Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver Failure.

BACKGROUND & AIMS: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. METHODS: Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. RESULTS: HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. CONCLUSIONS: Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.

Damage-associated cellular markers in the clinical and pathogenic profile of vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND: Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT. METHODS: Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. RESULTS: There were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT. CONCLUSION: The coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.

Detecting and Quantifying pADPr In Vivo.

Poly(ADP-ribose) polymerases (PARP) participate in diverse biological processes contributing to cellular homeostasis or exacerbating injury. PARP catalyzes the addition of ADP-ribose molecules (pADPr) to the target proteins, a process termed poly-ADP-ribosylation. Overactivation of PARP - reflected by increased poly-ADP-ribosylation and accumulation of pADPr-modified proteins or free pADPr - contributes to depletion of NAD+ and mitochondrial dysfunction, potentially leading to cell death. Thus, PARP overactivation and increases in free pADPr have been identified as key contributors to the pathobiology of many diseases. In stark contrast, PARP inhibitors are in clinical use in cancer patients where they potentiate cell death induced by chemotherapeutic agents. Accordingly, monitoring PARP-1 activation - responsible for up to 80-90% of cellular pADPr synthesis - by detecting and quantifying pADPr may provide valuable mechanistic insights as well as facilitating therapeutic drug monitoring for PARP inhibitors.Several non-isotopic immunodetection methods for quantifying pADPr are discussed: Western blotting of poly-ADP-ribosylated proteins, cellular localization of pADPr by immunohistochemistry, quantification of pADPr by enzyme-linked immunoassay, and small-scale two-dimensional gel electrophoresis.

Ethnic Differences in the Effects of Five Disciplinary Techniques on Subsequent Externalizing Behavior Problems.

To identify disciplinary alternatives to replace spanking, this study investigated ethnic differences in the associations of five disciplinary techniques with subsequent externalizing behavior problems in a national sample of 7- to 11-year-olds with ANCOVAs and difference-score analyses. Most techniques led to significant reductions in externalizing problems for African-Americans or Hispanics, but only after overcoming known biases in ANCOVA and not for other European-Americans. Privilege removal had the most significantly effective results, followed by grounding. Sending children to their room and spanking significantly reduced externalizing problems only in one or two analyses for African-Americans, whereas removing children's allowance was significantly effective in one overall analysis. Parenting research needs to distinguish between more vs. less effective use of all disciplinary techniques across multiple situational and cultural contexts.

Assessing for socioeconomic background diversity in behavioral health workforce development programs.

Assessing workforce diversity is an increasing area of evolution. A comprehensive assessment of socioeconomic diversity is important in that it can help identify needs and enable planned inclusion across a range of students. Subsequently, a more comprehensive set of background indicators is needed. The purpose of this brief report is to describe the approach we are using to determine socioeconomic background among individuals participating in a behavioral health workforce program. By using 3 strategies to assess background, we were able to determine that 4 individuals reported being unable to pay for housing, 3 indicated they had sold plasma, and 1 had experienced homelessness since starting graduate school. Our findings provide a starting point for using a comprehensive set of indicators to guide the recruitment and selection process in workforce development programs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Addressing the Challenge of COVID-19: One Health Care Site's Leadership Response to the Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic created an extremely disruptive challenge for health care leaders that required a rapid, dynamic, and innovative response. The purpose of this manuscript is to share the leadership actions and decisions at Mayo Clinic in Florida during the first 6 months of the pandemic (February to July 2020). We note 4 strategies that contributed to an effective response: (1) leverage experience with disaster preparedness and mobilize regional and national networks; (2) use surge models to anticipate and to address supply chain issues as well as practical and financial effects of the pandemic; (3) adapt creatively to establish new safety and procedural protocols in various areas for various populations; and (4) communicate timely information effectively and be the common source of truth. Mayo Clinic in Florida was able to address the surges of patients with COVID-19, to provide ongoing tertiary care, and to restore function within the first 6 months with new, strengthened practices and protocols.

Implementation and evaluation of a Project ECHO telementoring program for the Namibian HIV workforce.

