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Abstract We present a novel data set for drought in the continental US (CONUS) built to enable computationally efficient spatio-temporal statistical and probabilistic models of drought. We converted drought data obtained from the widely-used US Drought Monitor (USDM) from its native geo-referenced polygon format to a 0.5 degree regular grid. We merged known environmental drivers of drought, including those obtained from the North American Land Data Assimilation System (NLDAS-2), US Geological Survey (USGS) streamflow data, and National Oceanic and Atmospheric Administration (NOAA) teleconnections data. The resulting data set permits statistical and probabilistic modeling of drought with explicit spatial and/or temporal dependence. Such models could be used to forecast drought at short-range, seasonal to sub-seasonal, and inter-annual timescales with uncertainty, extending the reach and value of the current US Drought Outlook from the National Weather Service Climate Prediction Center. This novel data product provides the first common gridded dataset that includes critical variables used to inform hydrological and meteorological drought.

Using statewide administrative data from a sample of children enrolled in public prekindergarten (pre-K) programs in Massachusetts, I examined heterogeneity in children’s absenteeism patterns from pre-K to Grade 3 and linked these patterns to their Grade 3 academic outcomes. After latent class growth analysis, six absenteeism patterns emerged. The vast majority of children (85%) had consistently low absenteeism, and only a small percentage of children (1%) demonstrated consistently high absenteeism. Four patterns showed variation in absenteeism over time, with two characterized by high absenteeism in only the pre-K year, another with a peak during kindergarten, and a final one with rising absenteeism across grades. Children with always low absenteeism had higher average English language arts and math scores than did children in the other patterns, and children in the two high pre-K absenteeism patterns and peak in kindergarten pattern had higher math scores than those with rising and always high absenteeism patterns.

Abstract INTRODUCTION The precise apolipoprotein E (APOE) ε4‐specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS Plasma protein modules/cascades were analyzed using weighted gene co‐expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p‐tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C‐reactive protein (CRP), complement C3, and complement factor H (CFH), had dose‐dependent associations with CSF p‐tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION The study identifies the APOE ε4–specific CRP–C3–CFH inflammation pathway for AD, suggesting potential drug targets for the disease. Highlights Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD. CRP, C3, and CFH had dose‐dependent associations with CSF p‐Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes. Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

Abstract X-linked lymphoproliferative disease (XLP) is either caused by loss of the SLAM-associated protein (SAP; XLP-1) or the X-linked inhibitor of apoptosis (XIAP; XLP-2). In both instances, infection with the oncogenic human Epstein Barr virus (EBV) leads to pathology, but EBV-associated lymphomas only emerge in XLP-1 patients. Therefore, we investigated the role of XIAP during B cell transformation by EBV. Using humanized mice, IAP inhibition in EBV-infected mice led to a loss of B cells and a tendency to lower viral titers and lymphomagenesis. Loss of memory B cells was also observed in four newly described patients with XIAP deficiency. EBV was able to transform their B cells into lymphoblastoid cell lines (LCLs) with similar growth characteristics to patient mothers’ LCLs in vitro and in vivo. Gene expression analysis revealed modest elevated lytic EBV gene transcription as well as the expression of the tumor suppressor cell adhesion molecule 1 (CADM1). CADM1 expression on EBV-infected B cells might therefore inhibit EBV-associated lymphomagenesis in patients and result in the absence of EBV-associated malignancies in XLP-2 patients.

IntroductionKawasaki disease (KD) is an acute idiopathic systemic vasculitis with a self- limiting course that predominantly affects children under 5 years old, particularly in the East Asian countries. Nevertheless, to date, the data on KD in Malaysia are limited. This study aimed to evaluate the epidemiology, clinical features, treatment, and outcomes of KD among the pediatric patients admitted to Hospital Canselor Tunku Muhriz (HCTM), Kuala Lumpur, Malaysia.MethodA retrospective cohort study of 66,500 pediatric patients presented at HCTM from the year 2004 to 2021 was conducted.Results62 KD cases out of 66,500 pediatric admissions were reported, with a male-to-female ratio of 1.58 to 1. Majority of KD patients (95.0%) were younger than 5 years old. Prior infection was reported in 5 KD patients (8.1%). Apart from the classical features, manifestations of various organ systems including cardiovascular (16.1%), gastrointestinal (43.5%), neurological (1.61%), musculoskeletal (1.61%), and genitourinary (17.7%) systems were observed. There was a significant association between sterile pyuria and coronary artery aneurysm (CAA) (p

