RIP(K)ing away immunotherapy resistance.

Interferon signaling mediates resistance to immune checkpoint blockade therapy, but the underlying mechanisms are poorly understood. In this issue of Immunity, Cucolo et al. identify RIPK1 as an interferon-stimulated gene with potent effects on cell extrinsic and intrinsic immunotherapy resistance.

Common human genetic variants of APOE impact murine COVID-19 mortality.

Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population1 and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity2-5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.

εγ-Thalassemia, a New Hemoglobinopathy Category.

BACKGROUND: Large ß-globin gene cluster deletions (hereditary persistence of fetal hemoglobin [Hb] or ß-, δß-, γδß-, and ϵγδß-thalassemia), are associated with widely disparate phenotypes, including variable degrees of microcytic anemia and Hb F levels. When present, increased Hb A2 is used as a surrogate marker for ß-thalassemia. Notably, ϵγδß-thalassemias lack the essential regulatory locus control region (LCR) and cause severe transient perinatal anemia but normal newborn screen (NBS) results and Hb A2 levels. Herein, we report a novel deletion of the ϵ, Aγ, Gγ, and ψß loci with intact LCR, δ-, and ß-regions in 2 women and newborn twins. METHODS: Capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), DNA sequencing, multiplex ligation-dependent probe amplification (MLPA), gap-polymerase chain reaction (gap-PCR), and long-read sequencing (LRS) were performed. RESULTS: NBS showed an Hb A > Hb F pattern for both twins. At 20 months, Hb A2 was increased similarly to that in the mother and an unrelated woman. Unexplained microcytosis was absent and the twins lacked severe neonatal anemia. MLPA, LRS, and gap-PCR confirmed a 32 599 base pair deletion of ϵ (HBE1) through ψß (HBBP1) loci. CONCLUSIONS: This deletion represents a hemoglobinopathy category with a distinct phenotype that has not been previously described, an ϵγ-thalassemia. Both the NBS Hb A > F pattern and the subsequent increased Hb A2 without microcytosis are unusual. A similar deletion should be considered when this pattern is encountered and appropriate test methods selected for detection. Knowledge of the clinical impact of this new category will improve genetic counselling, with distinction from the severe transient anemia associated with ϵγδß-thalassemia.

2,2'-Bithiophene as sensor tag for ligand-protein binding assays based on Förster resonance energy transfer.

Ligand-protein binding assays based on intrinsic protein fluorescence are straightforward, inexpensive methods to study ligand-protein interactions. However, their applicability is limited to ligands that can interfere with protein emission. In this Note, we describe the applicability of 2,2'-bithiophene as a FRET-based sensor tag, that can be incorporated into high-affinity ligands to generate target-specific compounds able to quench protein fluorescence upon binding. The generated ligands were assessed in different assay designs. Considerations to account for possible sources of interference with the assay readout are addressed, besides interpretation of the obtained results.

An Effective Combination Therapy for the Treatment of Pediatric Monomorphic Post-transplant Lymphoproliferative Disorder With Plasmacytic Differentiation.

Post-transplant lymphoproliferative disorder (PTLD) is a complication of immunosuppressive therapy following solid organ or hematopoietic cell transplantation. Initial treatment typically includes a reduction of immunosuppression with or without rituximab. However, the optimal therapy for PTLD with plasmacytic differentiation is unclear. We present 3 cases of pediatric patients with plasmacytic PTLD. Two patients received a standard rituximab-based approach and relapsed, prompting additional chemotherapy. The third patient was treated with a novel regimen of bortezomib, dexamethasone, and daratumumab. This regimen was safe, well-tolerated, and resulted in a 2-year remission. Larger studies are needed to further explore this regimen.

Nasopharyngeal Swabs in Pediatric Patients With Thrombocytopenia and Anticoagulant Use.