BACKGROUND: The Namibian Ministry of Health and Social Services (MoHSS) piloted the first HIV Project ECHO (Extension for Community Health Outcomes) in Africa at 10 clinical sites between 2015 and 2016. Goals of Project ECHO implementation included strengthening clinical capacity, improving professional satisfaction, and reducing isolation while addressing HIV service challenges during decentralization of antiretroviral therapy. METHODS: MoHSS conducted a mixed-methods evaluation to assess the pilot. Methods included pre/post program assessments of healthcare worker knowledge, self-efficacy, and professional satisfaction; assessment of continuing professional development (CPD) credit acquisition; and focus group discussions and in-depth interviews. Analysis compared the differences between pre/post scores descriptively. Qualitative transcripts were analyzed to extract themes and representative quotes. RESULTS: Knowledge of clinical HIV improved 17.8% overall (95% confidence interval 12.2-23.5%) and 22.3% (95% confidence interval 13.2-31.5%) for nurses. Professional satisfaction increased 30 percentage points. Most participants experienced reduced professional isolation (66%) and improved CPD credit access (57%). Qualitative findings reinforced quantitative results. Following the pilot, the Namibia MoHSS Project ECHO expanded to over 40 clinical sites by May 2019 serving more than 140 000 people living with HIV. CONCLUSIONS: Similar to other Project ECHO evaluation results in the United States of America, Namibia's Project ECHO led to the development of ongoing virtual communities of practice. The evaluation demonstrated the ability of the Namibia HIV Project ECHO to improve healthcare worker knowledge and satisfaction and decrease professional isolation.

Engaging Community Health Workers and Social Care Staff as Social First Responders during the COVID-19 Crisis.

In this public health practice vignette, we describe an ongoing community and system intervention to identify and address social determinants of health and related needs experienced by ChristianaCare patients and the greater community during the Coronavirus pandemic. This intervention, being conducted by the ChristianaCare Office of Health Equity, in partnership with ChristianaCare's embedded research institute, the Value Institute, and the Community Outreach and Education division of the Helen F. Graham Cancer Center and Research Institute, engages more than 25 community health workers, health Guides, Latinx health promoters and other social care staff as social first responders during the COVID-19 crisis. These experienced front-line social care staff screen patients and community members for social needs; make referrals to agencies and organizations for needed assistance (e.g., food, housing, financial assistance); assess people's understanding of COVID-19 and preventive measures; provide education about COVID-19; and, connect patients and community members to COVID-19 testing and any relevant clinical services. While this ongoing intervention is under evaluation, we share here some preliminary lessons-learned and discuss the critical role that social first responders can play in reducing the growing adverse social and health impacts of COVID-19 across the state of Delaware.

Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver.

The constitutive androstane receptor (CAR/Nr1i3) regulates detoxification of drugs and other xenobiotics by the liver. Binding of these compounds, activating ligands, causes CAR to translocate to the nucleus and stimulate genes of detoxification. However, CAR activation also changes metabolism and induces rapid liver growth. To explain this gene regulation, we characterized the genome-wide early binding of CAR; its binding partner, RXRα; and the acetylation that they induced on H4K5. CAR-linked genes showed either stimulation or inhibition and regulated lipid, carbohydrate, and energy metabolism, as well as detoxification. Stimulation of expression increased, but inhibition did not decrease, H4K5Ac. Transcriptional inhibition occurred when CAR bound with HNF4α, PPARα, or FXR on the same enhancers. Functional competition among these bound nuclear receptors normally coordinates transcriptional resources as metabolism shifts. However, binding of drug-activated CAR to the same enhancers adds a new competitor that constitutively alters the normal balance of metabolic gene regulation.

Protein Import into the Endosymbiotic Organelles of Apicomplexan Parasites.

