outcome was American spinal injury association impairment scale (AIS) improvement, with secondary focus on ambulation restoration. Results showed 41% experienced AIS improvement, with 51% regaining ambulation over a median follow-up of 3.7 years. Significant AIS improvement (p < 0.001) and reduced bladder/bowel dysfunction (p < 0.001) were noted. Multivariable analysis identified initial AIS C-D (< 0.001), central cord syndrome (p = 0.016), and C0-C3 injury (p = 0.017) as positive AIS improvement predictors, while lower extremity motor score (LEMS) (p < 0.001) and longer ICU stays (p < 0.001) were negative predictors. Patients with initial AIS C-D (p < 0.001) and higher LEMS (p < 0.001) were more likely to regain ambulation. Finally, older age was a negative prognostic factor (p = 0.003). In conclusion, initial injury severity significantly predicted neurological improvement and ambulation. Recovery was observed even in severe cases, emphasizing the importance of tailored rehabilitation for improved outcomes., (© 2024. The Author(s).)

Programmed death-ligand 1 (PD-L1) is overexpressed in squamous cervical cancer (SCC) and can be used for targeted immunotherapy. The highest mortality rates of SCC are reported in sub-Saharan Africa, where Human immunodeficiency virus (HIV) prevalence is high. In Mozambique most SCC patients present at advanced stages. Thus, there is a need to introduce new treatment options. However, immunocompromised patients were frequently excluded in previous clinical trials. Our aim was to determine if PD-L1 expression in SCC is as prevalent among women living with HIV (WLWH) as among other patients. 575 SCC from Maputo Central Hospital were included. HIV status was available in 266 (46%) cases PD-L1 expression was scored through tumour proportion score (TPS) and combined positive score (CPS). PD-L1 was positive in 20.1% of the cases (n = 110), TPS (score ≥ 25%) and in 26.3% (n = 144), CPS (score ≥ 1). Stratifying according to the HIV status, WLWH were TPS positive in 16.7%, compared to 20.9%, p = 0.43, and concerning CPS 21.1% versus 28.7%, p = 0.19, respectively. PD-L1 status was not influenced by stage, Ki-67 or p16, CD8 expression influenced only CPS status. Our data indicates that the documented effect of PD-L1 therapy on SCC should be confirmed in randomized clinical trials in an HIV endemic milieu., (© 2024. The Author(s).)

The present study combined a supervised machine learning framework with an unsupervised method, finite mixture modeling, to identify prognostically meaningful subgroups of diverse chronic pain patients undergoing interdisciplinary treatment. Questionnaire data collected at pre-treatment and 1-year follow up from 11,995 patients from the Swedish Quality Registry for Pain Rehabilitation were used. Indicators measuring pain characteristics, psychological aspects, and social functioning and general health status were used to form subgroups, and pain interference at follow-up was used for the selection and the performance evaluation of models. A nested cross-validation procedure was used for determining the number of classes (inner cross-validation) and the prediction accuracy of the selected model among unseen cases (outer cross-validation). A four-class solution was identified as the optimal model. Identified subgroups were separable on indicators, predictive of long-term outcomes, and related to background characteristics. Results are discussed in relation to previous clustering attempts of patients with diverse chronic pain conditions. Our analytical approach, as the first to combine mixture modeling with supervised, targeted learning, provides a promising framework that can be further extended and optimized for improving accurate prognosis in pain treatment and identifying clinically meaningful subgroups among chronic pain patients., (© 2024. The Author(s).)

The COVID-19 pandemic has seen a rise in anxiety and depression among adolescents. This study aimed to investigate the longitudinal associations between sleep and mental health among a large sample of Australian adolescents and examine whether healthy sleep patterns were protective of mental health in the context of the COVID-19 pandemic. We used three waves of longitudinal control group data from the Health4Life cluster-randomized trial (N = 2781, baseline M age  = 12.6, SD =  0.51; 47% boys and 1.4% 'prefer not to say'). Latent class growth analyses across the 2 years period identified four trajectories of depressive symptoms: low-stable (64.3%), average-increasing (19.2%), high-decreasing (7.1%), moderate-increasing (9.4%), and three anxiety symptom trajectories: low-stable (74.8%), average-increasing (11.6%), high-decreasing (13.6%). We compared the trajectories on sociodemographic and sleep characteristics. Adolescents in low-risk trajectories were more likely to be boys and to report shorter sleep latency and wake after sleep onset, longer sleep duration, less sleepiness, and earlier chronotype. Where mental health improved or worsened, sleep patterns changed in the same direction. The subgroups analyses uncovered two important findings: (1) the majority of adolescents in the sample maintained good mental health and sleep habits (low-stable trajectories), (2) adolescents with worsening mental health also reported worsening sleep patterns and vice versa in the improving mental health trajectories. These distinct patterns of sleep and mental health would not be seen using mean-centred statistical approaches., (© 2024. The Author(s).)

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite and TNF-α is proinflammatory cytokine, both known to be associated with renal inflammation, fibrosis and chronic kidney disease. However, today there are no data showing the combined effect of TMAO and TNF-α on renal fibrosis-and inflammation. The aim of this study was to investigate whether TMAO can enhance the inflammatory and fibrotic effects of TNF-α on renal fibroblasts. We found that the combination of TNF-α and TMAO synergistically increased fibronectin release and total collagen production from renal fibroblasts. The combination of TMAO and TNF-α also promoted increased cell proliferation. Both renal proliferation and collagen production were mediated through Akt/mTOR/ERK signaling. We also found that TMAO enhanced TNF-α mediated renal inflammation by inducing the release of several cytokines (IL-6, LAP TGF-beta-1), chemokines (CXCL-6, MCP-3), inflammatory-and growth mediators (VEGFA, CD40, HGF) from renal fibroblasts. In conclusion, we showed that TMAO can enhance TNF-α mediated renal fibrosis and release of inflammatory mediators from renal fibroblasts in vitro. Our results can promote further research evaluating the combined effect of TMAO and inflammatory mediators on the development of kidney disease., (© 2024. The Author(s).)

In atherosclerotic lesions, monocyte-derived macrophages are major source of interferon gamma (IFN-γ), a pleotropic cytokine known to regulate the expression of numerous genes, including the antiviral gene RSAD2. While RSAD2 was reported to be expressed in endothelial cells of human carotid lesions, its significance for the development of atherosclerosis remains utterly unknown. Here, we harnessed publicly available human carotid atherosclerotic data to explore RSAD2 in lesions and employed siRNA-mediated gene-knockdown to investigate its function in IFN-γ-stimulated human aortic smooth muscle cells (hAoSMCs). Silencing RSAD2 in IFN-γ-stimulated hAoSMCs resulted in reduced expression and secretion of key CXCR3-chemokines, CXCL9, CXCL10, and CXCL11. Conditioned medium from RSAD2-deficient hAoSMCs exhibited diminished monocyte attraction in vitro compared to conditioned medium from control cells. Furthermore, RSAD2 transcript was elevated in carotid lesions where it was expressed by several different cell types, including endothelial cells, macrophages and smooth muscle cells. Interestingly, RSAD2 displayed significant correlations with CXCL10 (r =  0.45, p = 0.010) and CXCL11 (r = 0.53, p = 0.002) in human carotid lesions. Combining our findings, we uncover a novel role for RSAD2 in hAoSMCs, which could potentially contribute to monocyte recruitment in the context of atherosclerosis., (© 2024. The Author(s).)

