Cyberlindnera jadinii and Kluyveromyces lactis, two fungi used in food processes, have potential probiotic effects on gut inflammation.

IMPORTANCE: The food industry has always used many strains of microorganisms including fungi in their production processes. These strains have been widely characterized for their biotechnological value, but we still know very little about their interaction capacities with the host at a time when the intestinal microbiota is at the center of many pathologies. In this study, we characterized five yeast strains from food production which allowed us to identify two new strains with high probiotic potential and beneficial effects in a model of intestinal inflammation.

Acute Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The Good, the Bad, and the Ugly of Isolated Extramedullary Relapse in a Latin American Population.

Hematopoietic stem cell transplantation (HSCT) is an effective therapy for acute leukemia (AL). Relapse represents the main cause of mortality. Isolated extramedullary relapse (iEMR) is atypical and has been related to better outcomes. Here we describe the clinical characteristics and outcomes of AL relapse after HSCT in our study population and analyze the impacts of different types of relapse on survival outcomes. This retrospective, multicenter study included 124 patients age ≥15 years with AL who underwent HSCT between 2004 and 2019. At diagnosis, 66.1% of the patients had lymphocytic AL, 19.7% presented with high-risk features, and 18.5% had extramedullary disease (EMD). At HSCT, 83.1% of the patients were in complete remission (CR), and 44.8% had negative measurable residual disease (MRD). The vast majority of donors were related (96%), including 48.4% HLA-matched and 47.6% haploidentical. Myeloablative conditioning was provided to 80.6% of patients. The median overall survival (OS) was 15 months (95% confidence interval [CI] 9.9 to 20.1 months). Factors associated with improved OS were adolescent and young adult (AYA) patient (P = .035), first or second CR (P = .026), and chronic graft-versus-host disease (GVHD) (P < .001). Acute GVHD grade III-IV (P = .009) was associated with increased mortality. The median relapse-free survival was 13 months (95% CI, 7.17 to 18.8 months); early disease status (P = .017) and chronic GVHD (P < .001) had protective roles. Sixty-eight patients (55%) relapsed after HSCT, with a median time to relapse of 6 months (95% CI, 3.6 to 8.4 months). iEMR was reported in 16 patients (23.5%). The most commonly involved extramedullary sites were the central nervous system and skin. Compared to patients with bone marrow relapse, all patients with iEMR had a diagnosis of acute lymphoid leukemia (P = .008), and 93.8% belonged to the AYA group; regarding pre-HSCT characteristics, iEMR patients had higher rates of negative MRD (P = .06) and a history of EMD (P = .009). Seventy-seven percent of relapsed patients received additional treatment with curative intent. The median OS after relapse (OSr) was 4 months (95% CI, 2.6 to 5.4 months). Factors related to increased OSr included lymphoid phenotype (P = .03), iEMR (P = .0042), late relapse (≥6 months) (P = .014), receipt of systemic therapy including second HSCT (P < .001), and response to therapy (P < .001). Rates of relapse and iEMR were higher than those previously reported in other studies. Advanced disease, reduced-intensity conditioning, and a diminished graft-versus-leukemia effect were factors influencing these findings. At relapse, presenting with iEMR after 6 months and receiving intensive therapy with adequate response were associated with better outcomes. Our results strongly suggest that a personalized approach to treating patients with HSCT is needed to counterbalance specific adverse factors and can positively impact clinical outcomes.

Sustainable employment depends on quality relationships between supervisors and their employees on the autism spectrum.