: The organelles of endosymbiotic origin, plastids, and mitochondria, evolved through the serial acquisition of endosymbionts by a host cell. These events were accompanied by gene transfer from the symbionts to the host, resulting in most of the organellar proteins being encoded in the cell nuclear genome and trafficked into the organelle via a series of translocation complexes. Much of what is known about organelle protein translocation mechanisms is based on studies performed in common model organisms; e.g., yeast and humans or Arabidopsis. However, studies performed in divergent organisms are gradually accumulating. These studies provide insights into universally conserved traits, while discovering traits that are specific to organisms or clades. Apicomplexan parasites feature two organelles of endosymbiotic origin: a secondary plastid named the apicoplast and a mitochondrion. In the context of the diseases caused by apicomplexan parasites, the essential roles and divergent features of both organelles make them prime targets for drug discovery. This potential and the amenability of the apicomplexan Toxoplasma gondii to genetic manipulation motivated research about the mechanisms controlling both organelles' biogenesis. Here we provide an overview of what is known about apicomplexan organelle protein import. We focus on work done mainly in T. gondii and provide a comparison to model organisms.

Promoting Regulatory Reform: The African Health Profession Regulatory Collaborative (ARC) for Nursing and Midwifery Year 4 Evaluation.

As countries across sub-Saharan Africa work towards universal health coverage and HIV epidemic control, investments seek to bolster the quality and relevance of the health workforce. The African Health Profession Regulatory Collaborative (ARC) partnered with 17 countries across East, Central, and Southern Africa to ensure nurses and midwives were authorized and equipped to provide essential HIV services to pregnant women and children with HIV. Through ARC, nursing leadership teams representing each country identify a priority regulatory function and develop a proposal to strengthen that regulation over a 1-year period. Each year culminates with a summative congress meeting, involving all ARC countries, where teams present their projects and share lessons learned with their colleagues. During a recent ARC Summative Congress, a group survey was administered to 11 country teams that received ARC Year 4 grants to measure advancements in regulatory function using the five-stage Regulatory Function Framework, and a group questionnaire was administered to 16 country teams to measure improvements in national nursing capacity (February 2011-2016). In ARC Year 4, eight countries implemented continuing professional development projects, Botswana revised their scope of practice, Mozambique piloted a licensing examination to assess HIV-related competencies, and South Africa developed accreditation standards for HIV/tuberculosis specialty nurses. Countries reported improvements in national nursing leaders' teamwork, collaborations with national organizations, regional networking with nursing leaders, and the ability to garner additional resources. ARC provides an effective, collaborative model to rapidly strengthen national regulatory frameworks, which other health professional cadres or regions may consider using to ensure a relevant health workforce, authorized and equipped to meet the emerging demand for health services.

Regulatory Advances in 11 Sub-Saharan Countries in Year 3 of the African Health Profession Regulatory Collaborative for Nurses and Midwives (ARC).

Sub-Saharan Africa carries the greatest burden of the HIV pandemic. Enhancing the supply and use of human resources through policy and regulatory reform is a key action needed to improve the quality of HIV services in this region. In year 3 of the African Health Profession Regulatory Collaborative for Nurses and Midwives (ARC), a President's Emergency Plan for AIDS Relief initiative, 11 country teams of nursing and midwifery leaders ("Quads") received small grants to carry out regulatory improvement projects. Four countries advanced a full stage on the Regulatory Function Framework (RFF), a staged capability maturity model used to evaluate progress in key regulatory functions. While the remaining countries did not advance a full stage on the RFF, important gains were noted. The year-3 evaluation highlighted limitations of the ARC evaluation strategy to capture nuanced progress and provided insight into how the RFF might be adapted for future use.

Oral narratives in monolingual and bilingual preschoolers with SLI.

