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Background: Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies., Methods: To discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity., Findings: We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids., Interpretation: Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment., Funding: This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113)., Competing Interests: Declaration of interests The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper. The corresponding author of this manuscript, certify that the contributors’ and conflicts of interest statements included in this paper are correct and have been approved by all co-authors., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Development of an AI tool to assess velopharyngeal competence (VPC) in children with cleft palate, with/without cleft lip., Design: Innovation of an AI tool using retrospective audio recordings and assessments of VPC., Setting: Two datasets were used. The first, named the SR dataset, included data from follow-up visits to Skåne University Hospital, Sweden. The second, named the SC + IC dataset, was a combined dataset (SC + IC dataset) with data from the Scandcleft randomized trials across five countries and an intercenter study performed at six Swedish CL/P centers., Participants: SR dataset included 153 recordings from 162 children, and SC + IC dataset included 308 recordings from 399 children. All recordings were from ages 5 or 10, with corresponding VPC assessments., Interventions: Development of two networks, a convolutional neural network (CNN) and a pre-trained CNN (VGGish). After initial testing using the SR dataset, the networks were re-tested using the SC + IC dataset and modified to improve performance., Main Outcome Measures: Accuracy of the networks' VPC scores, with speech and language pathologistś scores seen as the true values. A three-point scale was used for VPC assessments., Results: VGGish outperformed CNN, achieving 57.1% accuracy compared to 39.8%. Minor adjustments in data pre-processing and network characteristics improved accuracies., Conclusions: Network accuracies were too low for the networks to be useful alternatives for VPC assessment in clinical practice. Suggestions for future research with regards to study design and dataset optimization were discussed., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Capturing the dynamic character of metal nanoparticles under the reaction conditions is one of the major challenges within heterogeneous catalysis. The role of nanoparticle dynamics is particularly important for metal alloys as the surface composition responds sensitively to the gas environment. Here, a first-principles-based kinetic Monte Carlo method is developed to compare the dynamics of dilute PdAu alloy nanoparticles in inert and CO-rich atmospheres, corresponding to reaction conditions for catalyst deactivation and activation. CO influences the dynamics of the activation by facilitating the formation of vacancies and mobile Au-CO complexes, which are needed to obtain CO-stabilized Pd monomers on the surface. The structure of the catalyst and the location of the Pd monomers determine the rate of deactivation. The rate of catalyst deactivation is slow at low temperatures, which suggests that metastable structures determine the catalyst activity at typical operating conditions. The developed method is general and can be applied to a range of metal catalysts and reactions.

Stress has been associated with less effective vaccine responses in adults. This review aims to investigate the evidence for a similar association in children. A systematic review search was conducted in January 2021 in three databases: Medline, Embase and PsycInfo. An updated search of the Medline database was systematically conducted until the most recent update on September 25th, 2023, to ensure the inclusion of the most current research available. Keywords related to stress, vaccines and children were used, and a total of 7263 (+1528) studies were screened by two independent investigators. Six studies met the inclusion criteria for data extraction and analysis. For quality assessment of the studies, the risk of bias in non-randomized studies-of interventions (ROBINS-I) tool was applied. Most of the studies suggest a negative role of stress on vaccine responses. However, the scarcity of studies, lack of confirmatory studies, risk of bias and heterogeneity according to age, type of vaccine, measures of stress and vaccine responses prevent a clear conclusion. Future studies should emphasize the use of as strict study designs as possible, including well-defined stress metrics and thorough examination of both pre- and post-vaccination responses. Systematic review registration: Prospero CRD42021230490., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Purpose: To investigate power Doppler (PD) activity and tendon structure (between the injured and contralateral limb) in patients with unilateral patellar tendinopathy (PT) using ultrasonography (US). Secondly, the aim was to determine the intra-rater reliability of the PD activity and tendon structure., Methods: This study analyzed US baseline data from 57 male participants with symptomatic unilateral PT who had been enrolled in one of two randomized clinical trials. Data were analyzed to examine if systematic differences existed between injured and contralateral limbs using Fiji ImageJ., Results: The PD activity of the symptomatic tendon was larger 25.6 (Q1 = 14.9; Q3 = 41.6) mm 2 than the asymptomatic 0 (Q1 = 0.0; Q3 = 0.0) mm 2 (p < 0.001). There was a significantly greater tendon thickness at the proximal (2.5 mm 95% CI [2.0; 3.0]), mid (0.8 mm 95% CI [0.5; 1.1]), and distal (0.2 mm 95% CI [0.1; 0.4]) part of the tendon for the symptomatic compared to the asymptomatic tendon. Intra-rater reliability for PD activity and tendon structure ranged from moderate-to-excellent (0.74; 0.99)., Conclusion: These results provide mean estimates for tendon thickness of symptomatic and asymptomatic tendons, that can be used for clinicians to reliably estimate pathological tendon thickness., (© 2024 The Authors. Journal of Clinical Ultrasound published by Wiley Periodicals LLC.)