PURPOSE: Employment outcomes for individuals on the autism spectrum may be contingent upon employers' knowledge of autism and provision of appropriate workplace supports. We aimed to understand the organizational factors that influenced the organizational socialization of autistic employees. MATERIALS AND METHODS: We wrote nine case histories based on interviews from managers, autistic employees, and job coaches. Intra-case analysis, then cross-case analysis, provided an understanding of organizational factors that lead to sustained employment of autistic employees. RESULTS: The quality of the relationship between managers and autistic employees was consistently seen as the key facilitator of organizational socialization and positive employment outcomes of autistic employees. These relationships, however, relied on the skilled facilitation of the job coach during each stage of the employment cycle (hiring, on-boarding, training, performance management), as they had an important role in building a mutual understanding between supervisors and employees. As such, our study draws upon and contributes to leader-member exchange theory. CONCLUSIONS: Consistent with prior research, our study shows the importance of high-quality relationships between supervisors and supervisees for positive employment outcomes of autistic employees in organization but adds skilled communication facilitation as a novel antecedent to leader-member exchange, as a potentially key factor for autistic employees. Implications for rehabilitationThe relationship between the a manager and their employee is an important factor in effective organizational socialization and workplace outcomes for autistic employees.Job coaches can play a crucial role in building mutual understanding and high-quality relationships between managers and employees.Job coaches can support the inclusion of autistic employees by illustrating the multi-faceted socioemotional performance benefits over the longer term.

Effects of Five Filamentous Fungi Used in Food Processes on In Vitro and In Vivo Gut Inflammation.

Food processes use different microorganisms, from bacteria to fungi. Yeast strains have been extensively studied, especially Saccharomyces cerevisiae. However, to date, very little is known about the potential beneficial effects of molds on gut health as part of gut microbiota. We undertook a comprehensive characterization of five mold strains, Penicillium camemberti, P. nalgiovense, P. roqueforti, Fusarium domesticum, and Geotrichum candidum used in food processes, on their ability to trigger or protect intestinal inflammation using in vitro human cell models and in vivo susceptibility to sodium dextran sulfate-induced colitis. Comparison of spore adhesion to epithelial cells showed a very wide disparity in results, with F. domesticum and P. roqueforti being the two extremes, with almost no adhesion and 20% adhesion, respectively. Interaction with human immune cells showed mild pro-inflammatory properties of all Penicillium strains and no effect of the others. However, the potential anti-inflammatory abilities detected for G. candidum in vitro were not confirmed in vivo after oral gavage to mice before and during induced colitis. According to the different series of experiments carried out in this study, the impact of the spores of these molds used in food production is limited, with no specific beneficial or harmful effect on the gut.

Potential effects of nectar microbes on pollinator health.

Floral nectar is prone to colonization by nectar-adapted yeasts and bacteria via air-, rain-, and animal-mediated dispersal. Upon colonization, microbes can modify nectar chemical constituents that are plant-provisioned or impart their own through secretion of metabolic by-products or antibiotics into the nectar environment. Such modifications can have consequences for pollinator perception of nectar quality, as microbial metabolism can leave a distinct imprint on olfactory and gustatory cues that inform foraging decisions. Furthermore, direct interactions between pollinators and nectar microbes, as well as consumption of modified nectar, have the potential to affect pollinator health both positively and negatively. Here, we discuss and integrate recent findings from research on plant-microbe-pollinator interactions and their consequences for pollinator health. We then explore future avenues of research that could shed light on the myriad ways in which nectar microbes can affect pollinator health, including the taxonomic diversity of vertebrate and invertebrate pollinators that rely on this reward. This article is part of the theme issue 'Natural processes influencing pollinator health: from chemistry to landscapes'.

Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy.

The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e., sorafenib and pazopanib). As monotherapy, EVT801 showed a potent antitumor effect in VEGFR-3-positive tumors, and in tumors with VEGFR-3-positive microenvironments. EVT801 suppressed VEGF-C-induced human endothelial cell proliferation in vitro and tumor (lymph)angiogenesis in different tumor mouse models. In addition to reduced tumor growth, EVT801 decreased tumor hypoxia, favored sustained tumor blood vessel homogenization (i.e., leaving fewer and overall larger vessels), and reduced important immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSC) in circulation. Furthermore, in carcinoma mouse models, the combination of EVT801 with immune checkpoint therapy (ICT) yielded superior outcomes to either single treatment. Moreover, tumor growth inhibition was inversely correlated with levels of CCL4, CCL5, and MDSCs after treatment with EVT801, either alone or combined with ICT. Taken together, EVT801 represents a promising anti(lymph)angiogenic drug for improving ICT response rates in patients with VEGFR-3 positive tumors. Significance: The VEGFR-3 inhibitor EVT801 demonstrates superior selectivity and toxicity profile than other VEGFR-3 tyrosine kinase inhibitors. EVT801 showed potent antitumor effects in VEGFR-3-positive tumors, and tumors with VEGFR-3-positive microenvironments through blood vessel homogenization, and reduction of tumor hypoxia and limited immunosuppression. EVT801 increases immune checkpoint inhibitors' antitumor effects.

