Evaluation of txt2MEDLINE and Development of Short Messaging Service–Optimized, Clinical Practice Guidelines in Botswana

Objective: Currently clinicians in sub-Saharan Africa have limited access to the Internet, whereas mobile phone access and use is extensive. The University of Pennsylvania in collaboration with the National Library of Medicine launched txt2MEDLINE, a short messaging service (SMS) query of PubMed/MEDLINE, and SMS-optimized clinical guidelines in Botswana. The objective of this project was to establish and evaluate the utility of these tools for clinicians in Botswana. Materials and Methods: A local server was established at the University of Botswana that allowed clinicians to send queries and receive results via local (in-country) SMS text messaging on any type of cellular phone. The queries sent via txt2MEDLINE were returned as abbreviated “the bottom line” summaries of abstracts. The 2007 Botswana Treatment Guide was converted into a format that can be queried by SMS. Various types of healthcare workers were recruited to use and evaluate these services. Results: Seventy-six healthcare workers attended training sessions for these services. In the preusage survey, most said they would use the services daily or weekly. During a 4-week trial period, use of these services dropped off dramatically. Participant feedback was collected and indicated that improvements in ease of use would increase the usage. Conclusions: This pilot project enables clinicians to query and receive PubMed abstract summaries and country-specific clinical guidelines using mobile phones. Feedback offers insight on how to improve this technology so that it can be adopted for long-term use. With further adjustments, these resources may provide an effective working model for other countries where limited Internet access impedes upon patient care

From Passion to Published

Have you been wondering how to get that picture book idea out of your head, onto the page, into an editor’s hands, and onto bookstore and library shelves? Join a diverse panel of picture book writers whose first books debuted in 2020 and 2021 as they talk about the ins and outs of writing, submitting, and publishing your first picture book with a traditional publisher. Whether you want to write fiction or nonfiction, write or illustrate–or both!–these book creators have tips and inspiration that will help you along your path to getting published

Can metal-tolerant endophytic biocontrol agents promote plant-growth under metal stress?

Five metal-tolerant endophytic isolates (Bipolaris sp. LF7, Diaporthe miriciae LF9, Trichoderma asperellum LF11, Phomopsis asparagi LF15, Saccharicola bicolor LF22), with known metal-tolerance attributes and biocontrol activities against Ganoderma boninense, were tested for growth-promoting activities independent of (in vitro) and associated with plants (height, weight, root mass and stem circumference) (in vivo). Results revealed that metal-tolerant endophytes did not significantly render benefit to host plants as plant growth was compromised by the presence of metals. Lower production of indole-acetic acid (0.74-21.77 μg mL-1), siderophores (8.82-90.26%), and deaminase activities of 1-aminocyclopropane carboxylic acid (3.00-69.2 μmol mg protein-1 hr-1) were observed

Inferring school district learning modalities during the COVID-19 pandemic with a hidden Markov model

In this study, learning modalities offered by public schools across the United States were investigated to track changes in the proportion of schools offering fully in-person, hybrid and fully remote learning over time. Learning modalities from 14,688 unique school districts from September 2020 to June 2021 were reported by Burbio, MCH Strategic Data, the American Enterprise Institute's Return to Learn Tracker and individual state dashboards. A model was needed to combine and deconflict these data to provide a more complete description of modalities nationwide. A hidden Markov model (HMM) was used to infer the most likely learning modality for each district on a weekly basis. This method yielded higher spatiotemporal coverage than any individual data source and higher agreement with three of the four data sources than any other single source. The model output revealed that the percentage of districts offering fully in-person learning rose from 40.3% in September 2020 to 54.7% in June of 2021 with increases across 45 states and in both urban and rural districts. This type of probabilistic model can serve as a tool for fusion of incomplete and contradictory data sources in support of public health surveillance and research efforts.Comment: 25 pages, 4 figure

TBK1 regulates regeneration of pancreatic β-cells

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells

Benefits and limitations of implementing Chronic Care Model (CCM) in primary care programs: a systematic review