BACKGROUND: Nasopharyngeal (NP) swabbing is a technique that is commonly used to test pediatric patients for viral infections with increased use during the coronavirus disease 2019 pandemic. Complications from NP swabbing are rare and seem to occur more frequently in patients at risk of bleeding. Little is known about institutional or individual practices and experiences with NP swab testing in pediatric patients with risk factors for bleeding. METHODS: We conducted a survey study of pediatric hematology/oncology (PHO) attending physicians to assess practices and experiences with NP swab testing in pediatric patients with thrombocytopenia and/or on anticoagulation. RESULTS: There were 130 total respondents (5.6%, n = 130/2327) from 6 countries. Relatively few respondents (n = 17/130, 13.1%) reported that their institution had a policy specifying a lower-level platelet cutoff for patients undergoing NP swabbing. The median platelet cutoff below which NP swabs are not performed according to existing policies is 30,000×10(9)/L (interquartile range: 20,000 to 40,000). The median cutoff based on the opinion of the respondents was 10,000 (interquartile range: 10,000 to 20,000). There were 24 episodes of epistaxis among PHO patients that were NP swabbed; many adverse events (56.5%, n = 13/23) were described as persistent, severe, and/or required intervention. Three reported cases of epistaxis with anticoagulation or antiplatelet therapy occurred in patients with concomitant thrombocytopenia. Only 1 respondent (n = 1/130, 0.7%) reported an institutional policy for limiting NP swabs in patients on anticoagulant therapy. NP (66.9%) and nares (33.1%) were the most common sources of coronavirus disease 2019 testing that were reported. CONCLUSION: A small percentage of institutions in this survey have a policy restricting NP swabs in PHO patients. The discrepancy between lower platelet cutoffs proposed by experts and institutional policy suggests that existing policies may be too conservative. Expert guidelines are needed on this topic. Other bleeding risk factors (eg, aspirin use and von Willebrand disease) should be considered in policies and guidelines.

The epidemiological and medico-legal characteristics of violent deaths and spousal homicides through a population of women autopsied within the Forensic Medicine Department of the University Hospital of Annaba.

BACKGROUND: Domestic violence is a real public health problem with considerable consequences, ranging from minor injuries to death. Our study aims to determine the epidemiological and forensic characteristics relating to the violent mortality of women, and more particularly spousal homicide. METHODS: To do this, a double survey was conducted. The first step was descriptive and retrospective, and the second survey was analytical and prospective. This latter step covered the most populous age group of murdered women in Algeria, which is eighteen-year-old and over, and subjected a number of these female victims to a medico-judicial autopsy at the level of the thanatology unit for over four years counting two years for each survey (2017-2018 and 2019-2020). Data were entered and processed using Epi-info6 software. RESULTS: During the initial period of our study, we identified 35 cases of violent deaths involving women and representing a frequency of 5.71% of the thanatological activity. During the second period, 12 spousal homicides were recorded and autopsied, representing a frequency of 1.79% of all forensic deaths in the corresponding study period. The average age of the victims was evaluated at 33 ± 12.91 years, with extremes of 19 to 56 years. The age of the perpetrators of spousal homicide was evaluated at 42 ± 10.76 years with extremes ranging from 30 to 60 years. For victims of violent death and spousal homicide, inactivity was a strongly implicated risk factor, with respective frequencies of (88.57%) and (58.33%). Two-thirds of the persecuted women were completely unknown to the healthcare environment and had never consulted a medical professional. This parameter could be one of the predictive signs of spousal homicide. The marital home was the preferred location for violent deaths and spousal homicides. These crimes occurred variably during the period of marriage and eventually after divorce. As for the modus operandi, the perpetrators use many sharp and spinous weapons, including firearms and blunt objects. CONCLUSION: Autopsy and medico-legal investigations took a decisive interest in the identification of the causes of spousal homicide; indeed, many serious traumatic lesions incompatible with life have been highlighted. We underline the crucial role that healthcare professionals must play in the process of identifying and evaluating potentially risky situations.