Reactions at the metal-water interface are essential in a range of fundamental and technological processes. Using Density Functional Theory calculations, we demonstrate that water substantially affects the adsorption of H and O 2 on Cu(111), Ag(111), Au(111), Pd(111) and Pt(111). In water, H is found to undergo a spontaneous charge separation, where a proton desorbs to the water solution while an electron is donated to the surface. The reaction is exothermic over Au and Pt and associated with low barriers. The process is facile also over Pd, albeit slightly endothermic. For O 2 , water is found to increase the metal-to-adsorbate charge transfer, enhancing the adsorption energy and O-O bond length as compared to the adsorption in the absence of water. The magnitudes of the effects are system dependent, which implies that calculations should treat water explicitly. The results elucidate previous experimental results and highlights the importance of charge-transfer effects at the metal-water interface; both to describe the potential energy landscape, and to account for alternative reaction routes in the presence of water., (© 2024 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib-lenalidomide-dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10 -5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10 -5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free ( p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10 -5 . Altogether 95% of the patients with sustained MRD <10 -5 , 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance ( p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.

Background: Muscle strain injuries in the human calf muscles are frequent sports injuries with high recurrence. Potential structural and functional changes in the medial head of the musculus gastrocnemius (GM) and the associated aponeurosis are not well documented., Purpose: To test whether a GM muscle strain injury affects muscle fascicle length, pennation angle, and the morphology of the deep aponeurosis at rest and during muscle contraction long time after the injury. Additionally, electromyography (EMG) of the GM and the soleus muscle during a unilateral heel rise was measured in the injured and uninjured calf., Methods: GM fascicle length, pennation angle, and aponeurosis thickness was analyzed on dynamic ultrasonography (US) recordings in 10 participants with a chronic calf strain. In addition, US images taken across the distal portion and mid-belly of the GM were analyzed at three different ankle positions. EMG recordings were obtained during a unilateral heel rise., Results: The pennation angle of the injured distal GM was significantly larger compared to the uninjured GM in the contracted, but not the relaxed state. Pennation angle increased more in the injured compared to the uninjured GM during contraction. Fascicle length was shorter in the most distal portion of the injured GM. Fascicles at the distal portion of the injured GM showed a pronounced curvilinear shape as the muscle contracted and the aponeurosis was enlarged in the injured compared to the uninjured GM. The ratio between GM and soleus EMG activity showed a significantly higher relative soleus activity in the injured compared to the healthy calf., Conclusion: The greater change in pennation angle and curvilinear fascicle shape during contraction suggest that a long-term consequence after a muscle strain injury is that some muscle fibers at the distal GM are not actively engaged. The significantly enlarged aponeurosis indicates a substantial and long-lasting connective tissue involvement following strain injuries., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Single atom alloy catalysts offer possibilities to obtain turnover frequencies and selectivities unattainable by their monometallic counterparts. One example is direct formation of H 2 O 2 from O 2 and H 2 over Pd embedded in Au hosts. Here, a first-principles-based kinetic Monte Carlo approach is developed to investigate the catalytic performance of Pd embedded in Au nanoparticles in an aqueous solution. The simulations reveal an efficient site separation where Pd monomers act as active centers for H 2 dissociation, whereas H 2 O 2 is formed over undercoordinated Au sites. After dissociation, atomic H may undergo an exothermic redox reaction, forming a hydronium ion in the solution and a negative charge on the surface. H 2 O 2 is preferably formed from reactions between dissolved H + and oxygen species on the Au surface. The simulations show that tuning the nanoparticle composition and reaction conditions can enhance the selectivity toward H 2 O 2 . The outlined approach is general and applicable for a range of different hydrogenation reactions over single atom alloy nanoparticles.

NADPH oxidases (NOXs) are major players in generating reactive oxygen species (ROS) and are implicated in various neurodegenerative ocular pathologies. The aim of this study was to investigate the role of a NOX4 inhibitor (GLX7013114) in two in vivo, experimental streptozotocin (STZ) paradigms depicting the early events of diabetic retinopathy (DR). Animals in the diabetic treated group received GLX7013114 topically (20 μL/eye, 10 mg/mL, once daily) for 14 days (paradigm A: preventive) and 7 days (paradigm B: treated) at 48 h and 4 weeks after STZ injection, respectively. Several methodologies were used (immunohistochemistry, Western blot, real-time PCR, ELISA, pattern electroretinography [PERG]) to assess the diabetes-induced early events of DR, namely oxidative stress, neurodegeneration, and neuroinflammation, and the effect of GLX7013114 on the diabetic insults. GLX7013114, administered as eye drops (paradigms A and B), was beneficial in treating the oxidative nitrative stress, activation of caspase-3 and micro- and macroglia, and attenuation of neuronal markers. It also attenuated the diabetes-induced increase in vascular endothelial growth factor, Evans blue dye leakage, and proinflammatory cytokine (TNF-α protein, IL-1β/IL-6 mRNA) levels. PERG amplitude values suggested that GLX7013114 protected retinal ganglion cell function (paradigm B). This study provides new findings regarding the pharmacological profile of the novel NOX4 inhibitor GLX7013114 as a promising therapeutic candidate for the treatment of the early stage of DR., Article Highlights: NADPH oxidases (NOXs) are implicated in the early pathological events of diabetic retinopathy (DR). The NOX4 inhibitor GLX7013114, topically administered, reduced oxidative damage and apoptosis in the rat streptozotocin model of DR. GLX7013114 protected retinal neurons and retinal ganglion cell function and reduced the expression of pro-inflammatory cytokines in the diabetic retina. GLX7013114 diminished the diabetes-induced increase in vascular endothelial growth factor levels and Evans blue dye leakage in retinal tissue. GLX7013114 exhibits neuroprotective, anti-inflammatory, and vasculoprotective properties that suggest it may have a role as a putative therapeutic for the early events of DR., (© 2023 by the American Diabetes Association.)