Household Debt, Maternal Well-Being, and Child Adjustment in Germany: Examining the Family Stress Model by Family Structure.

The amount of household debt tripled globally over the last decades and a sizable share of individuals and families are overindebted due to mortgages, credit cards, or consumer debt. Yet research on the distribution of debt across families, and potential ripple effects of the psychological burden related to debt on well-being and family relations, remains sparse. Our study aims to fill these gaps by examining the socio-demographic profiles of families that have accumulated household debt and the unique role that the psychological burden related to debt plays on associations between mothers' well-being, parental dynamics, and child adjustment based on the Family Stress Model (FSM). We used representative survey data collected in 2019 from Germany (N = 3271), which is one of the richest economies worldwide, yet about 10% of adults reported to be overindebted. Logistic regression results showed that single mothers were less likely to have debt compared to mothers in two-parent families. However, both single mothers and mothers in stepfamilies with high levels of perceived economic strain were particularly likely to report having debt. Structural equation modeling yielded that the links between the psychological burden of debt, maternal well-being, parental dynamics, and child adjustment were largely in line with the FSM, except for single mothers. We conclude that persisting financial disparities by family structure may be partially fostered by unique characteristics of the German welfare state, such as promoting more a traditional two-parent norm, and discuss our findings in light of practical implications.

Rigor, reproducibility, and transparency of randomized controlled trials in obstetrics and gynecology.

BACKGROUND: Randomized controlled trials are considered the highest level of evidence but fewer than half are reproducible. A rigorous methodology improves trial quality, but reproducibility may be limited by a lack of transparency in reporting. The Consolidated Standards of Reporting Trials guidelines define reporting standards, and pretrial registration requires a predefined methodology and predefined outcomes. OBJECTIVE: We evaluated obstetrics and gynecology trials published in 6 journals in terms of their adherence to the Consolidated Standards of Reporting Trials guidelines. Second, we evaluated pretrial registration compliance and concordance between the registry and publication. Furthermore, we evaluated the differences in trial characteristics among randomized controlled trials with the highest level of compliance and those with lower levels of compliance and adherence to guidelines by journal type. STUDY DESIGN: This was a cross-sectional study of obstetrics and gynecology trials published between 2017 and 2019 in 6 journals (American Journal of Obstetrics & Gynecology, BJOG: An International Journal of Obstetrics and Gynaecology, Obstetrics & Gynecology, The Journal of the American Medical Association, The Lancet, and The New England Journal of Medicine). Randomized controlled trials were identified via PubMed and manual journal archive searches. The primary outcome was adequate compliance with the Consolidated Standards of Reporting Trials guidelines defined as ≥80% of the checklist items present. Secondary outcomes included completion of pretrial registration and concordance between the pretrial registration and publication in terms of the outcomes and sample size. We compared the characteristics between trials with adequate compliance and those with inadequate compliance. Secondary analyses included comparisons of characteristics of the trials in the top quartile for compliance with the Consolidated Standards of Reporting Trials guidelines with those of the trials in lower quartiles and compliance with guidelines in obstetrics-gynecology vs non-obstetrics-gynecology journals. In an exploratory analysis, trends in compliance with the Consolidated Standards of Reporting Trials guidelines across the study period were assessed. A post hoc sensitivity analysis evaluated the outcomes after the exclusion of 2 retracted trials. RESULTS: Of the 170 trials included, 80% (95% confidence interval, 74%-86%) were adequately compliant with the Consolidated Standards of Reporting Trials manuscript guidelines and 66% (95% confidence interval, 59%-73%) were compliant with the abstract guidelines. Nearly all trials (98%) reported pretrial registration. Concordance between pretrial registration and publication in terms of the primary outcomes was identified for 77% of the trials, concordance in terms of the secondary outcomes was observed in 32% of the trials, and concordance in terms of sample size was observed in 60% of the trials. Trials with adequate compliance were more likely to be preregistered, include an a priori power calculation, and use an intent to treat analysis. Trials in the top quartile for compliance with the Consolidated Standards of Reporting Trials guidelines were more likely to be multicenter, international, and government funded. More trials from non-obstetrics-gynecology journals were in the top quartile for compliance with the Consolidated Standards of Reporting Trials guidelines than trials from obstetrics-gynecology journals (64.9% vs 25.7%; P<.001). No significant trends in adequate compliance were identified across the study period. Results did not differ significantly in the sensitivity analysis. CONCLUSION: Of all the trials included, 20% of obstetrics-gynecology trials published in 6 high-impact journals were not compliant with the Consolidated Standards of Reporting Trials guidelines, and there were major discrepancies between pretrial registration and publication. Transparency, reproducibility, and scientific rigor in obstetrics and gynecology trial reporting needs to be improved.