Insulin Dosing and Glycemic Outcomes Among Steroid-treated Hospitalized Patients.

OBJECTIVE: To determine the optimal insulin-to-steroid dose ratio for the attainment of glycemic control in hospitalized patients. METHODS: We retrospectively studied data collected from the electronic health records within an academic medical center from 18 599 patient-days where patients were treated concurrently with insulin and steroids. Multivariate logistic regression analyses, which included demographic and clinical variables, were performed to assess the relationships between the exposures of total and basal insulin-to-steroid ratios and the outcomes of glycemic control (all blood glucose readings on the following patient-day were >70 and ≤180 mg/dL) and hypoglycemia within 3 subgroups of steroid dosing: low (≤10-mg prednisone equivalent dose [PED]), medium (from >10-mg to ≤40-mg PED), and high (>40-mg PED). RESULTS: Increased insulin-to-steroid ratio was associated with increased odds of both glycemic control and hypoglycemia. The optimal total insulin-to-steroid ratio for attaining glycemic control was 0.294 U/kg/10-mg PED in the low-dose subgroup, 0.257 U/kg/10-mg PED in the medium-dose subgroup, and 0.085 U/kg/10-mg PED in the high-dose subgroup. The optimal basal insulin-to-steroid ratio was 0.215 U/kg/10-mg PED in the low-dose subgroup, 0.126 U/kg/10-mg PED in the medium-dose subgroup, and 0.036 U/kg/10-mg PED in the high-dose subgroup. CONCLUSION: Increasing insulin-to-steroid ratios are positively associated with glycemic control and hypoglycemia. Our study suggests that approximately 0.3 U/kg/10-mg PED is an optimal dose for low- and medium-dose steroids, whereas approximately 0.1 U/kg/10-mg PED is an optimal dose for high-dose steroids. Further prospective studies are needed to identify insulin regimens that will optimize glycemic control in steroid-treated patients while minimizing the risk of hypoglycemia.

Clinical and molecular characterization of hereditary spastic paraplegia in a spanish Southern region.

INTRODUCTION: Spastic paraplegia (SPG) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations. Despite of the new molecular technologies, many patients remain yet undiagnosed. OBJECTIVE: The purpose of this study was to describe the clinical presentation and molecular characteristics of a cohort of 27 patients from 18 different families with SPG in the south of Spain. METHODS: We used a targeted next-generation sequencing (NGS) approach to study a proband from each family. RESULTS: Variants in SPG11 gene were the most common cause of SPG in our area. We made a genetic diagnosis in 52% of cases, identified 3 novel variants and reclassified one uncertain variant in SPG11 gene as pathogenic variant. We identified a patient with two truncanting mutations in SPG11 gene and late onset disease and report another missense mutation outside of motor domain of KIF1A gene in a family with pure SPG. CONCLUSION: Our study contributes to enhance the scientific knowledge of SPG. It is important to note the large group of cases (48%) that were not genetically diagnosed in our cohort. Therefore NGS approach is an efficient diagnostic tool, but it still large the number of non-diagnosed subjects, suggesting further genetic heterogeneity.

Cryoprotection of humanin-like peptides in seminal plasma for ejaculated spermatozoa of crossbred bulls.