A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis , Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa , which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1 , we identified compound 27 , featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa , a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and ( S )- 27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.

Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug-target interactions at spatial resolution in protein arrays, cells and in tissues., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Hyperchloremic metabolic acidosis that develops during the treatment of diabetic ketoacidosis is usually attributed to the chloride content of resuscitation fluids. We explored an alternative explanation, namely that fluid-induced plasma volume expansion alters the absolute differences in the concentrations of sodium and chloride (the Na-Cl gap) enough to affect the acid-base balance. We analyzed data from a prospective single-center cohort study of 14 patients treated for diabetic ketoacidosis. All patients received 1 L of 0.9% saline over 30 min on two consecutive days. Blood gases were sampled before and after the infusions., Results: The initial plasma volume was estimated to be 25 ± 13% (mean ± SD) below normal on admission to the intensive care unit. At that time, most patients had an increased actual Na-Cl gap, which counteracts acidosis. However, the correction of the plasma volume deficit revealed that these patients would have had a decreased Na-Cl gap upon admission if they had been normovolemic at that time; the estimated "virtual Na-Cl gap" of 29 ± 5 mmol/L was significantly lower than the uncorrected value, which was 39 ± 5 mmol/L (P < 0.001). On Day 2, most patients had a decreased actual Na-Cl gap (33 ± 5 mmol/L), approaching the corrected value on Day 1., Conclusions: The hyperchloremic acidosis commonly seen in diabetic ketoacidosis may not be primarily caused by the chloride content of resuscitation fluids but, rather, by the restoration of plasma volume, which reveals the hidden metabolic acidosis caused by a decreased Na-Cl gap. Trial registration Clinical Trials Identifier NCT02172092, registered June 24, 2014, https://www., Clinicaltrials: gov/NCT02172092., (© 2022. The Author(s).)

Teamwork quality has been shown to influence patient safety, and simulation-based team-training (SBTT) is an effective means to increase this quality. However, long-term effects are rarely studied. This study aims to investigate the long-term effects of interprofessional SBTT in emergency medicine in terms of global confidence, self-efficacy in interprofessional communication and in emergency medicine situations. Newly graduated doctors, nurses, auxiliary nurses, and medical and nursing students participated. Four emergency medicine scenarios focused on teamwork according to the A-B-C-D-E-strategy. All participants increased their global confidence from 5.3 (CI 4.9-5.8) before to 6.8 (CI 6.4-7.2; p < .0001) after SBTT. Confidence in interprofessional communication increased from 5.3 (CI 4.9-5.8) to 7.0 (CI 6.6-7.4; p < .0001). Students had the greatest gain. The self-efficacy following the A-B-C-D-E strategy increased from 4.9 (CI 4.4-5.3) to 6.6 (CI 6.2-7.0). Again, students had the steepest increase. Newly graduated doctors achieved a superior increase in global confidence as compared to nurses and auxiliary nurses (p < .0001). Their propensity to recommend SBTT to colleagues was 9.9 (CI 9.8-10.0). The positive effects were sustained over a six-month period, indicating that interprofessional SBTT had a positive impact on competence development, and a potential to contribute to increased team quality in emergency medicine care.

Background: We wanted to evaluate if health care for multiple myeloma (MM) patients is equal in different regions of Sweden., Aim: To study differences in survival for MM depending on health care region and early use of modern treatment., Methods and Results: Data from the Swedish Myeloma Register from patients diagnosed between 2008 and 2017 was used. Cohorts were defined by the six healthcare regions (labeled A-F) in Sweden and modern initial treatment was defined as including certain drug combinations. To adjust for time to treatment bias, survival analyses were performed also for patients alive 6 months after diagnosis. In all treated MM patients (n = 5326), we observed a superior overall survival (OS) for region A compared to all other regions (p < .01 for all respectively). After adjusting for time to treatment there was also a superior survival in the region with highest use of modern initial treatment (region A) compared to the regions defined in the study as having intermediate and low use (p < .01 for both). In patients receiving autologous stem cell transplantation (ASCT) a superior survival was observed for region A compared to all regions besides region B. Similar results were seen when adjusting for a time to treatment bias. In patients not receiving ASCT, 75 years or older and adjusted for time to treatment bias, a difference was noted only between region A and E (log rank p = .04, HR 1.2, CI 1.00-1.44, p = .06). In multivariate analyses including age, international staging system stage and time period of diagnosis, differences in survival remained for patients receiving ASCT between region A versus C, D, E and F (p = .01, p < .01, p < .01, p = .03)., Conclusion: We observed a superior survival in region A for patients receiving ASCT. Explanations may be higher usage of modern initial treatment or regional residual confounding. For patients not receiving ASCT, 75 years or older, differences in survival could be adjusted for., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Objectives: This study examines the associations between ten family structure types and delinquency, including four groups of symmetrical and asymmetrical living arrangements. We also adjust for attachment to parents and parental monitoring., Methods: Data are drawn from four cross-sectional surveys conducted between 2016 and 2019 in southern Sweden. The sample consists of 3,838 adolescents, aged 14-15. Negative binomial models were used to calculate the associations between family structure and delinquency., Results: The results show that those living in single-father, single-mother, father-stepmother, mother-stepfather families report significantly more delinquency than adolescents living with both their parents. Adolescents living in "symmetrical" family arrangements, i.e. both parents are single or have a new partner, reported lower levels of delinquency, whereas adolescents living in "asymmetrical" family arrangements, i.e. where either the mother or the father, but not both, have a new partner, reported higher levels of delinquency. Most of the associations between family structure and delinquency decline when adjusted for attachment to parents and parental monitoring., Discussion: This study shows that it is important to move on to the use of more detailed categorisations of family structure in relation to delinquency. We need to increase our knowledge about the group of adolescents that moves between parents and especially about the different constellations of asymmetrical and symmetrical living arrangements., Competing Interests: The authors have declared no competing interest exist.