Despite decades of research, the role of the lattice and its coupling to the magnetisation during ultrafast demagnetisation processes is still not fully understood. Here we report on studies of both explicit and implicit lattice effects on laser induced ultrafast demagnetisation of bcc Fe and fcc Co. We do this using atomistic spin- and lattice dynamics simulations following a heat-conserving three-temperature model. We show that this type of Langevin-based simulation is able to reproduce observed trends of the ultrafast magnetization dynamics of fcc Co and bcc Fe. The parameters used in our models are all obtained from electronic structure theory, with the exception of the lattice dynamics damping term, where a range of parameters were investigated. It was found that while the explicit spin-lattice coupling in the studied systems does not impact the demagnetisation process notably, the lattice damping has a large influence on the details of the magnetization dynamics. The dynamics of Fe and Co following the absorption of a femtosecond laser pulse are compared with previous results for Ni and similarities and differences in the materials' behavior are analysed. For all elements investigated so far with this model, we obtain a linear relationship between the value of the maximally demagnetized state and the fluence of the laser pulse , which is in agreement with experiments. Moreover, we demonstrate that the demagnetization amplitude is largest for Ni and smallest for Co. This holds over a wide range of the reported electron-phonon couplings, and this demagnetization trend is in agreement with recent experiments., (© 2024. The Author(s).)

Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments., (© 2024. The Author(s).)

Metabolic and bariatric surgery (MBS) is widely considered the most effective option for treating obesity, a chronic, relapsing, and progressive disease. Recently, the American Society of Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) issued new guidelines on the indications for MBS, which have superseded the previous 1991 National Institutes of Health guidelines. The aim of this study is to establish the first set of consensus guidelines for selecting procedures in Class I and II obesity, using an Expert Modified Delphi Method. In this study, 78 experienced bariatric surgeons from 32 countries participated in a two-round Modified Delphi consensus voting process. The threshold for consensus was set at an agreement or disagreement of ≥ 70.0% among the experts. The experts reached a consensus on 54 statements. The committee of experts reached a consensus that MBS is a cost-effective treatment option for Class II obesity and for patients with Class I obesity who have not achieved significant weight loss through non-surgical methods. MBS was also considered suitable for patients with Type 2 diabetes mellitus (T2DM) and a body mass index (BMI) of 30 kg/m 2 or higher. The committee identified intra-gastric balloon (IGB) as a treatment option for patients with class I obesity and endoscopic sleeve gastroplasty (ESG) as an option for patients with class I and II obesity, as well as for patients with T2DM and a BMI of ≥ 30 kg/m 2 . Sleeve gastrectomy (1) and Roux-en-Y gastric bypass (RYGB) were also recognized as viable treatment options for these patient groups. The committee also agreed that one anastomosis gastric bypass (OAGB) is a suitable option for patients with Class II obesity and T2DM, regardless of the presence or severity of obesity-related medical problems. The recommendations for selecting procedures in Class I and II obesity, developed through an Expert Modified Delphi Consensus, suggest that the use of standard primary bariatric endoscopic (IGB, ESG) and surgical procedures (SG, RYGB, OAGB) are acceptable in these patient groups, as consensus was reached regarding these procedures. However, randomized controlled trials are still needed in Class I and II Obesity to identify the best treatment approach for these patients in the future., (© 2024. The Author(s).)

Fracture-related infections (FRI) pose a serious complication with an incidence of 1-2%. This study aimed to analyze compensation claims submitted to The Swedish National Patient Insurance Company (LÖF) because of FRI after closed/open reduction and internal fixation (C/ORIF) in the four most common fracture sites (proximal humerus, distal radius, hip, ankle). Patients registered in the LÖF database with a suspected FRI between 2011 and 2021 were identified by matching International Classification of Diseases and procedural codes indicative of a combination of fractures to the proximal humerus, distal radius, hip and ankle, C/ORIF and infection. Medical records were reviewed for fracture sites, pathogens and complications. Data from the Swedish Fracture Register (SFR) were extracted to estimate the proportion of reported claims to the presumed number of FRI. Of 122 FRI identified in the LÖF database, 34 were after C/ORIF in the proximal humerus, 12 in the distal radius, 28 in the hip and 48 in the ankle. LÖF compensated 111 patients (91%). Median time from C/ORIF to an FRI was 3 weeks (interquartile range 2-6), and 95% of all FRI occurred within 1 year after C/ORIF. Staphylococcus aureus was the most common pathogen in patients with a distal radius, hip and ankle FRI. In contrast, Cutibacterium spp. were the most common aetiology in FRI of the proximal humerus. The total number of fractures treated with C/ORIF in the four fracture sites registered in the SFR during 2021 was 18,711. Most of the FRI patients were diagnosed within the first year after C/ORIF, and 91% of the patients received compensation. Given an expected FRI incidence of 1-2%, our estimates with extrapolated data from the SFR indicate that < 10% of affected patients applied for compensation., (© 2023. The Author(s).)

Testosterone is thought to be incorporated in growing hair strands so that specific hair segments reflect average free hormone concentrations from the corresponding time period. However, the exact mechanisms of hormone integration in scalp hair have not yet been established and it is not known how testosterone is stored in the hair segments over time. The aim of this study was to investigate the stability of testosterone concentrations in hair as it grows and to determine if segmental hair analysis can be used as a retrospective testosterone diary. Thirty men and 40 women provided two hair samples and 16 saliva samples during a period of three months. Hair growth between the two samplings was measured. Hair samples were cut into 10 mm segments resulting in three segments from the first sampling and six segments from the second sampling. Hair samples were pulverised and extracted with methanol. Hair testosterone concentrations were analysed using an in-house radioimmunoassay. Salivary testosterone was analysed using a commercial enzyme-linked immunosorbent assay (Demeditec). The results demonstrated that there is a degree of segmental hormone conservation over time (rho = 0.405-0.461, p < 0.001, n = 66-67), but also highlighted three potential confounders. Firstly, testosterone concentrations were higher in distal hair segments (mean concentration ratio most distal by most scalp-near was 1.55, SD 0.70), which may be due to continuous hormone integration from sebum and changes in hair matrix composition. Secondly, more frequent hair washing stunted the increase in testosterone concentrations in distal segments (rho = -0.404, p =  < 0.001, n = 66). And lastly, intra- and inter- individual variability in hair growth rate influenced the temporal resolution along the hair, although mean growth rate was indeed 30.0 mm for three months. In a multiple regression model the biological sex, natural hair colour, and relationship status were significant explanatory variables to hair testosterone concentrations. The current results indicate that repeated hair sampling near the hair roots during a study may be preferable to analysing concentration changes between proximal and distal segments within the same hair sample. Also, hair testosterone analysis needs to be adjusted for sex and the natural hair colour., (© 2023. Springer Nature Limited.)

Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n = 10) and compared these with similar measurements from matched children who were either positive for a single autoantibody (n = 10) or autoantibody negative (n = 10). Following statistical analysis of the longitudinal data, targeted serum proteomics was used to verify 11 proteins putatively associated with the disease development in a similar yet independent and larger cohort of children who progressed to the disease within 5 years of age (n = 31) and matched autoantibody negative children (n = 31). These data reiterated extensive age-related trends for protein levels in young children. Further, these analyses demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who progressed to type 1 diabetes, in comparison to autoantibody negative children., (© 2023. Springer Nature Limited.)

Sepsis is a time dependent condition. Screening tools based on clinical parameters have been shown to increase the identification of sepsis. The aim of current study was to evaluate the additional predictive value of immunological molecular markers to our previously developed prehospital screening tools. This is a prospective cohort study of 551 adult patients with suspected infection in the ambulance setting of Stockholm, Sweden between 2017 and 2018. Initially, 74 molecules and 15 genes related to inflammation were evaluated in a screening cohort of 46 patients with outcome sepsis and 50 patients with outcome infection no sepsis. Next, 12 selected molecules, as potentially synergistic predictors, were evaluated in combination with our previously developed screening tools based on clinical parameters in a prediction cohort (n = 455). Seven different algorithms with nested cross-validation were used in the machine learning of the prediction models. Model performances were compared using posterior distributions of average area under the receiver operating characteristic (ROC) curve (AUC) and difference in AUCs. Model variable importance was assessed by permutation of variable values, scoring loss of classification as metric and with model-specific weights when applicable. When comparing the screening tools with and without added molecular variables, and their interactions, the molecules per se did not increase the predictive values. Prediction models based on the molecular variables alone showed a performance in terms of AUCs between 0.65 and 0.70. Among the molecular variables, IL-1Ra, IL-17A, CCL19, CX3CL1 and TNF were significantly higher in septic patients compared to the infection non-sepsis group. Combing immunological molecular markers with clinical parameters did not increase the predictive values of the screening tools, most likely due to the high multicollinearity of temperature and some of the markers. A group of sepsis patients was consistently miss-classified in our prediction models, due to milder symptoms as well as lower expression levels of the investigated immune mediators. This indicates a need of stratifying septic patients with a priori knowledge of certain clinical and molecular parameters in order to improve prediction for early sepsis diagnosis.Trial registration: NCT03249597. Registered 15 August 2017., (© 2023. Springer Nature Limited.)

This study aimed to establish the cost-effectiveness of home phototherapy versus hospital phototherapy treating hyperbilirubinemia in neonates more than 36 weeks. Based on clinical results from a randomised controlled trial showing that home phototherapy for hyperbilirubinemia in term neonates is as effective as hospital phototherapy, we performed a cost-minimisation analysis to identify the most cost-effective alternative. We included costs for health care resource use as well as costs for transportation in connection with re-visits. The cost per patient was €337 for home phototherapy compared with €1156 for the hospital alternative indicating average cost savings of €819 (95% confidence interval €613-1025) or 71% per patient. Transportation and outpatient costs were higher in the home treatment group and hospital care costs were higher in the hospital group. Sensitivity analysis shows that results are robust also when allowing for uncertainty. Home phototherapy for neonates more than 36 weeks costs less than in-hospital phototherapy while being equally effective, meaning that home phototherapy is a cost-effective alternative to hospital treatment for infants with neonatal hyperbilirubinemia.Trial registration NCT03536078 . Date of registration: 24/05/2018., (© 2023. The Author(s).)

Bear bile-farming is common in East and Southeast Asia and this farming practice often results in irreversible health outcomes for the animals. We studied long-term effects of chronic bacterial and sterile hepatobiliary inflammation in 42 Asiatic black bears (Ursus thibetanus) rescued from Vietnamese bile farms. The bears were examined under anesthesia at least twice as part of essential medical interventions. All bears were diagnosed with chronic low-grade sterile or bacterial hepatobiliary inflammation along with pathologies from other systems. Our main finding was that the chronic low-grade inflammatory environment associated with bile extraction in conjunction with the suboptimal living conditions on the farms promoted and accelerated the development of age-related pathologies such as chronic kidney disease, obese sarcopenia, cardiovascular remodeling, and degenerative joint disease. Through a biomimetic approach, we identified similarities with inflammation related to premature aging in humans and found significant deviations from the healthy ursid phenotype. The pathological parallels with inflammageing and immuno-senescence induced conditions in humans suggest that bile-farmed bears may serve as animal models to investigate pathophysiology and deleterious effects of lifestyle-related diseases., (© 2023. The Author(s).)

Incidence of tick-borne encephalitis (TBE) has increased during the last years in Scandinavia, but the underlying mechanism is not understood. TBE human case data reported between 2010 and 2021 were aggregated into postal codes within Örebro County, south-central Sweden, along with tick abundance and environmental data to analyse spatial patterns and identify drivers of TBE. We identified a substantial and continuing increase of TBE incidence in Örebro County during the study period. Spatial cluster analyses showed significant hotspots (higher number of cases than expected) in the southern and northern parts of Örebro County, whereas a cold spot (lower number of cases than expected) was found in the central part comprising Örebro municipality. Generalised linear models showed that the risk of acquiring TBE increased by 12.5% and 72.3% for every percent increase in relative humidity and proportion of wetland forest, respectively, whereas the risk decreased by 52.8% for every degree Celsius increase in annual temperature range. However, models had relatively low goodness of fit (R 2  < 0.27). Results suggest that TBE in Örebro County is spatially clustered, however variables used in this study, i.e., climatic variables, forest cover, water, tick abundance, sheep as indicator species, alone do not explain this pattern., (© 2023. The Author(s).)

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) pandemic has led to extensive virological monitoring by whole genome sequencing (WGS). Investigating the advantages and limitations of different protocols is key when conducting population-level WGS. SARS-CoV-2 positive samples with Ct values of 14-30 were run using three different protocols: the Twist Bioscience SARS‑CoV‑2 protocol with bait hybridization enrichment sequenced with Illumina, and two tiled amplicon enrichment protocols, ARTIC V3 and Midnight, sequenced with Illumina and Oxford Nanopore Technologies, respectively. Twist resulted in better coverage uniformity and coverage of the entire genome, but has several drawbacks: high human contamination, laborious workflow, high cost, and variation between batches. The ARTIC and Midnight protocol produced an even coverage across samples, and almost all reads were mapped to the SARS-CoV-2 reference. ARTIC and Midnight represent robust, cost-effective, and highly scalable methods that are appropriate in a clinical environment. Lineage designations were uniform across methods, representing the dominant lineages in Sweden during the period of collection. This study provides insights into methodological differences in SARS‑CoV‑2 sequencing and guidance in selecting suitable methods for various purposes., (© 2023. The Author(s).)