BACKGROUND: The body of literature on narratives of bilingual children with and without specific language impairment (SLI) is growing. However, little is known about the narrative abilities of bilingual preschool children with SLI and their patterns of growth. AIMS: To determine the similarities and differences in narrative abilities between preschoolers with and without SLI who are either monolingual or bilingual at two time points. METHODS & PROCEDURES: Forty children completed a narrative retell task in English at two test points. The mean ages were 52 and 58 months at Times 1 and 2, respectively. We examined performance on measures of narrative macrostructure (narrative information) and microstructure (sentence length, number of different words, verb accuracy, first mentions) in monolingual and bilingual children with and without SLI. The bilingual children were from diverse first-language backgrounds and all spoke English most of the time. OUTCOMES & RESULTS: A series of repeated-measures analyses of variance was used with language ability (typical development or SLI) and bilingual status (monolingual versus bilingual) as the between-subjects factors and time (Times 1 or 2) as the within-subjects factor. Results indicated a significant main effect of time for four measures (i.e., Information Score, lexical diversity, sentence length and verb accuracy). The between-subjects analyses indicated a significant difference between the typically developing children and the children with SLI in all measures and a significant difference between monolingual and bilingual children for verb accuracy only. CONCLUSIONS & IMPLICATIONS: This study showed that all four groups of children showed growth over a 6-month period and that bilingual children exposed predominantly to English in the home performed similarly to their monolingual peers in measures of narrative information, sentence length, number of different words and first mentions.

A survey of nurse-initiated and -managed antiretroviral therapy (NIMART) in practice, education, policy, and regulation in east, central, and southern Africa.

In sub-Saharan Africa, nurses and midwives perform many HIV service delivery tasks, such as diagnosis of HIV and prescription of antiretroviral therapy (ART), which used to be the responsibility of physicians. While this task shifting is critical to scaling-up HIV services in Africa, the extent of HIV task shifting is not well understood. A survey of senior nursing leadership teams from 15 African countries was carried out to describe the extent of nurse-initiated and -managed antiretroviral therapy (NIMART) in practice, education, policy, and regulation. The survey took place at the African Health Professions Regulatory Collaborative meeting in Pretoria, South Africa, in June 2012. The findings indicated that NIMART is widely practiced and authorized in policy, but is not reinforced by regulation nor incorporated into preservice education. Further investment in policy, regulation, and pre-service education is needed to ensure sustainable, high quality ART service expansion through the region.

1,4-Dimethyl-piperazin-1-ium 3-hy-droxy-2-naphtho-ate.

The reaction of 1,4-dimethyl-piperazine and 3-hy-droxy-2-naphthoic acid gives the title 1:1 salt, C(6)H(15)N(2) (+)·C(11)H(7)O(3) (-), with a singly protonated piperazinium cation. In the crystal, a single N-H⋯O hydrogen bond links the cations and anions into discrete pairs and the aromatic anions stack along the crystallographic a-axis direction. This results in layers of cations and anions alternating along the crystallographic c-axis direction. An intra-molecular O-H⋯O hydrogen bond is also present.

Narrative abilities in monolingual and dual language learning children with specific language impairment.

PURPOSE: The aim of this study was to compare narrative abilities in children with specific language impairment (SLI) who are monolingual and those who are dual language learners. METHOD: The participants were 26 children with SLI, 14 monolingual English speakers and 12 dual language learners. The dual language learners were English dominant and spoke a variety of other languages in the home. The two SLI groups were compared using standardized tests and measures from two narrative samples. RESULTS: Compared to the monolingual children, the dual language learners achieved lower scores on standardized tests of morphosyntax but not on measures of language form derived from the narrative samples. Both groups achieved below average scores on productivity, narrative structure, literate language, and language form measures from the narrative samples. CONCLUSION: The data suggest that narrative samples can be a sensitive way to assess the language skills of dual language learners with specific language impairment. Furthermore, the findings are consistent with the position that English standardized tests may be a biased assessment measure when used with dual language learners, particularly for the assessment of expressive morphosyntactic skills. LEARNING OUTCOMES: Readers will be able to (1) describe the narrative abilities of typically developing dual language learners; (2) describe similarities between the narrative abilities of children with SLI who are monolingual and dual language learners; (3) identify ways to analyses narratives at a variety of levels.

The contribution of processing impairments to SLI: insights from attention-deficit/hyperactivity disorder.