Summary: Background: Published literature documents tremendous gender inequities in the social, economic and health effects of the COVID-19 pandemic, but less evidence has come from low- and middle-income countries (LMICs) and even less from LMIC-based authors. We examine whether a) COVID-19 burden and b) LMIC-based authorship were associated with academic publications related to COVID-19 and women's well-being in LMICs. Methods: We reviewed academic articles on COVID-19 and women's well-being in LMICs published between February 2020 and May 2021 (n=1076 articles), using six electronic databases (PubMed, Web of Science, PsycInfo, EconLit, RePeC, NBER). Multilevel, mixed effects linear regressions assessed the relationships between each of our independent variables - a) COVID-19 burden (cases/100 population, deaths/100 population, deaths/cases) and b) author's country of primary affiliation, with publications related to COVID-19 and women's well-being, both overall and stratified by country income group. Findings: Eight-eight percent of articles had lead and/or senior authors affiliated with in-country institutions. Linear mixed effect models indicate that COVID-19 cases and case fatality ratios in a country were significantly and positively associated with the number of publications related to COVID-19 and women's well-being, though these relationships were significant only in upper-middle income group countries in stratified analyses. LMIC lead and senior authorship were also significantly and positively associated with our outcome, after adjusting for COVID-19 burden. Interpretation: While the majority of COVID-19 research examining women's well-being in LMICs in the first year and a half of the pandemic included country-affiliated author leadership, there were important gaps in representation. Findings highlight the importance of LMIC-based scholars to build local and gendered research in crises. Funding: Bill and Melinda Gates Foundation (INV-018007).

Hepatocellular carcinoma has one of the poorest survival rates amongst cancers. Here, the authors highlight the intra-tumour heterogeneity of this disease, finding that spatially closer tumour sectors are genetically more similar and that intra-hepatic metastasis is accompanied by rapid genetic diversification.

TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.

Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID.

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.

Student absenteeism affects students' engagement in school and academic and professional success. While research documents a significant association between school bullying/fighting and student absenteeism due to fear of being at school or getting to school, little research has examined the association of adolescent dating violence (ADV) victimization with this type of absenteeism. This study examined the relationship between physical and/or sexual ADV victimization in the past year (dichotomized as yes or no), and number of days of student absenteeism due to feeling unsafe at school or on the way to school in the past month (dichotomized as any vs. none). We analyzed cross-sectional data from the 2019 Youth Risk Behavior Survey (YRBS), a nationally representative survey of U.S. high school students (n = 9507). We conducted crude and multivariate regression models for the total sample and stratified by sex to assess our hypothesized association of ADV victimization and absenteeism; sex, grade, race/ethnicity, and sexual identity were included as covariates in adjusted models. Findings demonstrate that students reporting past year ADV victimization had 3.69 times the odds of student absenteeism due to feeling unsafe, when compared to students who did not report ADV victimization (95% CI: 3.06-4.45, p < 0.001). Sex-stratified models reveal that this effect is significantly stronger for males than for females, as indicated by non-overlapping confidence intervals (male AOR: 5.67, 95% CI: 4.18-7.68; female AOR: 2.95, 95% CI: 2.32-3.74). The multivariate models also show that Black and Latinx compared with White students, and lesbian/gay/bisexual/unsure compared with heterosexual students, had higher odds of student absenteeism due to feeling unsafe. Findings indicate the need to address ADV victimization and student absenteeism with integrated and gender-tailored responses, and with consideration of greater vulnerabilities for queer students and students of color.

BackgroundPublished literature documents tremendous gender inequities in the social, economic and health effects of the COVID-19 pandemic, but less evidence has come from low- and middle-income countries (LMICs) and even less from LMIC-based authors. We examine whether a) COVID-19 burden and b) LMIC-based authorship were associated with academic publications related to COVID-19 and women's well-being in LMICs.MethodsWe reviewed academic articles on COVID-19 and women's well-being in LMICs published between February 2020 and May 2021 (n=1076 articles), using six electronic databases (PubMed, Web of Science, PsycInfo, EconLit, RePeC, NBER). Multilevel, mixed effects linear regressions assessed the relationships between each of our independent variables - a) COVID-19 burden (cases/100 population, deaths/100 population, deaths/cases) and b) author's country of primary affiliation, with publications related to COVID-19 and women's well-being, both overall and stratified by country income group.FindingsEight-eight percent of articles had lead and/or senior authors affiliated with in-country institutions. Linear mixed effect models indicate that COVID-19 cases and case fatality ratios in a country were significantly and positively associated with the number of publications related to COVID-19 and women's well-being, though these relationships were significant only in upper-middle income group countries in stratified analyses. LMIC lead and senior authorship were also significantly and positively associated with our outcome, after adjusting for COVID-19 burden.InterpretationWhile the majority of COVID-19 research examining women's well-being in LMICs in the first year and a half of the pandemic included country-affiliated author leadership, there were important gaps in representation. Findings highlight the importance of LMIC-based scholars to build local and gendered research in crises.FundingBill and Melinda Gates Foundation (INV-018007).