The aim of this study was to compare LAP with OPEN regarding short-term mortality, morbidity and completeness of the cancer resection for colon cancer in a routine health care setting using population based register data. All 13,683 patients who were diagnosed 2012-2018 and underwent elective surgery for right-sided or sigmoid colon cancer were included from the Swedish Colorectal Cancer Registry and the National Patient Registry. Primary outcome was 30-day mortality. Secondary outcomes were 90-day mortality, length of hospital stay, reoperation, readmission and positive resection margin (R1). Weighted and unweighted multi regression analyses were performed. There were no difference in 30-day mortality: LAP (0.9%) and OPEN (1.3%) (OR 0.89, 95% CI 0.62-1.29, P = 0.545). The weighted analyses showed an increased 90-day mortality following OPEN, P < 0.001. Re-operations and re-admission were more frequent after OPEN and length of hospital stay was 2.9 days shorter following LAP (P < 0.001). R1 resections were significantly more common in the OPEN group in the unweighted and weighted analysis with P = 0.004 and P < 0.001 respectively. Therefore, the favourable short-term outcomes following elective LAP versus OPEN resection for colon cancer in routine health care indicate an advantage of laparoscopic surgery., (© 2023. The Author(s).)

Bacterial resistance towards antibiotics is a major global health issue. Very few novel antimicrobial agents and therapies have been made available for clinical use during the past decades, despite an increasing need. Antimicrobial peptides have been intensely studied, many of which have shown great promise in vitro. We have previously demonstrated that the bacteriocin Plantaricin NC8 αβ (PLNC8 αβ) from Lactobacillus plantarum effectively inhibits Staphylococcus spp., and shows little to no cytotoxicity towards human keratinocytes. However, due to its limitations in inhibiting gram-negative species, the aim of the present study was to identify novel antimicrobial peptidomimetic compounds with an enhanced spectrum of activity, derived from the β peptide of PLNC8 αβ. We have rationally designed and synthesized a small library of lipopeptides with significantly improved antimicrobial activity towards both gram-positive and gram-negative bacteria, including the ESKAPE pathogens. The lipopeptides consist of 16 amino acids with a terminal fatty acid chain and assemble into micelles that effectively inhibit and kill bacteria by permeabilizing their cell membranes. They demonstrate low hemolytic activity and liposome model systems further confirm selectivity for bacterial lipid membranes. The combination of lipopeptides with different antibiotics enhanced the effects in a synergistic or additive manner. Our data suggest that the novel lipopeptides are promising as future antimicrobial agents, however additional experiments using relevant animal models are necessary to further validate their in vivo efficacy., (© 2023. The Author(s).)

Criminal behaviour has previously been associated with an increased risk for several mental health problems, but little is known about the association between criminal behaviour and dementia. We aimed to examine how the criminal background (type of crime, number of convictions, length of the sentence) is associated with dementia and mild cognitive impairment (MCI), and how mental and physical health disorders and educational attainment influenced these associations. A nationwide cohort of 3,617,028 individuals born between 1932 and 1962 were linked with criminal and medical records using Swedish national registers. We used Cox regression models to examine the associations. Increased risks for dementia (Hazard ratios (HRs) 1.54, 95% confidence interval (CI) 1.50-1.57) and MCI (1.55, 1.50-1.61) were found in individuals with criminal background, particularly among those who committed violent or several crimes, or with long sentences. After full adjustment of covariates, the associations attenuated but remained statistically significant for dementia (1.25, 1.22-1.28) and MCI (1.27, 1.22-1.32). The attenuation was mostly explained by mental health problems -depression, anxiety, schizophrenia spectrum disorders, substance use disorder (SUD), and bipolar disorder- (dementia: 1.34, 1.31-1.37; MCI: 1.35, 1.30-1.40). SUD contributed the most to attenuate the associations. Our results may provide important insights to health and penal systems by showing the importance of considering the severity of the criminal background and life-course mental health when assessing the risk of neurodegenerative disorders., (© 2023. The Author(s).)

In a previous study, we showed that serine/threonine-protein kinase 4 (STK4) is involved in the control on proliferation and migration of endometrial cancer (EC) cells in vitro. In the present paper, we studied STK4 expression in EC tissues from a large cohort of patients to determine whether STK4 can serve as a marker for the aggressiveness and prognosis of EC. Tissue samples from patients with EC were examined for tumor type, grade, and stage. The STK4 protein expression in EC cells was assessed by immunohistochemistry and related to clinicopathological data of patients, such as progression and patient survival rate. The STK4 mRNA levels and its relation to the survival rate were analyzed also in publicly available databases. The STK4 gene expression was low at both, the mRNA and protein levels in EC, especially in serous tumors. Comparison of STK4 expression with the patient survival rate shows that the higher expression is associated with worse prognosis in serous EC, while no such dependence was found in endometrioid EC. Hence, the determination of the SKT4 expression pattern could be used as a putative prognostic marker for serous EC., (© 2022. The Author(s).)

Previous studies have demonstrated that environmental and temporal factors may affect the incidence of acute type A aortic dissection (ATAAD). Here, we aimed to investigate the hypothesis that national holidays and weekends influence the incidence of surgery for ATAAD. For the period 1st of January 2005 until 31st of December 2019, we investigated a hypothesised effect of (country-specific) national holidays and weekends on the frequency of 2995 surgical repairs for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Compared to other days, the number of ATAAD repairs were 29% (RR 0.71; 95% CI 0.54-0.94) lower on national holidays and 26% (RR 0.74; 95% CI 0.68-0.82) lower on weekends. As day of week patterns of symptom duration were assessed and the primary analyses were adjusted for period of year, our findings suggest that the reduced surgical incidence on national holidays and weekends does not seem to correspond to seasonal effects or surgery being delayed and performed on regular working days., (© 2022. The Author(s).)

The Structured Water Dance Intervention (SWAN) is a dance-oriented aquatic group activity directed to give opportunities for the joy of movement, relaxation, and reduced stress. This study aimed to evaluate the effects of SWAN on salivary cortisol and stress in adults with profound intellectual and multiple disabilities (PIMD). A total of 34 adults with PIMD at four habilitation centres in Sweden completed the SWAN intervention. The intervention was administered for 40 min once a week during a 12-week period. Saliva cortisol was collected in the morning and evening at baseline one week before the intervention, thrice during the intervention period, and one week after the intervention. Moreover, in connection with the SWAN sessions, the participants' level of stress was also assessed by the accompanying assistants. The results showed that salivary cortisol and participants stress decreased significantly, directly after the SWAN sessions compared with measures directly before sessions. The study demonstrates that adults with PIMD have diurnal salivary cortisol patterns consistent with those observed in adults without disability and that the SWAN reduces salivary cortisol levels and stress in people with PIMD; this justifies that SWAN could be considered in the choice of interventions to reduce stress in adults with PIMD.Trial registration: This study is registered 09/04/2019 on ClinicalTrials.gov (ID: NCT03908801)., (© 2022. The Author(s).)