The General Movements Assessment in Neonates With Hypoxic Ischemic Encephalopathy.

BACKGROUND: Clinical measures after birth and studies such as electroencephalogram (EEG) and brain imaging do not fully predict neurodevelopmental outcomes of infants with hypoxic-ischemic encephalopathy. Early detection of adverse neurologic outcomes, and cerebral palsy in particular, in high-risk infants is essential for ensuring timely management. The General Movements Assessment is a tool that can be used in the early detection of cerebral palsy in infants with brain injury. The majority of studies on the General Movements Assessment in the late preterm and term population were performed prior to the introduction of therapeutic hypothermia. AIMS: To apply the General Movements Assessment in late preterm and term infants with hypoxic-ischemic encephalopathy (including those who received therapeutic hypothermia), to determine if clinical markers of hypoxic-ischemic encephalopathy predict abnormal General Movements Assessment findings, and to evaluate interrater reliability of the General Movements Assessment in this population. Study design: Pilot prospective cohort study Subjects: We assessed 29 late preterm and full-term infants with mild, moderate, and severe hypoxic-ischemic encephalopathy in Philadelphia, PA. RESULTS: Most infants' general movements normalized by the fidgety age. Only infants with moderate or severe hypoxic-ischemic encephalopathy had abnormal general movements in both the writhing and the fidgety ages (n = 6). Seizure at any point during the initial hospitalization was the clinical sign most predictive of abnormal general movements in the fidgety age (sensitivity 100%, specificity 55%, positive predictive value 40%, negative predictive value 100%). Interrater reliability was greatest during the fidgety age (κ = 0.67). CONCLUSIONS: Seizures were the clinical predictor most closely associated with abnormal findings on the General Movements Assessment. However, clinical markers of hypoxic-ischemic encephalopathy are not fully predictive of abnormal General Movements Assessment findings. Larger future studies are needed to evaluate the associations between the General Movements Assessment and childhood neurologic outcomes in patients with hypoxic-ischemic encephalopathy who received therapeutic hypothermia.

Burden of disease and costs associated with type 2 diabetes in emerging and established markets: systematic review analyses.