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a "death ligand"-a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-kappaB and JNK signalling pathways. To determine the role of TGF-beta-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1-/- MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-kappaB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-kappaB, protected TAK1-/- MEFs against TRAIL killing, suggesting that TAK1 activation of NF-kappaB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-kappaB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK1-/- MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1-NF-kappaB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance.

During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-[8.sup.ECKO]) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-[8.sup.ECKO] pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP., Introduction Functional blood vessels are of vital importance. Impaired vessel formation contributes to many pathological situations, including ischemic and inflammatory disorders. Ischemic retinopathies are the main causes of severe visual [...]

INTRODUCTION: The precise apolipoprotein E (APOE) ε4‐specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co‐expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p‐tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C‐reactive protein (CRP), complement C3, and complement factor H (CFH), had dose‐dependent associations with CSF p‐tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4–specific CRP–C3–CFH inflammation pathway for AD, suggesting potential drug targets for the disease. Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose‐dependent associations with CSF p‐Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers. [ABSTRACT FROM AUTHOR]

Abstract A drug–drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5‐probe cytochrome P450 (CYP) substrate cocktail, guided by in vitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static‐mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co‐medications metabolized by CYP3A4 (area under the concentration–time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co‐medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co‐administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30‐μg EE and 150‐μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle‐stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.

AbstractThis research explores discussions surrounding news stories on r/news after two separate school shooting events in 2018 and 2023 to understand how and when variables related to knowledge exchange and framing emerge in context. These activities were found to be an antecedent to engagement, and exchanges of disagreement resulted in longer chains of discussion. ‘Metaframing’ was found to be linked to media distrust. Users in 2023 were far more ideologically aligned and shared knowledge more frequently, but cited sources less frequently, than in 2018. Implications for impacts of news, disagreement, and content moderation on online civic discourse are offered.

Abstract Background Understanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer’s disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD. Methods The study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models. Results The estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period. Conclusions The findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling.

Abstract INTRODUCTION We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI‐Q]), and cognitive impairment in Alzheimer's disease (AD). METHODS We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR‐global. RESULTS Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI‐Q scores increased steeply with MCI (NPI‐Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI‐Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). DISCUSSION CDR‐global staged AD by capturing differences in relevant outcomes along AD progression. Highlights There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living. Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia). Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages.

Connected and automated vehicles have become more common in recent years, increasing the need to assess their societal level impacts. In this paper a methodology is presented to explore and define these impacts as a starting point for quantitative impact assessment. The many interrelations between impacts increases the complexity of obtaining a complete overview. Therefore, a structured approach is used, which shows many similarities with the modelling of causal-loop-diagrams. Feedback loops between impacts are taken into account at an early stage and both literature review and expert interviews are used to produce a holistic overview of impacts. The methodology was developed and applied in the European H2020 project LEVITATE. The impact taxonomy and interrelations between impacts resulting from this project are presented and further steps needed to perform a quantitative evaluation of the impacts are discussed.

This qualitative study examines Tonya Harding’s experiences after she was excoriated by news media in the 1990s and given an opportunity in 2017 to tell her story through the film, I, Tonya. The critical thematic analysis of a semi-structured interview with Harding contends that her assessment of how her image was recuperated by the film is informed by her experiences with news media’s classism and sexism before and following the notorious attack on Nancy Kerrigan.