Monobutyrin (MB) and monovalerin (MV), glycerol esters of short-chain fatty acids (SCFAs), have been shown to positively influence lipid profile and biomarkers in the gut and brain. This study examined whether MB and MV in high-fat diets, affected microbiota composition and gut-blood-brain markers in apolipoprotein E deficient (ApoE-/-) rats, a model for studies of lipid-associated disorders, and neurodegenerative processes in Alzheimer's disease (AD). ApoE-/- rats fed MB and MV increased Tenericutes and the brain neurotransmitter γ-aminobutyric acid (GABA), while the blood stress hormone corticosterone decreased compared to control rats. Only rats that received MB showed a significant increase in cholic acid and Adlercreutzia in the caecum. In rats fed MV, the decrease of Proteobacteria was associated with decreased corticosterone levels. Conclusively, dietary supplementation of SCFA glycerol esters can modulate gut-blood-brain markers and alter gut microbiota composition in ApoE-/- rats, suggesting that SCFAs also could counteract lipid disorders-related diseases., (© 2022. The Author(s).)

The soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2) are suggested to play dual roles on physiological and pathophysiological actions of TNF-α. The aim of this study was to investigate the dynamic changes of these biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). Blood was collected from 165 STEMI patients at admission, 1-3 days and 3 months after percutaneous coronary intervention (PCI) and from 40 healthy blood donors. sTNFR1 and sTNFR2 were measured with ELISA. The plasma levels of both sTNFR1 and sTNFR2 were significantly higher than in healthy donors at all three time points. We found no significant differences in sTNFR1 or sTNFR2 when comparing patients with patent versus occluded culprit vessels, or between patients having a thrombus aspiration or not. Survival analysis was performed comparing patients with levels of biomarkers above and below the median values at that time point. We found significant differences in survival for sTNFR2 in acute samples (p = 0.0151) and for both sTNFR1 and sTNFR2 in samples 1-3 days after PCI (p = 0.0054 and p = 0.0003, respectively). Survival analyses suggest that sTNFR1 or sTNFR2 could be promising markers to predict mortality in STEMI patients after PCI., (© 2022. The Author(s).)

Porphyromonas gingivalis has been strongly associated to active periodontitis sites. A number of studies have tried to elucidate the association between female steroid sex hormones and gingival health. However, until now, there is limited knowledge on estradiol effects on the virulence traits of P. gingivalis. The aim of the study was to investigate the impact of estradiol exposure on the virulence characteristics of P. gingivalis strain W50. We found that a pre- and postmenopausal concentration of estradiol increased the growth and biofilm formation of P. gingivalis W50. We also found that estradiol increased the release of lysine and arginine gingipains from W50. We then showed that IL-1β, CXCL10 and TGF-β1 release from gingival epithelial cells was significantly lowered by W50 pre-exposed to estradiol compared to W50 alone. Real time-qPCR showed that the gene expression of IL-18, IL-6, IL-8, TGF-β1 and NLRP3 in gingival epithelial cells was significantly lowered by W50 pre-exposed to estradiol compared to W50 alone. We also found that estradiol in a dose-dependent manner increased P. gingivalis colonization and invasion of gingival epithelial cells. Taken together, our findings show that estradiol has the ability to alter the virulence traits of P. gingivalis., (© 2022. The Author(s).)

"Quality in Psychiatric Care-Forensic Inpatient Staff (QPC-FIPS) is an instrument of Swedish origin validated to measure the perception of the quality of mental health care provided by forensic psychiatry professionals. The aim of this study was to cross-culturally adapt the QPC-FIPS instrument and to evaluate the psychometric properties of the Spanish version of the instrument. A psychometric study was carried out. For validity, content validity, convergent validity and construct validity were included. For reliability, the analysis of internal consistency and temporal stability was included. The sample consisted of 153 mental health professionals from four Forensic Psychiatry units. The adapted Spanish version of the QPC-FIPS scale was configured with the same number of items and dimensions as the original. The psychometric properties, in terms of temporal stability and internal consistency, were adequate and the factor structure, such as the homogeneity of the dimensions of the Spanish version of the QPC-FIPS, was equivalent to the original Swedish version. We found that the QPC&#95;FIPS-Spanish is a valid, reliable and easy-to-apply instrument for assessing the self-perception of professionals regarding the care they provide., (© 2022. The Author(s).)

Whole genome sequencing (WGS) of methicillin-resistant Staphylococcus aureus (MRSA) provides high-resolution typing, facilitating surveillance and outbreak investigations. The aim of this study was to evaluate the genomic variation rate in MRSA, by comparing commonly used core genome multilocus sequencing (cgMLST) against single nucleotide polymorphism (SNP) analyses. WGS was performed on 95 MRSA isolates, collected from 20 carriers during years 2003-2019. To assess variation and methodological-related differences, two different cgMLST schemes were obtained using Ridom SeqSphere+ and the cloud-based 1928 platform. In addition, two SNP methods, 1928 platform and Northern Arizona SNP Pipeline (NASP) were used. The cgMLST using Ridom SeqSphere+ and 1928 showed a median of 5.0 and 2.0 allele variants/year, respectively. In the SNP analysis, performed with two reference genomes COL and Newman, 1928 showed a median of 13 and 24 SNPs (including presumed recombination) and 3.8 respectively 4.0 SNPs (without recombination) per individual/year. Accordantly, NASP showed a median of 5.5 and 5.8 SNPs per individual/year. In conclusion, an estimated genomic variation rate of 2.0-5.8 genetic events per year (without recombination), is suggested as a general guideline to be used at clinical laboratories for surveillance and outbreak investigations independently of analysis approach used., (© 2022. The Author(s).)

Although development of microbiota in childhood has been linked to chronic immune-related conditions, early childhood determinants of microbiota development have not been fully elucidated. We used 16S rRNA sequencing to analyse faecal and saliva samples from 83 children at four time-points during their first 2 years of life and from their mothers. Our findings confirm that gut microbiota in infants have low diversity and highlight that some properties are shared with the oral microbiota, although inter-individual differences are present. A considerable convergence in gut microbiota composition was noted across the first 2 years of life, towards a more diverse adult-like microbiota. Mode of delivery accounted for some of the inter-individual variation in early childhood, but with a pronounced attenuation over time. Our study extends previous research with further characterization of the major shift in gut microbiota composition during the first 2 years of life., (© 2022. The Author(s).)

This study aimed to evaluate the effect of Structured Water Dance Intervention (SWAN) on muscular hypertonia in individuals with profound intellectual and multiple disability (PIMD). Muscular hypertonia has a multitude of negative consequences for people with PIMD because it can lead to contractures, pain, mobility impairment, pressure ulcers that limits functional behavior as well as gross and fine motor function. Thirty-six individuals with PIMD in four Swedish regions were randomized to two groups in a multicenter, crossover design. Two withdrew participation, thus 34 individuals completed the intervention. The intervention was administered for 40 min once a week during a 12-week period. Outcomes related to muscular hypertonia were examined using the Modified Ashworth Scale (MAS), and based on accompanying assistants' assessments. Hypertonia decreased from baseline to the end of the intervention period, as demonstrated by a decrease in MAS score. Hypertonia also decreased during the sessions, as shown by the assistants' ratings. In conclusion, this study demonstrates that SWAN holds potential to reduce muscular hypertonia in people with PIMD and points out the importance of customized physical treatment alternatives. The study provides useful information for the design of future non-invasive, non-pharmacological interventions to reduce muscular hypertonia in PIMD., (© 2022. The Author(s).)