Background: Chronic Care Model (CCM) has been developed to improve patients' health care by restructuring health systems in a multidimensional manner. This systematic review aims to summarize and analyse programs specifically designed and conducted for the fulfilment of multiple CCM components. We have focused on programs targeting diabetes mellitus, hypertension and cardiovascular disease. Method and results: This review was based on a comprehensive literature search of articles in the PubMed database that reported clinical outcomes. We included a total of 25 eligible articles. Evidence of improvement in medical outcomes and the compliance of patients with medical treatment were reported in 18 and 14 studies, respectively. Two studies demonstrated a reduction of the medical burden in terms of health service utilization, and another two studies reported the effectiveness of the programs in reducing the risk of heart failure and other cardiovascular diseases. However, CCMs were still restricted by limited academic robustness and social constraints when they were implemented in primary care. Higher professional recognition, tighter system collaborations and increased financial support may be necessary to overcome the limitations of, and barriers to CCM implementation. Conclusion: This review has identified the benefits of implementing CCM, and recommended suggestions for the future development of CCM

Netazepide inhibits expression of Pappalysin 2 in type-1 gastric neuroendocrine tumors

Background & Aims: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. Methods: We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGS GR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. Results: Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGS GR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGS GR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. Conclusions: In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide

Partial reconstitution of DNA large loop repair with purified proteins from Saccharomyces cerevisiae

Small looped mispairs are corrected by DNA mismatch repair. In addition, a distinct process called large loop repair (LLR) corrects heteroduplexes up to several hundred nucleotides in bacteria, yeast and human cells, and in cell-free extracts. Only some LLR protein components are known, however. Previous studies with neutralizing antibodies suggested a role for yeast DNA polymerase δ (Pol δ), RFC and PCNA in LLR repair synthesis. In the current study, biochemical fractionation studies identified FEN1 (Rad27) as another required LLR component. In the presence of purified FEN1, Pol δ, RFC and PCNA, repair occurred on heteroduplexes with loops ranging from 8 to 216 nt. Repair utilized a 5′ nick, with correction directed to the nicked strand, irrespective of which strand contained the loop. In contrast, repair of a G/T mismatch occurred at low levels, suggesting specificity of the reconstituted system for looped mispairs. The presence of RPA enhanced reactivity on some looped substrates, but RPA was not required for activity. Although additional LLR factors remain to be identified, the excision and resynthesis steps of LLR from a 5′ nick can be reconstituted in a purified system with FEN1 and Pol δ, together with PCNA and its loader RFC

Purification and Functional Characterization of SET8, a Nucleosomal Histone H4-Lysine 20-Specific Methyltransferase

AbstractBackground: Covalent modifications of histone N-terminal tails play fundamental roles in regulating chromatin structure and function. Extensive studies have established that acetylation of specific lysine residues in the histone tails plays an important role in transcriptional regulation. Besides acetylation, recent studies have revealed that histone methylation also has significant effects on heterochromatin formation and transcriptional regulation. Histone methylation occurs on specific arginine and lysine residues of histones H3 and H4. Thus far, only 2 residues on histone H4 are known to be methylated. While H4-arginine 3 (H4-R3) methylation is mediated by PRMT1, the enzyme(s) responsible for H4-lysine 20 (H4-K20) methylation is not known.Results: To gain insight into the function of H4-K20 methylation, we set out to identify the enzyme responsible for this modification. We purified and cloned a novel human SET domain-containing protein, named SET8, which specifically methylates H4 at K20. SET8 is a single subunit enzyme and prefers nucleosomal substrates. We find that H4-K20 methylation occurs in a wide range of higher eukaryotic organisms and that SET8 homologs exist in C. elegans and Drosophila. We demonstrate that the Drosophila SET8 homolog has the same substrate specificity as its human counterpart. Importantly, disruption of SET8 in Drosophila reduces levels of H4-K20 methylation in vivo and results in lethality. Although H4-K20 methylation does not correlate with gene activity, it appears to be regulated during the cell cycle.Conclusions: We identified and characterized an evolutionarily conserved nucleosomal H4-K20-specific methyltransferase and demonstrated its essential role in Drosophila development

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28