Abstract Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR]

Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID. [ABSTRACT FROM AUTHOR]

Abstract Introduction Costs related to road crashes represent an important societal burden. Additionally they constitute an essential input variable to assess the cost efficiency of road safety measures. While most attention is usually spent on costs related to fatal crashes, this paper focuses on costs related to serious injuries. Method A review of these costs is presented based on different data sets and methods. Results A survey collecting crash cost estimates in European countries shows considerable variation in the costs related to serious injuries. The reported cost per serious injury varies between €28,205 and €975,074 and the total costs related to serious injuries vary between 0.04% and 2.7% of a country’s GDP. The applied methodology to estimate human costs appears to have a large influence. Other potential explanations are the applied definition for seriously injured victims, the registration procedure of crashes with serious injuries and the cost components that are included. Detailed analyses of medical costs and production loss that are based on country-specific datasets show the importance of assessing medical costs on the long term and taking into account the variation of these costs for different subgroups of traffic victims. A comparison of approaches to estimate monetary values for human costs shows that most countries use the Willingness To Pay method. While having a sound theoretical background, this method is rather limited in the specification of injuries. The use of Quality Adjusted Life Years gives the possibility to provide values for a larger diversity of injury types.

The importance of neutrophil extracellular traps (NETs) in innate immunity is well established but the molecular mechanisms responsible for their formation are still a matter of scientific dispute. Here, we aim to characterize a possible role of the receptor-interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) signaling pathway, which are known to cause necroptosis, in NET formation. Using genetic and pharmacological approaches, we investigated whether this programmed form of necrosis is a prerequisite for NET formation. NETs have been defined as extracellular DNA scaffolds associated with the neutrophil granule protein elastase that are capable of killing bacteria. Neither Ripk3-deficient mouse neutrophils nor human neutrophils in which MLKL had been pharmacologically inactivated, exhibited abnormalities in NET formation upon physiological activation or exposure to low concentrations of PMA. These data indicate that NET formation occurs independently of both RIPK3 and MLKL signaling. [ABSTRACT FROM AUTHOR]

There is compelling evidence suggesting that the immune-modulating effects of many conventional chemotherapeutics, including platinum-based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor-specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an 'anticancer vaccine'. In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A PtII N-heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small-molecule immuno-chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

The article discusses research conducted to investigate the interaction of the Apolipoprotein E (ApoE) genotype and angiotensin converting enzyme (ACE) inhibitors in Alzheimer's disease. Researchers evaluated 355 patients. They found that ApoE4 carriers treated with ACE inhibitors had more diagnoses of AD than those who did not, that ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele and that the effects of ACE inhibitors on AD may be different depending on ApoE genotype.

The Ukrainian prison service is going through a process of reform. One of the areas that is in urgent need of intervention is prison mental health. In collaboration with the Ministry of Justice a team of international experts assessed the current situation with regard to penitentiary psychiatry and came to a set of recommendations. This article reflects the outcome of the assessment visit and the recommendations made to the ministry.

Background. Though there is an effective intervention, pain after surgical intervention is undermanaged worldwide. A systematic implementation is required to increase the utilization of available evidence-based intervention to manage the inevitable pain after surgery. The aim of this research project is to develop a scalable model for managing pain after cesarean section by implementing the World Health Organization’s (WHO) pain management guidelines through a combination of implementation research and quality improvement methods. Methods. We implemented the World Health Organization (WHO) pain management guidelines using effective implementation strategies. First, we conducted a formative qualitative exploration to identify enablers and obstacles. In addition, we took base-line assessment on pain management implementation process and outcome using a checklist prepared from the guideline and an adapted American Pain Outcome assessment tool version 2010, respectively. Then, we integrated the guidelines into the existing practice by using collaborative iterative learning strategy. We analyzed the data by Statistical Packages for Social Sciences (SPSS) version 21. We compared the before and after data using chi-squared and Fischer’s exact test. A change in any measurement was considered as significant at p value 0.05. Result. We collected data from 106 mothers before and 110 mothers after intervention implementation. We successfully integrated pain as a fifth vital sign in more than 87% (p value

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a ''death ligand''-a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-κB and JNK signalling pathways. To determine the role of TGF-β-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1-/- MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-κB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-κB, protected TAK1-/- MEFs against TRAIL killing, suggesting that TAK1 activation of NF-κB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-κB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK12/2 MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1-NF-κB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance. [ABSTRACT FROM AUTHOR]

Over the past decades, road safety in highly-motorised countries has made significant progress. Although we have a fair understanding of the reasons for this progress, we don't have conclusive evidence for this. A new generation of road safety management approaches has entered road safety, starting when countries decided to guide themselves by setting quantitative targets (e.g. 50% less casualties in ten years' time). Setting realistic targets, designing strategies and action plans to achieve these targets and monitoring progress have resulted in more scientific research to support decision-making on these topics. Three subjects are key in this new approach of evidence-based and data-driven road safety management: ex-post and ex-ante evaluation of both individual interventions and intervention packages in road safety strategies, and transferability (external validity) of the research results. In this article, we explore these subjects based on recent experiences in four jurisdictions (Western Australia, the Netherlands, Sweden and Switzerland). All four apply similar approaches and tools; differences are considered marginal. It is concluded that policy-making and political decisions were influenced to a great extent by the results of analysis and research. Nevertheless, to compensate for a relatively weak theoretical basis and to improve the power of this new approach, a number of issues will need further research. This includes ex-post and ex-ante evaluation, a better understanding of extrapolation of historical trends and the transferability of research results. This new approach cannot be realized without high-quality road safety data. Good data and knowledge are indispensable for this new and very promising approach.