Prostate cancer (PC) is a common cancer among men, and preventive strategies are warranted. Benzoxazinoids (BXs) in rye have shown potential against PC in vitro but human studies are lacking. The aim was to establish a quantitative method for analysis of BXs and investigate their plasma levels after a whole grain/bran rye vs refined wheat intervention, as well as exploring their association with PSA, in men with PC. A quantitative method for analysis of 22 BXs, including novel metabolites identified by mass spectrometry and NMR, was established, and applied to plasma samples from a randomized crossover study where patients with indolent PC (n = 17) consumed 485 g whole grain rye/rye bran or fiber supplemented refined wheat daily for 6 wk. Most BXs were significantly higher in plasma after rye (0.3-19.4 nmol/L in plasma) vs. refined wheat (0.05-2.9 nmol/L) intake. HBOA-glc, 2-HHPAA, HBOA-glcA, 2-HPAA-glcA were inversely correlated to PSA in plasma (p < 0.04). To conclude, BXs in plasma, including metabolites not previously analyzed, were quantified. BX metabolites were significantly higher after rye vs refined wheat consumption. Four BX-related metabolites were inversely associated with PSA, which merits further investigation., (© 2022. The Author(s).)

The onset of both chronic pain and insomnia is high during adolescence. Although a bidirectional relationship between pain and insomnia has support, how pain and sleep co-develop throughout adolescence remains unknown. Sleep-wake patterns, pre-sleep behavior and pre-sleep arousal may influence the co-development of pain and insomnia. Four waves of longitudinal self-report data were used (N baseline  = 2767, Age baseline M = 13.65 years, SD = 0.65). Multidimensional growth mixture modeling was used to identify four subgroups of adolescents with different concurrent trajectories of pain and insomnia. The trajectories followed each other across time in all classes: one class of consistently low pain and insomnia (68.7%), one class with persistent high symptoms (4.9%), as well as one class of increasing (13.9%), and one of decreasing (12.5%), trajectories. Later sleep-wake patterns and more pre-sleep cognitive-emotional arousal predicted both increasing and decreasing trajectories of concurrent pain and insomnia. The current study showed that developmental trajectories of pain and insomnia follow each other within adolescents and across adolescence. Both sleep-phase focused interventions as well as psychological interventions that focus on pre-sleep cognitive-emotional arousal may prove beneficial for adolescents with comorbid pain and insomnia., (© 2022. The Author(s).)

Quality of care is a multidimensional concept that should include the perspectives of all parties involved. There are few instruments with adequate psychometric properties for the assessment of the quality of psychiatric care in community mental health. Quality in Psychiatric Care-Outpatient Staff (QPC-OPS) instrument has adequate psychometric properties to evaluate the quality of psychiatric care from the perspective of professionals. The aim of this study was to validate the Spanish version of the QPC-OPS instrument. The instrument was translated and back-translated, and then was administered to 260 professionals from distinct community mental health services. To assess test-retest reliability, it was re-administered after 7-14 days (n = 157). Confirmatory factor analysis revealed an 8-factor-structure identical to the original version, showing the good fit of the model. The internal consistency coefficient (Cronbach's alpha) was 0.885. The intraclass correlation coefficient was 0.847 (95% IC 0.790-0.888), which was higher than 0.70 in all factors bar one. The NT394 General Satisfaction Scale was used for analysis of convergent validity showing a rho correlation of 0.31 (p < 0.0001). Results show that the Spanish version of the QPC-OPS instrument is valid and reliable for the assessment of the quality of psychiatric care in the community setting., (© 2022. The Author(s).)

The inflammasome-associated proteins caspase-1, caspase-4 and NLRP3 have been emphasised to be essential in the host cell response during urinary tract infection (UTI) by regulating IL-1β release. Our aim was to investigate how the inflammasome-associated proteins regulate the cell response of bladder epithelial cells during infection with uropathogenic Escherichia coli (UPEC). Human bladder epithelial cells (5637) and CRISPR/Cas9 generated caspase-1, caspase-4 and NLRP3 knockdown cells were stimulated with the UPEC strain CFT073. Using Olink proteomics and real time RT-PCR, we showed that caspase-1, caspase-4 and NLRP3 are vital for the expression of many inflammatory genes and proteins from bladder epithelial cells. When investigating the effect of inflammasome-associated proteins on neutrophils, we found that conditioned medium from UPEC-infected caspase-4 knockdown cells significantly increased phagocytosis of CFT073 and significantly decreased ROS production from neutrophils. In contrast, conditioned medium from UPEC-infected NLRP3 knockdown cells significantly decreased the phagocytosis of CFT073 and significantly increased the ROS production from neutrophils. In conclusion, we showed that the inflammasome-associated proteins contribute to the host cell response during UPEC infection., (© 2022. The Author(s).)

We compared the odds of smoking cessation at 2-months post-myocardial infarction (MI), before and after implementing routines optimizing use of evidence-based smoking cessation methods, with start during admission. The following routines were implemented at six Swedish hospitals: cardiac rehabilitation nurses offering smokers consultation during admission, optimizing nicotine replacement therapy and varenicline prescription, and contacting patients by telephone during the 1st week post-discharge. Using logistic regression, odds for smoking cessation at 2-months before (n smokers/n admitted = 188/601) and after (n = 195/632) routine implementation were compared. Secondary outcomes included adherence to implemented routines and assessing the prognostic value of each routine on smoking cessation. After implementation, a larger proportion of smokers (65% vs. 54%) were abstinent at 2-months (OR 1.60 [1.04-2.48]). Including only those counselled during admission (n = 98), 74% were abstinent (2.50 [1.42-4.41]). After implementation, patients were more often counselled during admission (50% vs. 6%, p < 0.001), prescribed varenicline (23% vs. 7%, p < 0.001), and contacted by telephone post-discharge (18% vs. 2%, p < 0.001). Being contacted by telephone post-discharge (adjusted OR 2.74 [1.02-7.35]) and prescribed varenicline (adjusted OR 0.39 [0.19-0.83]) predicted smoking cessation at 2-months. In conclusion, readily available methods for aiding smoking cessation can be implemented effectively in routine practice, with beneficial effects for post-MI patients., (© 2022. The Author(s).)