BACKGROUND: Cryopreservation process negatively affects spermatozoa functions. Humanin, a small polypeptide encoded in the mitochondrial genome, is well known for its role in cell survival. OBJECTIVE: To quantify the endogenous levels of humanin in seminal plasma of crossbred Frieswal bulls and to study its role in cryoprotection. The presence of humanin in bull spermatozoa was also investigated. MATERIALS AND METHODS: A total of 40 semen samples were separated into two groups based on the initial progressive motility (IPM): Good (IPM >70%) and Poor (IPM <50%) groups; and/or based on the post-thaw motility (PTM): Freezable (PTM>50%) and Non-freezable (PTM < 50%) groups. Humanin concentration in seminal plasma (SP-HN) was quantified using ELISA. RESULTS: SP-HN concentration ranged from undetectable to 67.6 pg/mL with a median level of 35.2 pg/mL. SP-HN level was significantly higher in the good quality semen group than in the poor quality semen group (p<0.001), and also significantly higher in the freezable group than in the non-freezable group (p<0.001). SP-HN level was positively correlated with initial progressive motility, post-thaw semen motility, viability, acrosome intactness and plasma membrane integrity, but negatively correlated the level of reactive oxygen species and malondialdehyde content. Immunochemical localization showed the presence of humanin in the proximal region of the middle piece of spermatozoa. CONCLUSION: Endogenous humanin level had significant correlation with semen quality and might protect sperm cells against freeze-induced oxidative stress. doi.org/10.54680/fr22510110712.

A computational network perspective on pediatric anxiety symptoms.

BACKGROUND: While taxonomy segregates anxiety symptoms into diagnoses, patients typically present with multiple diagnoses; this poses major challenges, particularly for youth, where mixed presentation is particularly common. Anxiety comorbidity could reflect multivariate, cross-domain interactions insufficiently emphasized in current taxonomy. We utilize network analytic approaches that model these interactions by characterizing pediatric anxiety as involving distinct, inter-connected, symptom domains. Quantifying this network structure could inform views of pediatric anxiety that shape clinical practice and research. METHODS: Participants were 4964 youths (ages 5-17 years) from seven international sites. Participants completed standard symptom inventory assessing severity along distinct domains that follow pediatric anxiety diagnostic categories. We first applied network analytic tools to quantify the anxiety domain network structure. We then examined whether variation in the network structure related to age (3-year longitudinal assessments) and sex, key moderators of pediatric anxiety expression. RESULTS: The anxiety network featured a highly inter-connected structure; all domains correlated positively but to varying degrees. Anxiety patients and healthy youth differed in severity but demonstrated a comparable network structure. We noted specific sex differences in the network structure; longitudinal data indicated additional structural changes during childhood. Generalized-anxiety and panic symptoms consistently emerged as central domains. CONCLUSIONS: Pediatric anxiety manifests along multiple, inter-connected symptom domains. By quantifying cross-domain associations and related moderation effects, the current study might shape views on the diagnosis, treatment, and study of pediatric anxiety.

Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy.

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth. Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure. Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05). Limitations: Limitations included the modest sample size and the cross-sectional design. Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.

Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes.

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

Hereditary Thrombotic Thrombocytopenic Purpura in a 9-Month-old: Diagnosing and Managing an Ultra-rare Disorder.

Hereditary thrombotic thrombocytopenic purpura is an ultra-rare disorder caused by biallelic mutations in the ADAMTS13 gene. Because it can be difficult to diagnose, plasma ADAMTS13 activity assessment should be considered in patients with thrombocytopenia, anemia, and schistocytes on peripheral blood smear. We present the diagnostic evaluation of a patient with hereditary thrombotic thrombocytopenic purpura. Genetic testing revealed one known pathogenic mutation and one novel mutation of ADAMTS13 classified as likely pathogenic on the basis of parental genetic testing and in silico analyses. We further discuss off-label use of prophylactic plasma-derived Factor VIII (Koate-DVI) and the benefit of rare disease registries.

Shifts in Composition and Activity of Oral Biofilms After Fluoride Exposure.