Background: Previous research on the relationship between social media use and well-being in adolescents has yielded inconsistent results. We addressed this issue by examining the association between various digital media activities, including a new and differentiated measure of social media use, and well-being (internalizing symptoms) in adolescent boys and girls., Method: The sample was drawn from the four cross-sectional surveys from the Öckerö project (2016-2019) in eight municipalities in southern Sweden, consisting of 3957 adolescents in year 7 of compulsory education, aged 12-13. We measured the following digital media activities: playing games and three different activities of social media use (chatting, online sociability, and self-presentation). Our outcome measure was internalizing symptoms. Hypotheses were tested with linear regression analysis., Results: Social media use and playing games were positively associated with internalizing symptoms. The effect of social media use was conditional on gender, indicating that social media use was only associated with internalizing symptoms for girls. Of the social media activities, only chatting and self-presentation (posting information about themselves) were positively associated with internalizing symptoms. Self-presentation was associated with internalizing symptoms only for girls., Conclusion: Our study shows the importance of research going beyond studying the time spent on social media to examine how different kinds of social media activities are associated with well-being. Consistent with research in psychology, our results suggest that young girls posting information about themselves (i.e. self-presentation) might be especially vulnerable to display internalizing symptoms., (© 2022. The Author(s).)

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors., (© 2022. The Author(s).)

Dry age-related macular degeneration (AMD) is a currently untreatable vision threatening disease. Impaired proteasomal clearance and autophagy in the retinal pigment epithelium (RPE) and subsequent photoreceptor damage are connected with dry AMD, but detailed pathophysiology is still unclear. In this paper, we discover inhibition of cytosolic protease, prolyl oligopeptidase (PREP), as a potential pathway to treat dry AMD. We showed that PREP inhibitor exposure induced autophagy in the RPE cells, shown by increased LC3-II levels and decreased p62 levels. PREP inhibitor treatment increased total levels of autophagic vacuoles in the RPE cells. Global proteomics was used to examine the phenotype of a commonly used cell model displaying AMD characteristics, oxidative stress and altered protein metabolism, in vitro. These RPE cells displayed induced protein aggregation and clear alterations in macromolecule metabolism, confirming the relevance of the cell model. Differences in intracellular target engagement of PREP inhibitors were observed with cellular thermal shift assay (CETSA). These differences were explained by intracellular drug exposure (the unbound cellular partition coefficient, Kp uu ). Importantly, our data is in line with previous observations regarding the discrepancy between PREP's cleaving activity and outcomes in autophagy. This highlights the need to further explore PREP's role in autophagy so that more effective compounds can be designed to battle diseases in which autophagy induction is needed. The present work is the first report investigating the PREP pathway in the RPE and we predict that the PREP inhibitors can be further optimized for treatment of dry AMD., (Copyright © 2021. Published by Elsevier Masson SAS.)

As a result of the COVID-19 pandemic, many agile practitioners had to transition into a remote work environment. Despite remote work not being a new concept for agile software practitioners, the forced or recommended nature of remote work is new. This study investigates how the involuntary shift to remote work and how social restrictions imposed by the COVID-19 pandemic have affected agile software development (ASD), and how agile practitioners have been affected in terms of ways of working. An explanatory sequential mixed methods study was performed. Data were collected one year into the COVID-19 pandemic through a questionnaire with 96 respondents and in-depth semi-structured interviews with seven practitioners from seven different companies. Data were analyzed through Bayesian analysis and thematic analysis. The results show, in general, that the aspects of ASD that have been the most affected is communication and social interactions, while technical work aspects have not experienced the same changes. Moreover, feeling forced to work remotely has a significant impact on different aspects of ASD, e.g., productivity and communication, and industry practitioners' employment of agile development and ways of working have primarily been affected by the lack of social interaction and the shift to digital communication. The results also suggest that there may be a group maturing debt when teams do go back into office, as digital communication and the lack of psychological safety stand in the way for practitioners' ability to have sensitive discussions and progress as a team in a remote setting., Competing Interests: Conflict of Interests/Competing InterestsNot applicable, (© The Author(s) 2022.)