Uropathogenic Escherichia coli (UPEC) may undergo a cyclic cascade of morphological alterations that are believed to enhance the potential of UPEC to evade host responses and re-infect host cell. However, knowledge on the pathogenic potential and host activation properties of UPEC during the morphological switch is limited. Microarray analysis was performed on mRNA isolated from human bladder epithelial cells (HBEP) after exposure to three different morphological states of UPEC (normal coliform, filamentous form and reverted form). Cells stimulated with filamentous bacteria showed the lowest number of significant gene alterations, although the number of enriched gene ontology classes was high suggesting diverse effects on many different classes of host genes. The normal coliform was in general superior in stimulating transcriptional activity in HBEP cells compared to the filamentous and reverted form. Top-scored gene entities activated by all three morphological states included IL17C, TNFAIP6, TNF, IL20, CXCL2, CXCL3, IL6 and CXCL8. The number of significantly changed canonical pathways was lower in HBEP cells stimulated with the reverted form (32 pathways), than in cells stimulated with the coliform (83 pathways) or filamentous bacteria (138 pathways). A host cell invasion assay showed that filamentous bacteria were unable to invade bladder cells, and that the number of intracellular bacteria was markedly lower in cells infected with the reverted form compared to the coliform. In conclusion, the morphological state of UPEC has major impact on the host bladder response both when evaluating the number and the identity of altered host genes and pathways., (© 2022. The Author(s).)

This research evaluates the effect on herbal crops of mechanical stress induced by two specially developed robotic platforms. The changes in plant morphology, metabolite profiles, and element content are evaluated in a series of three empirical experiments, conducted in greenhouse and CNC growing bed conditions, for the case of basil plant growth. Results show significant changes in morphological features, including shortening of overall stem length by up to 40% and inter-node distances by up to 80%, for plants treated with a robotic mechanical stress-induction protocol, compared to control groups. Treated plants showed a significant increase in element absorption, by 20-250% compared to controls, and changes in the metabolite profiles suggested an improvement in plants' nutritional profiles. These results suggest that repetitive, robotic, mechanical stimuli could be potentially beneficial for plants' nutritional and taste properties, and could be performed with no human intervention (and therefore labor cost). The changes in morphological aspects of the plant could potentially replace practices involving chemical treatment of the plants, leading to more sustainable crop production., (© 2021. The Author(s).)

Previous studies suggested cervical spondylosis as a risk factor for development of obstructive sleep apnoea (OSA). We aimed to assess lumbar disc degeneration in patients with OSA and correlate the findings with symptoms and disease severity. Twenty-seven patients with OSA and 29 non-OSA controls underwent sleep studies and lumbar magnetic resonance imaging (MRI), and completed the Epworth Sleepiness Scale and the 24-item Roland-Morris Disability Questionnaire (RMDQ) questionnaires. Plasma klotho was determined with enzyme-linked immunosorbent assay. Patients with OSA had higher number of disc bulges (4.6 ± 3.7 vs. 1.7 ± 2.5, p < 0.01) and anterior spondylophytes (2.7 ± 4.2 vs. 0.8 ± 2.1, p < 0.01), increased disc degeneration (total Pfirrmann score 16.7 ± 4.7 vs. 13.2 ± 4.1, p < 0.01) and vertebral fatty degeneration (7.8 ± 4.7 vs. 3.8 ± 3.7, p < 0.01). There was no difference in the RMDQ score (0/0-3.5/ vs. 0/0-1/, p > 0.05). Markers of OSA severity, including the oxygen desaturation index and percentage of total sleep time spent with saturation < 90% as well as plasma levels of klotho were correlated with the number of disc bulges and anterior spondylophytes (all p < 0.05). OSA is associated with lumbar spondylosis. Our study highlights the importance of lumbar imaging in patients with OSA reporting lower back pain., (© 2021. The Author(s).)

The intestinal barrier plays a crucial role in maintaining gut health, and an increased permeability has been linked to several intestinal and extra-intestinal disorders. There is an increasing demand for interventions aimed at strengthening this barrier and for in vivo challenge models to assess their efficiency. This study investigated the effect of sauna-induced dehydration on intestinal barrier function (clinicaltrials.gov: NCT03620825). Twenty healthy subjects underwent three conditions in random order: (1) Sauna dehydration (loss of 3% body weight), (2) non-steroidal anti-inflammatory drug (NSAID) intake, (3) negative control. Intestinal permeability was assessed by a multi-sugar urinary recovery test, while intestinal damage, bacterial translocation and cytokines were assessed by plasma markers. The sauna dehydration protocol resulted in an increase in gastroduodenal and small intestinal permeability. Presumably, this increase occurred without substantial damage to the enterocytes as plasma intestinal fatty acid-binding protein (I-FABP) and liver fatty acid-binding protein (L-FABP) were not affected. In addition, we observed significant increases in levels of lipopolysaccharide-binding protein (LBP), IL-6 and IL-8, while sCD14, IL-10, IFN-ɣ and TNF-α were not affected. These results suggest that sauna dehydration increased intestinal permeability and could be applied as a new physiological in vivo challenge model for intestinal barrier function., (© 2021. The Author(s).)

Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.

Multidrug resistance bacteria constitue an increasing global health problem and the development of novel therapeutic strategies to face this challenge is urgent. Antimicrobial peptides have been proven as potent agents against pathogenic bacteria shown by promising in vitro results. The aim of this study was to characterize the antimicrobial effects of PLNC8 αβ on cell signaling pathways and inflammatory responses of human keratinocytes infected with S. aureus. PLNC8 αβ did not affect the viability of human keratinocytes but upregulated several cytokines (IL-1β, IL-6, CXCL8), MMPs (MMP1, MMP2, MMP9, MMP10) and growth factors (VEGF and PDGF-AA), which are essential in cell regeneration. S. aureus induced the expression of several inflammatory mediators at the gene and protein level and PLNC8 αβ was able to significantly suppress these effects. Intracellular signaling events involved primarily c-Jun via JNK, c-Fos and NFκB, suggesting their essential role in the initiation of inflammatory responses in human keratinocytes. PLNC8 αβ was shown to modulate early keratinocyte responses, without affecting their viability. The peptides have high selectivity towards S. aureus and were efficient at eliminating the bacteria and counteracting their inflammatory and cytotoxic effects, alone and in combination with low concentrations of gentamicin. We propose that PLNC8 αβ may be developed to combat infections caused by Staphylococcus spp.

Brown bears (Ursus arctos) hibernate for 5-6 months during winter, but despite kidney insufficiency, dyslipidemia and inactivity they do not seem to develop atherosclerosis or cardiovascular disease (CVD). IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) are associated with less atherosclerosis, CVD and mortality in uremia in humans and have anti-inflammatory and other potentially protective properties. PC but not MDA is exposed on different types of microorganisms. We determine anti-PC and anti-MDA in brown bears in summer and winter. Paired serum samples from 12 free ranging Swedish brown bears were collected during hibernation in winter and during active state in summer and analyzed for IgM, IgG, IgG1/2 and IgA anti-PC and anti-MDA by enzyme linked immunosorbent assay (ELISA). When determined as arbitrary units (median set at 100 for summer samples), significantly raised levels were observed in winter for anti-PC subclasses and isotypes, and for IgA anti-PC the difference was striking; 100 IQR (85.9-107.9) vs 782.3, IQR (422.8-1586.0; p < 0.001). In contrast, subclasses and isotypes of anti-MDA were significantly lower in winter except IgA anti-MDA, which was not detectable. Anti-PCs are significantly raised during hibernation in brown bears; especially IgA anti-PC was strikingly high. In contrast, anti-MDA titers was decreased during hibernation. Our observation may represent natural immunization with microorganisms during a vulnerable period and could have therapeutic implications for prevention of atherosclerosis.