Oral diseases are biofilm-mediated diseases caused by imbalances in the ecology of resident microflora. Among them, dental caries (tooth decay) is considered the most common disease worldwide, and toothbrushing, which physically eliminates the oral biofilm, is the most widespread prevention strategy. Although it is well established that fluoride increases enamel resistance to acidic pH and promotes tooth remineralization, its effect on the biofilm bacterial communities' composition and metabolism is not fully understood. We have grown in vitro oral biofilms and used 16S rRNA Illumina sequencing to study the effect of fluoride on DNA- and RNA-based bacterial populations. In addition, a metatranscriptomic approach has also been performed, in which total RNA has been sequenced to study gene expression profiles in the presence/absence of 500 ppm sodium fluoride. Our data show a lower pH drop and a clear shift in total and metabolically active bacterial composition after fluoride exposure. Streptococcus oralis was the species most affected, with a 10-fold reduction in both DNA and RNA samples, whereas Rothia mucilaginosa underwent an 8-fold increase in the DNA and S. salivarius a 4- and 5-fold increase in the RNA and DNA samples, respectively. The metatranscriptomes indicated that fluoride exposure induced a dramatic shutdown of sugar metabolism, including significant under-expression of different sugar transporters, fucosidases, and a pyruvate oxidase, among others. The reduction in saccharolytic organisms and the inhibition of sugar fermentation pathways by fluoride may therefore be considered instrumental for the beneficial effect of fluoride-containing oral hygiene products.

Improving emotion recognition in anorexia nervosa: An experimental proof-of-concept study.

OBJECTIVE: Previous research has found increasing evidence for difficulties in emotion recognition ability (ERA) and social cognition in anorexia nervosa (AN), and recent models consider these factors to contribute to the development and maintenance of the disorder. However, there is a lack of experimental studies testing this hypothesis. Therefore, the present proof-of-concept study examined whether ERA can be improved by a single session of a computerized training in AN, and whether this has short-term effects on eating disorder symptoms. METHOD: Forty inpatients (22.20 ± 7.15 years) with AN were randomly assigned to receive a single session of computerized training of ERA (TERA) or a sham training (training the recognition of different types of clouds). ERA, self-reported eating disorder symptoms, and body mass index (BMI) were assessed within 3 days before and after training. RESULTS: After training, both groups showed improved ERA, reduced self-reported eating disorder symptoms, and an increased BMI. As compared to patients in the control group, patients who received TERA showed greater improvements in ERA and self-reported eating disorder symptoms. DISCUSSION: ERA can be effectively trained in patients with AN. Moreover, short-term improvements in self-reported eating disorder symptoms provide tentative support for the hypothesis that difficulties in ERA contribute to the maintenance of AN, and that specific trainings of ERA hold promise as an additional component in AN treatment. Future studies are needed to replicate these findings in larger samples, and to investigate long-term effects and transfer into real-world settings.

Does bladder stone composition predict kidney stone composition?

INTRODUCTION Bladder stones have historically been associated with urinary stasis secondary to bladder outlet obstruction (BOO). Recent studies indicate that the role of BOO in bladder stone formation is minor. We evaluate the role of urinary lithogenic factors in bladder stone formation by comparing the compositions of bladder stones and kidney stones in patients with multi-site urinary calculi. MATERIALS AND METHODS: We identified patients who were treated for concomitant bladder stones and kidney stones between 2008-2019, and had both stone compositions available. Patients with bladder stone size < 10 mm, urinary foreign bodies, encrusted stents or tumors were excluded. Data regarding urinary symptoms, residual volumes, stone composition and 24-hours urine data were collected. RESULTS: We identified 40 males with a median age of 72 years (IQR 6-14), median residual volume of 76 mL (IQR 41-200), and a median prostate volume of 52 mL (IQR 32-102). Bladder outlet procedures were performed concomitantly with cystolitholapaxy in 21 (53%) patients. The most common bladder stone and kidney stone compositions were CaOx (47.5% and 65%), uric acid (32.5% and 22.5%), calcium phosphate (15% and 10%), and struvite (5% and 2.5%), respectively. Bladder stone and kidney stone compositions were identical in 70% of patients. Bladder stone composition was predictive of kidney stone composition, regardless of the PVR, bladder stone size, or whether an outlet procedure was performed. CONCLUSION: We found a high concordance between bladder stone and kidney stone composition, suggesting that metabolic abnormalities have a significant role in bladder stone formation. Bladder stone composition can be used to guide surgical and medical treatment for kidney stones in metabolically active stone patients.

Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors.

Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three in vitro cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC50) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than N-acetyl-piperizinyl derivatives. The IC50 values in cell-based assay systems were comparable to those obtained by direct inhibition of 5-LO activity, confirming that the compounds are direct inhibitors of 5-LO. Particularly, compounds PH-249 and PH-251 had outstanding potencies (IC50 < 1 µM), comparable to that of the prototype 5-LO inhibitor, zileuton. Pronounced in vivo activity was demonstrated in zymosan-induced peritonitis in mice. These novel oxazolidinone hydroxamic acid derivatives are, therefore, potent 5-LO inhibitors with potential application as anti-allergic and anti-inflammatory agents.

Compliance with infection control rules among adolescents in Oslo during the COVID-19 pandemic. / Smittevern blant Oslo-ungdom under covid-19-pandemien.

BACKGROUND: Effective infection control is crucial for combatting the COVID-19 pandemic. We investigated whether adolescents in Oslo reported compliance with the Norwegian infection control rules during the pandemic and whether compliance with the rules was associated with sociodemographic characteristics, trust in the authorities and acceptance of the infection control rules. MATERIAL AND METHOD: Students in lower and upper secondary schools completed an electronic questionnaire (N = 12 686, 37 % response rate) during a period with strict infection control measures in force. We used self-reporting of compliance with the infection control rules, sociodemographic characteristics, trust in the authorities and people in general, and acceptance of the infection control rules. We used logistic regression analysis. RESULTS: The majority reported that they always or to a large extent complied with the rules for hand washing (n = 9 915, 84 %), refrained from shaking hands/hugging (n = 8 730, 74 %) and avoided large groups (n = 8 565, 73 %). Fewer reported to maintain physical distance (n = 5 859, 50 %). The level of trust in the government (n = 8 742, 80 %) and health authorities (n = 9 962, 92 %) was high. The highest compliance with the rules was among girls, adolescents from immigrant backgrounds, those with a high level of trust in the authorities and people in general, and those who showed acceptance of the infection control rules. INTERPRETATION: A large proportion reported to comply with the infection control rules. Adolescents from immigrant backgrounds and those who were living in the outer eastern suburbs of Oslo also more frequently reported to comply with the rules. Trust and acceptance of the rules were also important factors.

Life satisfaction among adolescents before and during the COVID-19 pandemic. / Livstilfredshet blant ungdom før og under covid-19-pandemien.

BACKGROUND: The COVID-19 pandemic in the spring of 2020 involved closure of schools and strict limitations on social contact. The study examines whether this had an effect on the life satisfaction and subjective well-being among adolescents. MATERIAL AND METHOD: An online survey among students in lower secondary schools in Oslo (N = 8 116, 46 % response rate) was conducted during the period with closed schools and strict infection control measures. The results were compared to equivalent surveys conducted in Oslo in 2018 (N = 13 790, 83 % response rate) and several other counties in 2020 before the COVID-19 restrictions were introduced (N = 19 799, 49 % response rate). Identical measurements were used for life satisfaction, subjective well-being and background factors. We used logistic regression analysis and corrected for sociodemographic differences. RESULTS: Among boys, the proportion reporting high life satisfaction (a score of 6 or higher on a scale from 0 to 10) declined markedly, from 88 % in 2018 and 92 % in 2020 before the COVID-19 restrictions to 71 % during the period of restrictions (p < 0.001). The equivalent figures for girls were 78 %, 81 % and 62 % (p < 0.001). The social inequality in life satisfaction was smaller during the restrictions than in other periods. Concerns about illness and infection were associated with lower life satisfaction. INTERPRETATION: The reduction in life satisfaction and subjective well-being can most likely be explained by the heavy restrictions placed on activities that promote well-being and by concerns about infection. The results also indicate that resourceful adolescents experienced an especially strong reduction in their life satisfaction.