Objectives: To estimate the clinical and economic burden of type 2 diabetes (T2D) in established (EST) and emerging markets (EMG).Methods: Three systematic literature reviews were conducted in MEDLINE and Embase to capture all relevant publications reporting 1) the epidemiology of T2D and complications in T2D and 2) the economic burden of T2D and associated complications.Results: In total, 294 studies were included in this analysis. Evidence indicates a high and increasing overall prevalence of T2D globally, ranging up to 23% in EMG markets and 14% in EST markets. Undiagnosed cases were higher in EMG versus EST markets (up to 67% vs 38%), potentially due to a lack of education and disease awareness in certain regions, that could lead to important clinical and economic consequences. Poor glycemic control was associated with the development of several complications (e.g. retinopathy, cardiovascular diseases and nephropathy) that increase the risk of morbidity and mortality. Direct costs were up to 9-fold higher in patients with vs without T2D-related complications.Conclusions: The burden of T2D, related complications and inherent costs are higher in emerging versus established market countries. This review explores potential strategies to reduce costs and enhance outcomes of T2D treatment in developing countries.

Comparison of International Classification of Diseases and Related Health Problems, Tenth Revision Codes With Electronic Medical Records Among Patients With Symptoms of Coronavirus Disease 2019.

Importance: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes are used to characterize coronavirus disease 2019 (COVID-19)-related symptoms. Their accuracy is unknown, which could affect downstream analyses. Objective: To compare the performance of fever-, cough-, and dyspnea-specific ICD-10 codes with medical record review among patients tested for COVID-19. Design, Setting, and Participants: This cohort study included patients who underwent quantitative reverse transcriptase-polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 at University of Utah Health from March 10 to April 6, 2020. Data analysis was performed in April 2020. Main Outcomes and Measures: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ICD-10 codes for fever (R50*), cough (R05*), and dyspnea (R06.0*) were compared with manual medical record review. Performance was calculated overall and stratified by COVID-19 test result, sex, age group (<50, 50-64, and >64 years), and inpatient status. Bootstrapping was used to generate 95% CIs, and Pearson χ2 tests were used to compare different subgroups. Results: Among 2201 patients tested for COVD-19, the mean (SD) age was 42 (17) years; 1201 (55%) were female, 1569 (71%) were White, and 282 (13%) were Hispanic or Latino. The prevalence of fever was 66% (1444 patients), that of cough was 88% (1930 patients), and that of dyspnea was 64% (1399 patients). For fever, the sensitivity of ICD-10 codes was 0.26 (95% CI, 0.24-0.29), specificity was 0.98 (95% CI, 0.96-0.99), PPV was 0.96 (95% CI, 0.93-0.97), and NPV was 0.41 (95% CI, 0.39-0.43). For cough, the sensitivity of ICD-10 codes was 0.44 (95% CI, 0.42-0.46), specificity was 0.88 (95% CI, 0.84-0.92), PPV was 0.96 (95% CI, 0.95-0.97), and NPV was 0.18 (95% CI, 0.16-0.20). For dyspnea, the sensitivity of ICD-10 codes was 0.24 (95% CI, 0.22-0.26), specificity was 0.97 (95% CI, 0.96-0.98), PPV was 0.93 (95% CI, 0.90-0.96), and NPV was 0.42 (95% CI, 0.40-0.44). ICD-10 code performance was better for inpatients than for outpatients for fever (χ2 = 41.30; P < .001) and dyspnea (χ2 = 14.25; P = .003) but not for cough (χ2 = 5.13; P = .16). Conclusions and Relevance: These findings suggest that ICD-10 codes lack sensitivity and have poor NPV for symptoms associated with COVID-19. This inaccuracy has implications for any downstream data model, scientific discovery, or surveillance that relies on these codes.

A 3D Human Liver Model of Nonalcoholic Steatohepatitis.