Background: Developing a better understanding of drinking patterns across immigrant generations and how these change over time is important for the development of effective alcohol polices. This study investigates the direction and rate of change in youth alcohol intoxication over time, based on immigrant status, and by family structure and parental employment status., Method: The study is based on eight nationally representative school surveys conducted by the Swedish National Council for Crime Prevention between 1999 and 2017, with a combined sample of 50,657 adolescents. Group by time interactions were examined to compare rates of change of alcohol intoxication over time across immigrant generations., Results: The results show a decreasing trend in alcohol intoxication among both first and second generation immigrant youth, and also among immigrant youth across different family structures and parental employment statuses. The results also show that the decrease in alcohol intoxication over time is greater for youths born abroad and for youths with two immigrant parents than for native Swedes, and that the decrease over time is greater for youths from intact families than for native Swedish youths from non-intact families and youths with one immigrant parent., Conclusion: Native and first- and second-generation immigrant youth may differ substantially from one another in many ways, and may therefore manifest different patterns of drinking behaviours. From a policy and prevention perspective, the data in this study imply that native youths and youths with one immigrant parent should be a central target group for alcohol prevention policy in Sweden., Competing Interests: Declarations of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

It is well known that cells can generate endogenous forces onto the extracellular matrix, but to what extent the mechanical properties of the matrix influences these endogenous cellular forces remains unclear. We therefore sought to quantify the influence of matrix rigidity on cell-matrix interactions by inducing cross-links using increasing concentrations of genipin (0.01-1 mM) or by blocking cross-link formation using beta-aminopropionitrile (BAPN) in engineered human tendon tissue constructs. The cell-matrix mechanics of the tendon constructs were evaluated as cell-generated tissue re-tensioning and stress-relaxation responses using a novel custom-made force monitor, which can apply and detect tensional forces in real-time in addition to mechanical failure testing. Genipin treatment had no influence on the biochemical profile (hydroxyproline, glycosaminoglycan and DNA content) of the constructs and cell viability was comparable between genipin-treated and control constructs, except at the highest genipin concentration. Endogenous re-tension after unloading was significantly decreased with increasing genipin concentrations compared to controls. Mechanical failure testing of tendon constructs showed increased (56%) peak stress at the highest genipin concentration but decreased (72%) with BAPN treatment when compared to controls. Tendon construct stiffness increased with high genipin concentrations (0.1 and 1 mM) and decreased by 70% in BAPN-treated constructs, relative to the controls. These data demonstrate that human tendon fibroblasts regulate their force exertion inversely proportional to increased cross-link capacity but did so independently of matrix stiffness. Overall, these findings support the notion of an interaction between cell force generation and cross-linking, and thus a role for this interplay in mechanical homeostasis of the tissue., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The stay-at-home restrictions to control the spread of COVID-19 led to unparalleled sudden change in daily life, but it is unclear how they affected urban crime globally. We collected data on daily counts of crime in 27 cities across 23 countries in the Americas, Europe, the Middle East and Asia. We conducted interrupted time series analyses to assess the impact of stay-at-home restrictions on different types of crime in each city. Our findings show that the stay-at-home policies were associated with a considerable drop in urban crime, but with substantial variation across cities and types of crime. Meta-regression results showed that more stringent restrictions over movement in public space were predictive of larger declines in crime., (© 2021. The Author(s).)

Aims: Alexithymia has been linked to cardiovascular disease. The aim was to explore whether the immuno-inflammatory variables galectin-3 binding protein (Gal3BP), soluble (s)CD163 and galectin-3 were independently associated with alexithymia, while controlling for known risk factors for cardiovascular disease, such as depression, anxiety, impaired glycemic control, obesity, smoking, and physical inactivity in patients with type 1 diabetes (T1D). Methods: Cross-sectional design. The participants were consecutively recruited from one diabetes out-patient clinic. Alexithymia, depression and anxiety were assessed by self-report instruments. Blood samples, anthropometrics, and blood pressure were collected, supplemented with data from electronic health records. High Gal3BP was defined as ≥3.3 μg/ml, high sCD163 as ≥0.6 μg/ml, high galectin-3 as ≥2.6 ng/ml, impaired glycemic control as HbA1c >70 mmol/mol (>8.6%) and abdominal obesity as waist circumference ≥ 1.02 m for men and ≥ 0.88 m for women. Results: Two hundred and ninety two patients participated (men 56%, aged 18-59 years, alexithymia prevalence 15%). Patients with alexithymia had higher prevalence of depression (34 vs. 6%, p < 0.001), anxiety (61 vs. 30%, p < 0.001), high Gal3BP levels (39 vs. 17%, p = 0.004), high HbA1c levels (46 vs. 24%, p = 0.006), and abdominal obesity (29 vs. 15%, p = 0.045). Depression [adjusted odds ratio (AOR) 6.5 , p < 0.001], high Gal3BP levels (AOR 2.4, p = 0.035), and age (AOR 0.96, p = 0.027) were independently associated with alexithymia. Abdominal obesity (AOR 4.0, p < 0.001), high Gal3BP levels (AOR 2.8, p = 0.002), and depression (AOR 2.9, p = 0.014) were associated with high HbA1c. Abdominal obesity and anxiety were associated [Crude odds ratio (COR) 2.4, p = 0.006]. Conclusions: T1D patients with alexithymia had higher prevalence of high Gal3BP levels, depression, impaired glycemic control, anxiety, and abdominal obesity, which are known risk factors for cardiovascular disease. Only high Gal3BP levels, depression, and younger age were independently associated with alexithymia in adult patients with T1D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Melin, Svensson, Dereke and Hillman.)