Abstract Advances in genome sequencing have progressed at a rapid pace, with increased throughput accompanied by plunging costs. But these advances go far beyond faster and cheaper. High‐throughput sequencing technologies are now routinely being applied to a wide range of important topics in biology and medicine, often allowing researchers to address important biological questions that were not possible before. In this review, we discuss these innovative new approaches—including ever finer analyses of transcriptome dynamics, genome structure and genomic variation—and provide an overview of the new insights into complex biological systems catalyzed by these technologies. We also assess the impact of genotyping, genome sequencing and personal omics profiling on medical applications, including diagnosis and disease monitoring. Finally, we review recent developments in single‐cell sequencing, and conclude with a discussion of possible future advances and obstacles for sequencing in biology and health.

Although the majority of emerging infectious diseases can be linked to wildlife sources, most pathogen spillover events to people could likely be avoided if transmission was better understood and practices adjusted to mitigate risk. Wildlife trade can facilitate zoonotic disease transmission and represents a threat to human health and economies in Asia, highlighted by the 2003 SARS coronavirus outbreak, where a Chinese wildlife market facilitated pathogen transmission. Additionally, wildlife trade poses a serious threat to biodiversity. Therefore, the combined impacts of Asian wildlife trade, sometimes termed bush meat trade, on public health and biodiversity need assessing. From 2010 to 2013, observational data were collected in Lao PDR from markets selling wildlife, including information on volume, form, species and price of wildlife; market biosafety and visitor origin. The potential for traded wildlife to host zoonotic diseases that pose a serious threat to human health was then evaluated at seven markets identified as having high volumes of trade. At the seven markets, during 21 observational surveys, 1,937 alive or fresh dead mammals (approximately 1,009 kg) were observed for sale, including mammals from 12 taxonomic families previously documented to be capable of hosting 36 zoonotic pathogens. In these seven markets, the combination of high wildlife volumes, high risk taxa for zoonoses and poor biosafety increases the potential for pathogen presence and transmission. To examine the potential conservation impact of trade in markets, we assessed the status of 33,752 animals observed during 375 visits to 93 markets, under the Lao PDR Wildlife and Aquatic Law. We observed 6,452 animals listed by Lao PDR as near extinct or threatened with extinction. The combined risks of wildlife trade in Lao PDR to human health and biodiversity highlight the need for a multi-sector approach to effectively protect public health, economic interests and biodiversity.

Con un enfoque comparativo se exploraron las condiciones en que surgieron y han perdurado las organizaciones sociales para la pesca ribereña, en la península de Baja California. En la actualidad operan más de trescientas, e incluyen cooperativas pesqueras, sociedades de producción rural y de solidaridad social y uniones de pescadores. Los factores que han contribuido a su formación son la lógica de los pescadores, los incentivos institucionales y los actores externos, y hay otros que parecen perjudicar su persistencia como los incentivos organizativos, inversión en capital fijo y social, la solidaridad social, como principio rector de sus actividades, y la capacidad de autogestión. La presente evaluación es un primer paso para entender las condiciones en las que estas organizaciones han participado y pueden hacerlo, para mejorar la gestión de los recursos pesqueros de la región.

This paper describes the variation in traffic volumes in the Dutch city of Almelo. For this study, we used traffic counts which were collected at about 20 intersections from September 2004 until September 2005. The objective of this study is to provide insight in both periodic and random variation in urban traffic volumes. This insight is used by policy makers and traffic managers to determine a suitable set of traffic measures. It is also a basis for short term predictions of volumes. We conclude that we can distinguish the following types of variation with respect to the average daily volume profile. (1) Seasonal variations with time-scales of weeks and weekly variations that describe the variation from day to day. These variations can be as large as 10% for the city of Almelo. (2) Periodic variations at time-scales of typically 30 minutes. These variations are recurrent and are often larger than 10%. (3) Noise. This variation has a random character. We show that the noise can be approximated by a Poisson distribution.