Immunogenicity related to treatment with TNF inhibitors (TNFi) is one of the causes for the decreased attainment of clinical response in patients with rheumatoid arthritis (RA). The B-cell activating factor (BAFF) may be playing a role in the development of immunogenicity. The objective of this study was to analyse the association of baseline concentration of serum B-cell activating factor (BAFF) with immunogenicity after 6 months of TNFi treatment. A total of 127 patients with RA starting a TNFi (infliximab, adalimumab, certolizumab pegol or golimumab) were followed-up for 6 months. Serum samples were obtained at baseline and at 6 months and anti-drug antibody (ADA) and BAFF concentrations were measured. Logistic regression models were employed in order to analyse the association between BAFF concentrations and immunogenicity. Receiver operating characteristic analysis was performed to determine the BAFF concentrations with a greater likelihood of showing immunogenicity association. At 6 months, 31 patients (24%) developed ADA. A significant interaction between the age and baseline BAFF concentration was found for the development of ADA (Wald chi-square value = 5.30; p = 0.02); therefore, subsequent results were stratified according to mean age (≤ / > 55 years). Baseline serum BAFF concentration was independently associated with ADA development only in patients over 55 years (OR = 1.51; 95% CI 1.03-2.21). Baseline serum BAFF ≥ 1034 pg/mL predicted the presence of ADA at 6 months (AUC = 0.81; 95% confidence interval (CI) 0.69-0.93; p = 0.001; positive likelihood ratio = 3.7). In conclusion, our results suggest that the association of BAFF concentration and immunogenicity depends on the patient's age. Baseline serum BAFF concentration predicts the presence of ADA within 6 months of TNFi therapy in older patients with RA.

Exposure to endocrine disrupting chemicals (EDCs) may impact early growth, although information is limited on exposure to combination of multiple EDCs. We aimed to evaluate the effect of prenatal exposure to EDC mixtures on birthweight z-scores and childhood weight trajectories. Twenty-six proven and suspected EDCs, were analyzed in prenatal urine and blood samples from 1118 mothers participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study. Two growth parameters were estimated from each child's weight trajectory from birth to 5.5 years of age: infant growth spurt rate and age at infant peak growth velocity (PGV). Weighted quantile sum (WQS) regression was used to estimate the mixture effect and identify chemicals of concern. A one-unit increase in the EDC mixture WQS index, was associated with decreased birthweight z-scores of 0.11 (95% CI - 0.16, - 0.06), slower infant growth spurt rate of 0.01 (95% CI - 0.03, - 0.01, on the log 10 scale), and delayed age at infant PGV of 0.15 months (95% CI 0.07, 0.24) after adjusting for potential confounders. Stratified analysis by sex, showed that delayed age at infant PGV was mostly observed in girls with 0.51 months (95% CI 0.26, 0.76). Identified chemicals of concern included perfluorinated alkyl substances (PFAS), Triclosan, phthalates, non-phthalate plasticizers, bisphenols, polycyclic aromatic hydrocarbons, pesticides and PCBs. Prenatal exposure to EDC mixtures was associated with lower birthweight and altered infant weight gain trajectories.

In the next few years, the number of long-term space missions will significantly increase. Providing safe concepts for emergencies including airway management will be a highly challenging task. The aim of the present trial is to compare different airway management devices in simulated microgravity using a free-floating underwater scenario. Five different devices for airway management [laryngeal mask (LM), laryngeal tube (LT), I-GEL, direct laryngoscopy (DL), and video laryngoscopy (VL)] were compared by n = 20 paramedics holding a diving certificate in a randomized cross-over setting both under free-floating conditions in a submerged setting (pool, microgravity) and on ground (normogravity). The primary endpoint was the successful placement of the airway device. The secondary endpoints were the number of attempts and the time to ventilation. A total of 20 paramedics (3 female, 17 male) participated in this study. Success rate was highest for LM and LT and was 100% both during simulated microgravity and normogravity followed by the I-GEL (90% during microgravity and 95% during normogravity). However, the success rate was less for both DL (60% vs. 95%) and VL (20% vs. 60%). Fastest ventilation was performed with the LT both in normogravity (13.7 ± 5.3 s; n = 20) and microgravity (19.5 ± 6.1 s; n = 20). For the comparison of normogravity and microgravity, time to ventilation was shorter for all devices on the ground (normogravity) as compared underwater (microgravity). In the present study, airway management with supraglottic airways and laryngoscopy was shown to be feasible. Concerning the success rate and time to ventilation, the optimum were supraglottic airways (LT, LM, I-GEL) as their placement was faster and associated with a higher success rate. For future space missions, the use of supraglottic airways for airway management seems to be more promising as compared to tracheal intubation by DL or VL.

A rising incidence of meningococcal serogroup W disease has been evident in many countries worldwide. Serogroup W isolates belonging to the sequence type (ST)-11 clonal complex have been associated with atypical symptoms and increased case fatality rates. The continued expansion of this clonal complex in the later part of the 2010s has been largely due to a shift from the so-called original UK strain to the 2013 strain. Here we used single-molecule real-time (SMRT) sequencing to determine the methylomes of the two major serogroup W strains belonging to ST-11 clonal complex. Five methylated motifs were identified in this study, and three of the motifs, namely 5'-GATC-3', 5'-GAAGG-3', 5'-GCGCGC-3', were found in all 13 isolates investigated. The results showed no strain-specific motifs or difference in active restriction modification systems between the two strains. Two phase variable methylases were identified and the enrichment or depletion of the methylation motifs generated by these methylases varied between the two strains. Results from this work give further insight into the low diversity of methylomes in highly related strains and encourage further research to decipher the role of regions with under- or overrepresented methylation motifs.

Infectious keratitis is a potentially sight threatening ophthalmological emergency. Contact lens wear is a common risk factor. Diagnostic advances such as MALDI-TOF MS provides new insights into the spectrum of corneal pathogens and on microbes previously considered as commensals. Corynebacterium macginleyi was described in 1995, and in 2018, the genomic features of three isolates were reported after whole-genome sequencing. Here we describe the clinical characteristics of patients with infectious keratitis (n = 29) presumably caused by Corynebacterium macginleyi, and analyze the genomic features of C. macginleyi (n = 22) isolated from the corneal ulcers of these patients. The disease course was uneventful apart from minor interventions such as corneal cross-linking and amniotic membrane transplant. Genome sequencing and comparison revealed a highly conserved core genome of C. macginleyi. Based on the analyses of single nucleotide polymorphisms, the population could be divided into two main clades that also differed in a few clade-specific genomic islands. Patients infected with an isolate belonging to the minor clade (n = 7) presented a more severe disease. Comparisons with other corynebacterial species clearly separated C. macginleyi. C. macginleyi may be considered a corneal pathogen; genomic analysis provided insights into its population structure and disease-causing potential.