Background: Several studies have examined the effect of community interventions on youth alcohol consumption, and the results have often been mixed. The aim of this study is to evaluate the effectiveness of a community intervention known as the Öckerö Method on adolescent alcohol consumption and perceived parental attitudes towards adolescent drinking., Method: The study is based on a quasi-experimental design, using matched controls. Self-report studies were conducted among adolescents in grades 7-9 of compulsory education in four control and four intervention communities in the south of Sweden in 2016-2018. Baseline measures were collected in autumn 2016 before the intervention was implemented in the intervention communities. Outcomes were the adolescents' alcohol consumption, past-year drunkenness, past-month drunkenness and perceived parental attitudes towards alcohol., Results: Estimating Difference-in-Difference models using Linear Probability Models, we found no empirical evidence that the intervention has any effect on adolescents' drinking habits, or on their perceptions of their parents' attitudes towards adolescent drinking., Conclusion: This is the first evaluation of this method, and we found no evidence that the intervention had any effect on the level of either young people's alcohol consumption or their past-year or past-month drunkenness, nor on their parents' perceived attitudes toward adolescent drinking. A further improvement would be to employ a follow-up period that is longer than the three-year period employed in this study., Trial Registration: ISRCTN registry: Study ID: 51635778 , 31th March 2021 (Retrospectively registered).

Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT2*6) but lack the wild-type allele in their tumors due to loss of heterozygosity (LOH) at 8p22. These tumors were sensitive to treatment with a cytotoxic substrate of NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), and pointed to NAT2 loss being a therapeutically exploitable vulnerability of CRC tumors. To better estimate the total number of treatable CRC patients, we here determined whether tumor cells retaining also other NAT2 low activity variants after LOH respond to APA treatment. The prevalent low activity alleles NAT2*5 and NAT2*14, but not NAT2*7, were found to be low metabolizers with high sensitivity to APA. By analysis of two different CRC patient cohorts, we detected heterozygosity for NAT2 alleles targetable by APA, along with allelic imbalances pointing to LOH, in ~ 24% of tumors. Finally, to haplotype the NAT2 locus in tumor and patient-matched normal samples in a clinical setting, we develop and demonstrate a long-read sequencing based assay. In total, > 79.000 CRC patients per year fulfil genetic criteria for high sensitivity to a NAT2 LOH therapy and their eligibility can be assessed by clinical sequencing.

Background: Early treatment of severe hyperglycemia involves large shifts of body fluids that entail a risk of hemodynamic instability. We studied the feasibility of applying a new electrolyte equation that estimates the degree of volume depletion and the distribution of infused 0.9% saline in this setting., Methods: The new equation was applied to plasma and urinary concentrations of sodium and chloride measured before and 30 min after a 30-min infusion of 1 L of 0.9% saline on two consecutive days in 14 patients with severe hyperglycemia (mean age 50 years). The extracellular fluid (ECF) volume was also estimated based on the volume dilution kinetics of chloride., Results: On day 1, the baseline ECF volume amounted to 11.5 L. The saline infusion expanded the ECF space by 160 mL and the intracellular fluid space by 375 mL. On day 2, the ECF volume was 15.5 L, and twice as much of the infused fluid remained in the ECF space. The chloride dilution kinetics yielded baseline ECF volumes of 11.6 and 15.2 L on day 1 and day 2, respectively. No net uptake of glucose to the cells occurred during the two 1-h measurement periods despite insulin administration in the intervening time period., Conclusions: The electrolyte equation was feasible to apply in a group of hyperglycemic patients. The ECF space was 3 L smaller than expected on admission but normal on the second day. Almost half of the infused fluid was distributed intracellularly.

Here we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites., Competing Interests: The authors have declared that no competing interests exist.