Background and Aims: To better understand nonalcoholic steatohepatitis (NASH) disease progression and to evaluate drug targets and compound activity, we undertook the development of an in vitro 3D model to mimic liver architecture and the NASH environment. Methods: We have developed an in vitro preclinical 3D NASH model by coculturing primary human hepatocytes, human stellate cells, liver endothelial cells and Kupffer cells embedded in a hydrogel of rat collagen on a 96-well plate. A NASH-like environment was induced by addition of medium containing free fatty acids and tumor necrosis factor-α. This model was then characterized by biochemical, imaging and transcriptomics analyses. Results: We succeeded in defining suitable culture conditions to maintain the 3D coculture for up to 10 days in vitro, with the lowest level of steatosis and reproducible low level of inflammation and fibrosis. NASH disease was induced with a custom medium mimicking NASH features. The cell model exhibited the key NASH disease phenotypes of hepatocyte injury, steatosis, inflammation, and fibrosis. Hepatocyte injury was highlighted by a decrease of CYP3A4 expression and activity, without loss of viability up to day 10. Moreover, the model was able to stimulate a stable inflammatory and early fibrotic environment, with expression and secretion of several cytokines. A global gene expression analysis confirmed the NASH induction. Conclusions: This is a new in vitro model of NASH disease consisting of four human primary cell-types that exhibits most features of the disease. The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

Timing of Referral to Early Intervention Services in Infants With Severe Bronchopulmonary Dysplasia.

This study is a secondary analysis of an observational prospective case series of 50 infants with severe bronchopulmonary dysplasia that describes patient factors associated with the time between initial hospital discharge and referral to early intervention (EI) services. It also evaluates associations between (1) timing of EI referral and reception of EI services and (2) early referral to EI and developmental outcomes at 18 to 36 months corrected age. The results demonstrated that a referral from a neonatologist versus a pediatrician was associated with fewer days between discharge and EI referral. Earlier EI referrals were associated with a shorter time to intake evaluation and service initiation. The Bayley-III (Bayley Scales of Infant and Toddler Development, 3rd Edition) scores at 24 months corrected age (n = 28) were not associated with timing of EI referral. In conclusion, an early referral to EI promoted earlier evaluation and initiation of EI services and should be standard for high-risk infants.

Idiopathic Pulmonary Fibrosis: Prospective, Case-Controlled Study of Natural History and Circulating Biomarkers.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with 3 to 5 years' survival. Although FVC is used to assess disease progression and treatment response, identifying predictive circulating blood biomarkers could help identify specific biologic pathways for treatment. An international, prospective, noninterventional, case-controlled, 52-week study was therefore conducted to identify a clinical and biomarker baseline profile predictive of longitudinal disease behavior. METHODS: Patients with IPF and control subjects had lung function tests and blood sampling for biomarker quantification (control subjects at baseline only). The primary end point was disease progression rate (composite end point: decrease ≥ 10% from baseline in FVC % predicted, decrease ≥ 15% from baseline in diffusing capacity of the lung for carbon monoxide % predicted, lung transplantation, death) at week 52 and its relationship to selected biomarkers at baseline. RESULTS: Altogether, 211 subjects (154 patients with IPF and 57 control subjects) were enrolled; one-third of patients (n = 47) with IPF had progressed by week 52. Biomarkers CC-chemokine ligand 18 (CCL18), intercellular adhesion molecule 1, Krebs von den Lungen-6, surfactant protein (SP)-A, SP-D, matrix metallopeptidase 7, urokinase-type plasminogen activator receptor, and two novel biomarkers, human epididymis protein-4 (HE4) and prostasin, discriminated patients with IPF vs control subjects. There was no difference in baseline CCL18 concentration between progressors and nonprogressors at week 52 (area under the receiver operating characteristic curve, 0.62; corrected P = .161). No biomarkers were predictive for disease progression. CONCLUSIONS: Several biomarkers, including CCL18, were associated with IPF, but none predicted disease progression. Two novel biomarkers, HE4 and prostasin, were identified and warrant further investigation.

Adolescent total knee arthroplasty.