UNLABELLED: Slowed speed of processing and impaired rapid temporal processing (RTP) have been proposed to underlie specific language impairment (SLI), but it is not clear that these dysfunctions are unique to SLI. We considered the contribution of attention-deficit/hyperactivity disorder (ADHD), which frequently co-occurs with language impairments, to performances on processing tasks. School-aged children who had SLI without concurrent ADHD (n=14), ADHD without concurrent SLI (n=14), and typical development (TD, n=28) performed two nonverbal speeded tasks and one auditory RTP task. RTP impairments were found in many children with SLI and ADHD, and some children with TD. Children with ADHD demonstrated slower processing speed than children with SLI or TD. Overall, findings questioned the uniqueness of these processing dysfunctions to language impairments and the validity of the behavioural paradigms traditionally used to estimate processing dysfunctions. Accounts of SLI should be further scrutinized by considering the influence of other disorders. LEARNING OUTCOMES: Readers will (1) become familiar with areas of overlap between SLI and ADHD, (2) understand some of the confounds associated with behavioural measures of processing speed in children, and (3) recognize the value in testing models of language disorders by including participants with other types of disorders.

Twenty-year follow-up of children with and without speech-language impairments: family, educational, occupational, and quality of life outcomes.

PURPOSE: Parents, professionals, and policy makers need information on the long-term prognosis for children with communication disorders. Our primary purpose in this report was to help fill this gap by profiling the family, educational, occupational, and quality of life outcomes of young adults at 25 years of age (N = 244) from the Ottawa Language Study, a 20-year, prospective, longitudinal study of a community sample of individuals with (n = 112) and without (n = 132) a history of early speech and/or language impairments. A secondary purpose of this report was to use data from earlier phases of the study to predict important, real-life outcomes at age 25. METHOD: Participants were initially identified at age 5 and subsequently followed at 12, 19, and 25 years of age. Direct assessments were conducted at all 4 time periods in multiple domains (demographic, communicative, cognitive, academic, behavioral, and psychosocial). RESULTS: At age 25, young adults with a history of language impairments showed poorer outcomes in multiple objective domains (communication, cognitive/academic, educational attainment, and occupational status) than their peers without early communication impairments and those with early speech-only impairments. However, those with language impairments did not differ in subjective perceptions of their quality of life from those in the other 2 groups. Objective outcomes at age 25 were predicted differentially by various combinations of multiple, interrelated risk factors, including poor language and reading skills, low family socioeconomic status, low performance IQ, and child behavior problems. Subjective well-being, however, was primarily associated with strong social networks of family, friends, and others. CONCLUSION: This information on the natural history of communication disorders may be useful in answering parents' questions, anticipating challenges that children with language disorders might encounter, and planning services to address those issues.

The Met protooncogene is a transcriptional target of NF kappaB: implications for cell survival.

NF kappaB transcription factor regulates gene expression in response to extracellular stimuli such as TNF alpha. The genes regulated by NF kappaB encode for proteins which control cell growth and survival. Met is the tyrosine kinase receptor for hepatocyte growth factor, and it too promotes cell mitogenesis and survival. Previously, we showed that Met gene expression is regulated by TNF alpha. In this report, we identify and characterize a TNF alpha response element in the Met promoter. This element contains tandem C/EBP sites adjacent to an NF kappaB site. Binding of the NF kappaB p65 subunit and C/EBP beta to this element is induced by TNF alpha. To examine the interplay of NF kappaB and Met in vivo, we determined that Met mRNA and protein levels are reduced in the livers of p65-/- mice as compared to controls. In p65-/- mouse embryonic fibroblasts (MEFs), Met induction by TNF alpha is abrogated while Met's basal gene expression is reduced by half as compared to controls. When overexpressed in p65-/- MEFs, Met confers resistance to TNF-alpha-mediated cell death. Conversely, expression of dominant negative Met in wild-type MEFs renders them sensitive to cell death induced by TNF alpha. A similar response following TNF alpha challenge was observed in hepatocytic cells treated with siRNA to knockdown endogenous Met. Together, these results indicate that the Met gene is a direct target of NF kappaB and that Met participates in NF kappaB-mediated cell survival.