Background: Infusion with 0.9% saline is a mainstay in the treatment of severe hyperglycemia, but the kinetics of the saline volume in this setting has not been studied., Methods: An intravenous infusion of 1 L of 0.9% saline over 30 minutes was given on 31 occasions to 17 patients with hyperglycemia due to poorly controlled diabetes (mean age 51 years). A two-volume kinetic model was fitted to serial data on the hemodilution and urinary excretion, using mixed-effects modeling software., Results: Plasma glucose was 36 ± 9 mmol/L on arrival to the hospital. The central volume of distribution (the plasma) was only 2.38 L (mean; 95% confidence interval 1.73-3.04) on the day of admission. Uptake into a remote compartment, believed to be the cells, amounted to 300 mL of the first liter of saline, although only small amounts of insulin were given. Plasma glucose, plasma bicarbonate, urine glucose, and plasma creatinine served as covariates in the kinetic model and mathematically affected the urinary excretion. For example, elimination of the infused fluid tripled from an increase in plasma glucose from 5 to 35 mmol/L and doubled from a reduction in plasma bicarbonate from 24 to 5 mmol/L., Conclusions: The excretion of 0.9% saline was increased depending on the degree of hyperglycemia. The kinetics was characterized by glucose-accelerated diuresis, and an intracellular uptake that occurred at two thirds the urine flow rate. These data could help to determine appropriate volumes and rates of infusion of crystalloids in hyperglycemia., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: In this study we examine whether the association between internet use and drinking could be different for different types of internet activities among adolescents. We also adjust for a number of theoretically relevant factors such as peer influence, unstructured activities, impulsivity and parental monitoring., Method: The data are drawn from four cross-sectional surveys from the years 2016-2019 in eight municipalities in southern Sweden. The sample consist of 3733 adolescents in year 9 of compulsory education, aged 14-15., Results: The results show that there is an association between internet activities and drinking and that there are differences depending on what young people do online. Self-presentation and online sociality are both positively associated with drinking, whereas news consumption and playing games are negatively associated with drinking. The results also show that the association between the different internet activities and drinking becomes weaker when adjusting for the control variables., Conclusion: This study suggests that more research is needed to examine the correlations between different forms of internet activities and drinking among adolescents in more detail., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM., Methods: Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio., Results: Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P = .0015)., Conclusion: In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes.

Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg -1 showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30 , effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II., (This journal is © The Royal Society of Chemistry 2019.)

Background: Depression, metabolic disturbances and inflammation have been linked to cardiovascular disease and mortality. Low levels of high-density lipoprotein cholesterol (HDL-cholesterol), a known marker of cardiovascular risk, have been observed in patients with major depression in psychiatric populations. Our main aim was to explore associations between depression, antidepressants, and metabolic and inflammatory variables in patients with type 1 diabetes (T1D). A secondary aim was to explore variables associated with HDL-cholesterol., Methods: Cross-sectional design. T1D patients (n = 292, men 55%, age18-59 years, diabetes duration ≥1 year) were consecutively recruited from one specialist diabetes clinic. Depression was defined as ≥8 points for Hospital Anxiety and Depression Scale-Depression sub scale. Blood samples, anthropometrics, blood pressure, and data regarding medication and life style were collected from electronic health records. Non-parametric tests, multiple logistic and linear regression analyses were performed., Results: The depression prevalence was 10 and 8% used antidepressants. Median (q 1 , q 3 ) HDL-cholesterol (mmol/l) was for the depressed 1.3 (1.2, 1.5) and for the non-depressed 1.6 (1.3, 1.8), p = 0.001. HDL-cholesterol levels (per mmol/l) were negatively associated with depression (Adjusted odds ratio (AOR) 0.2, p = 0.007), and the use of antidepressants was positively associated with depression (AOR 8.1, p <  0.001). No other metabolic or inflammatory variables, or life style factors, were associated with depression when adjusted for antidepressants. Abdominal obesity was associated with antidepressants in women (AOR 4.6, p = 0.029). Decreasing HDL-cholesterol levels were associated with increasing triglyceride levels (p <  0.001), increasing high-sensitive C-reactive protein (hs-CRP) levels (p = 0.021), younger age (p <  0.001), male sex (p <  0.001), and depression (p = 0.045)., Conclusions: Lower HDL-cholesterol levels, known predictors of cardiovascular disease, were associated with depression in patients with T1D. The use of antidepressants was associated with abdominal obesity in women. Depression, low-grade inflammation measured as hs-CRP, higher triglycerides, male sex, and lower age were independently associated with lower HDL-cholesterol levels.

The dipeptide amide H-Phe-Phe-NH 2 (1) that previously was identified as a ligand for the substance P 1-7 (SP 1-7 ) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP 1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP 1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH 2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED 50 ) of 4 was superior as compared to gabapentin and morphine that are used in clinic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Treatment strategies for Achilles tendon rupture vary considerably, and clinical outcome may depend on the magnitude of tendon elongation after surgical repair. The aim of this project was to examine whether tendon elongation, mechanical properties, and functional outcomes during rehabilitation of surgically repaired acute Achilles tendon ruptures were influenced by different rehabilitation regimens during the early postsurgical period., Hypothesis: Restricted early weightbearing that permits only limited motion about the ankle in the early phase of tendon healing limits tendon elongation and improves functional outcome., Study Design: Randomized controlled trial; Level of evidence, 1., Methods: 75 consecutive patients with an acute Achilles tendon rupture were included. They underwent surgical repair, and tantalum beads were placed in the distal and proximal parts of the tendon; thereafter, the patients were randomized into 3 groups. The first group was completely restricted from weightbearing until week 7. The second group was completely restricted from weightbearing until week 7 but performed ankle joint mobilization exercises. The first and second groups were allowed full weightbearing after week 8. The third group was allowed partial weightbearing from day 1 and full weightbearing from week 5. All patients received the same instructions in home exercise guidelines starting from week 9., Results: The rehabilitation regimen in the initial 8 weeks did not significantly influence any of the measured outcomes including tendon elongation. Achilles tendon elongation and tendon compliance continued for up to 6 months after surgery, and muscle strength, muscle endurance, and patient-reported functional scores did not reach normal values at 12 months., Conclusion: Differences in rehabilitation loading pattern in the initial 8 weeks after the repair of an Achilles tendon rupture did not measurably alter the outcome. The time to recover full function after an Achilles tendon rupture is at least 12 months. Registration: NCT02422004 ( ClinicalTrials.gov identifier).