BACKGROUND: Management of adolescent patients with end-stage arthritis is challenging. Nonoperative treatments may be ineffective and total knee arthroplasty (TKA) is rarely performed. Currently, minimal long-term data are available on the outcomes in this patient population. Our goal was to describe TKA for patients with end-stage arthritis who were aged 20 years and younger. METHODS: The Joint Registry at our institution was used to identify 19 patients (29 TKAs) aged 20 years and younger that underwent a primary TKA. The average age was 18 years (range 14-20 years) and follow-up was 14.5 years (range: 2.1-25.5 years). RESULTS: The preoperative diagnoses were juvenile idiopathic arthritis (n = 19), avascular necrosis (n = 4), sepsis (n = 2), trauma (n = 2), dysplasia (n = 1), and hemophilia (n = 1). There was a decrease in the number of TKAs performed for inflammatory arthritis over the last several decades. Implant survivorship at 5 and 10 years was 96% and 94%, respectively. CONCLUSIONS: We identified a 95% 10-year implant survivorship utilizing standard TKA components in pediatric patients. Performing a TKA in adolescent patients has long-term potential risks including infection and bone loss but may provide pain relief and good long-term results and should be used with caution.

Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome.

BACKGROUND AND PURPOSE: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). METHODS: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. RESULTS: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). CONCLUSION: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.

The Impact of Neurofibromatosis Type 1 on the Health and Wellbeing of Australian Adults.

The complications of neurofibromatosis type 1 (NF1) are widespread, unpredictable and variable and each person's experience of this disorder is unique. However, few studies have addressed the impact of NF1 from an individual's perspective. This qualitative study aims to identify the ways in which NF1 impacts upon affected Australian adults. Sixty adults with NF1, with a range of disease severity and visibility participated in a semi-structured interview about the ways in which NF1 impacted upon their life and health. Data were analyzed using grounded theory methodology. Results indicated that NF1 impacts upon affected adults in five major ways: 1) cosmetic burden of disease 2) learning difficulties 3) concerns about the risk of passing NF1 to offspring 4) uncertain disease progression, and 5) pain. Participants identified the aspects of NF1 that bothered them the most, creating a hierarchy of NF1 concerns within the cohort. Importantly, mildly affected adults shared many of the same concerns as those more severely affected. This study enhances our current understanding of the impact of NF1 in adulthood, and augments existing recommendations for the care of these patients.

Child-led enquiry in primary science.

This research describes and evaluates the application of a child-led approach to scientific enquiry (the Community of Scientific Enquiry, CoSE) to children aged 8-11 (Key Stage 2) in Northern Ireland. Primary teachers were introduced to CoSE at a workshop and asked to evaluate its implementation with their class. Results from children (n = 364) and teachers (n = 19) found that CoSE engaged children with their science learning, and also developed confidence and oracy. However, teachers require more experience developing facilitation skills and in fitting science into a thematic teaching unit.

FISH comets show that the salvage enzyme TK1 contributes to gene-specific DNA repair.

Thymidine kinase 1 (TK1) is a salvage enzyme that phosphorylates thymidine, imported from surrounding fluids, to create dTMP, which is further phosphorylated to the DNA precursor dTTP. TK1 deficiency has for a long time been known to cause increased cellular sensitivity to DNA damage. We have examined preferential strand break repair of DNA domains in TK1(+) and TK1(-) clones of the Raji cell line, by the Comet-FISH technique, in bulk DNA and in the actively transcribed tumor suppressor (TP53) and human telomerase reverse transcriptase (hTERT) gene regions, over 1 h after 5Gy γ-irradiation. Results showed that repair of the TP53 and hTERT gene regions was more efficient in TK1(+) compared to TK1(-) cells, a trend also reflected to a lesser degree in genomic DNA repair between the cell-lines. The targeted gene-specific repair in TK(+) cells occurred rapidly, mainly over the first 15 min repair-period. Therefore, TK1 is needed for preferential repair of actively transcribed regions, through a previously unsuspected mechanism. In principle, TK1 could exert its protective effects through supply of a supplementary dTTP pool for accurate repair of damaged genes; but Raji TK1(+) cells in thymidine free media still show preferential repair of transcribed regions. TK1 therefore does not exert its protective effects through dTTP pools, but through another unidentified mechanism, which affects sensitivity to and mutagenicity by DNA damaging agents.