Objectives: Feasibility testing of a psychoeducational method -The Affect School and Script Analyses (ASSA) - in a Swedish primary care setting. Exploring associations between psychological, and medically unexplained physical symptoms (MUPS)., Design: Pilot study., Setting: Three Swedish primary care centers serving 20,000 people., Intervention: 8 weekly 2-hour sessions with a 5-7 participant group led by two instructors - followed by 10 individual hour-long sessions., Subjects: Thirty-six patients, 29 women (81%), on sick-leave due to depression, anxiety, or fibromyalgia., Outcome Measures: Feasibility in terms of participation rates and expected improvements of psychological symptoms and MUPS, assessed by self-report instruments pre-, one-week post-, and 18 months post-intervention. Regression coefficients between psychological symptoms and MUPS., Results: The entire 26-hour psychoeducational intervention was completed by 30 patients (83%), and 33 patients (92%) completed the 16-hour Affect School. One-week post-intervention median test score changes were significantly favorable for 27 respondents, with p < .05 after correction for multiple testing for 9 of 11 measures (depression, anxiety, alexithymia, MUPS, general health, self-affirmation, self-love, self-blame, and self-hate); 18 months post intervention the results remained significantly favorable for 15 respondents for 7 of 11 measures (depression, alexithymia, MUPS, general health, self-affirmation, self-love, and self-hate)., Conclusions: A psychoeducational method previously untested in primary care for mostly women patients on sick-leave due to depression, anxiety, or fibromyalgia had >80% participation rates, and clear improvements of self-assessed psychological symptoms and MUPS. The ASSA intervention thus showed adequate feasibility in a Swedish primary care setting. Key Points  A pilot study of a psychoeducational intervention - The Affect School and Script Analyses (ASSA) - was performed in primary care   • The intervention showed feasibility for patients on sick-leave due to depression, anxiety, or fibromyalgia   • 92% completed the 8 weeks/16 hours Affect School and 83% completed the entire 26-hour ASSA intervention   • 9 of 11 self-reported measures improved significantly one-week post intervention   • 7 of 11 self-reported measures improved significantly 18 months post-intervention.

Background: There is a well-documented gender difference in offending, with evidence that boys, on average, are more involved in crime than girls. Opinions differ, however, on whether the causes of crime apply to girls and boys similarly., Aims: Our aim is to explore crime propensity in boys and girls. Our research questions were (1) are there differences between boys and girls in moral values and self-control; (2) are these attributes similarly correlated with offending among girls and boys; and (3) is any interaction effect between morality and self-control identical for girls and boys., Methods: Data were drawn from the Malmö Individual and Neighbourhood Development Study, which includes 481 girls and boys aged 16-17. An 8-item self-control scale was derived from Grasmick's self-control instrument; we created a 16-item morality scale. Analysis of variance was used to test for differences in scale scores., Results: There were significant gender differences in moral values but not self-control. Moral values and self-control were significantly correlated with offending among both girls and boys. In the multiple regression analysis, the three-way interaction term used to test the interaction between gender, self-control and moral values was non-significant, indicating that the magnitude of the self-control-moral value interaction is not affected by gender., Conclusions: Our findings indicate that effects of morality and self-control are general and apply to girls and boys similarly, so more research is needed to explain gender differences in crime prevalence. © 2018 The Authors Criminal Behaviour and Mental Health Published by John Wiley & Sons Ltd., (© 2018 The Authors Criminal Behaviour and Mental Health Published by John Wiley & Sons Ltd.)

The original PDF version of this Article listed the authors as "Marcus J.G.W. Ladds," where it should have read "Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al. # ".Also in the PDF version, it was incorrectly stated that "Correspondence and requests for materials should be addressed to S. Lín.", instead of the correct "Correspondence and requests for materials should be addressed to S. Laín."This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.

Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4g, with an IC 50 of 2.6 µM as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4i, with an IC 50 of 0.35 µM.

Substance P 1-7 (SP 1-7 , Arg 1 -Pro 2 -Lys 3 -Pro 4 -Gln 5 -Gln 6 -Phe 7 ) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP 1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP 1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP 1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP 1-7 amide 1 (Arg 1 -Pro 2 -Lys 3 -Pro 4 -Gln 5 -Gln 6 -Phe 7 -NH 2 ) was previously shown to be superior to the endogenous SP 1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP 1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys 3 ]SP 1-7 amide (3) and the [MeGln 5 ]SP 1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg 1 and C-terminal Phe 7 , anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP 1-7 amide (1), the [MeLys 3 ]SP 1-7 amide (3) amide and the [MeGln 5 ]SP 1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain., (Copyright © 2017 Elsevier B.V. All rights reserved.)