bluuebunny/crossref_metadata_2025 huggingface dataset:
Providing Support for Rural Special Educators During Nontraditional Instruction: One State’s Response
Authors: Ault Melinda Jones , Courtade Ginevra , Miracle Sally A. , Bruce Amanda E.
Published: October 2020

In the midst of the COVID-19 global pandemic, teachers were forced to quickly determine how to deliver a free appropriate public education to their students when in-person instruction was not possible. School districts and states have a variety of ways to provide supports to their teachers. One method for providing technical assistance, professional development, consultation, and mentoring to teachers is through the use of regional cooperatives. In this Practice in Action article, two educational cooperative consultants present their experiences in supporting their teachers in the face of the pandemic. Successful strategies the cooperatives developed for teachers included providing trainings in online formats, creating an organized list of resources appropriate for online teaching, and facilitating opportunities for teachers to work together to problem solve in the era of the novel COVID-19. Challenges for teachers providing instruction for their students when schools were closed to face-to-face instruction are discussed.
Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice
Authors: Raboso-Gallego Javier , Casado-García Ana , Jiang Xiaoyu , Isidro-Hernández Marta , Gentles Andrew J. , Zhao Shuchun , Natkunam Yaso , Blanco Oscar , Domínguez Verónica , Pintado Belén , Alonso-López Diego , De Las Rivas Javier , Vicente-Dueñas Carolina , Lossos Izidore S. , Sanchez-Garcia Isidro
Published: October 2020

Diffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell–specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.
A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner
Authors: Elsaid Ramy , Meunier Sylvain , Burlen-Defranoux Odile , Soares-da-Silva Francisca , Perchet Thibaut , Iturri Lorea , Freyer Laina , Vieira Paulo , Pereira Pablo , Golub Rachel , Bandeira Antonio , Perdiguero Elisa Gomez , Cumano Ana
Published: October 2020

During embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave, and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here, we show that the first wave of thymic progenitors comprises a unique population of bipotent T and innatel lymphoid cells (T/ILC), generating a lymphoid tissue inducer cells (LTi's), in addition to invariant Vγ5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and, more precisely, the LTi-associated transcripts were expressed in the first, but not in the second, wave of thymic progenitors. Depletion of early thymic progenitors in a temporally controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator–expressing medullary thymic epithelial cells (mTECs). We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid-associated transcripts in yolk sac (YS) erythromyeloid-restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system.
The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis
Authors: Nayak Manasa K. , Ghatge Madankumar , Flora Gagan D. , Dhanesha Nirav , Jain Manish , Markan Kathleen R. , Potthoff Matthew J. , Lentz Steven R. , Chauhan Anil K.
Published: October 2020

Very little is known about the role of metabolic regulatory mechanisms in platelet activation and thrombosis. Dimeric pyruvate kinase M2 (PKM2) is a crucial regulator of aerobic glycolysis that facilitates the production of lactate and metabolic reprogramming. Herein, we report that limiting PKM2 dimer formation, using the small molecule inhibitor ML265, negatively regulates lactate production and glucose uptake in human and murine stimulated platelets. Furthermore, limiting PKM2 dimer formation reduced agonist-induced platelet activation, aggregation, clot retraction, and thrombus formation under arterial shear stress in vitro in both human and murine platelets. Mechanistically, limiting PKM2 dimerization downregulated phosphatidylinositol 3-kinase (PI3K)-mediated protein kinase B or serine/threonine-specific protein kinase (Akt)/glycogen synthase kinase 3 (GSK3) signaling in human and murine platelets. To provide further evidence for the role of PKM2 in platelet function, we generated a megakaryocyte or platelet-specific PKM2−/− mutant strain (PKM2fl/flPF4Cre+). Platelet-specific PKM2-deficient mice exhibited impaired agonist-induced platelet activation, aggregation, clot retraction, and PI3K-mediated Akt/GSK3 signaling and were less susceptible to arterial thrombosis in FeCl3 injury–induced carotid- and laser injury–induced mesenteric artery thrombosis models, without altering hemostasis. Wild-type mice treated with ML265 were less susceptible to arterial thrombosis with unaltered tail bleeding times. These findings reveal a major role for PKM2 in coordinating multiple aspects of platelet function, from metabolism to cellular signaling to thrombosis, and implicate PKM2 as a potential target for antithrombotic therapeutic intervention.
Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study
Authors: Stein Eytan M. , DiNardo Courtney D. , Fathi Amir T. , Mims Alice S. , Pratz Keith W. , Savona Michael R. , Stein Anthony S. , Stone Richard M. , Winer Eric S. , Seet Christopher S. , Döhner Hartmut , Pollyea Daniel A. , McCloskey James K. , Odenike Olatoyosi , Löwenberg Bob , Ossenkoppele Gert J. , Patel Prapti A. , Roshal Mikhail , Frattini Mark G. , Lersch Frederik , Franovic Aleksandra , Nabhan Salah , Fan Bin , Choe Sung , Wang Hongfang , Wu Bin , Hua Lei , Almon Caroline , Cooper Michael , Kantarjian Hagop M. , Tallman Martin S.
Published: October 2020

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor’s known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
TNFR2 is required for RIP1-dependent cell death in human leukemia
Authors: Aguadé-Gorgorió Júlia , McComb Scott , Eckert Cornelia , Guinot Anna , Marovca Blerim , Mezzatesta Caterina , Jenni Silvia , Abduli Liridon , Schrappe Martin , Dobay Maria Pamela , Stanulla Martin , von Stackelberg Arend , Cario Gunnar , Bourquin Jean-Pierre , Bornhauser Beat C.
Published: October 2020

Despite major advances in the treatment of patients with acute lymphoblastic leukemia in the last decades, refractory and/or relapsed disease remains a clinical challenge, and relapsed leukemia patients have an exceedingly dismal prognosis. Dysregulation of apoptotic cell death pathways is a leading cause of drug resistance; thus, alternative cell death mechanisms, such as necroptosis, represent an appealing target for the treatment of high-risk malignancies. We and other investigators have shown that activation of receptor interacting protein kinase 1 (RIP1)–dependent apoptosis and necroptosis by second mitochondria derived activator of caspase mimetics (SMs) is an attractive antileukemic strategy not currently exploited by standard chemotherapy. However, the underlying molecular mechanisms that determine sensitivity to SMs have remained elusive. We show that tumor necrosis factor receptor 2 (TNFR2) messenger RNA expression correlates with sensitivity to SMs in primary human leukemia. Functional genetic experiments using clustered regularly interspaced short palindromic repeats/Cas9 demonstrate that TNFR2 and TNFR1, but not the ligand TNF-α, are essential for the response to SMs, revealing a ligand-independent interplay between TNFR1 and TNFR2 in the induction of RIP1-dependent cell death. Further potential TNFR ligands, such as lymphotoxins, were not required for SM sensitivity. Instead, TNFR2 promotes the formation of a RIP1/TNFR1-containing death signaling complex that induces RIP1 phosphorylation and RIP1-dependent apoptosis and necroptosis. Our data reveal an alternative paradigm for TNFR2 function in cell death signaling and provide a rationale to develop strategies for the identification of leukemias with vulnerability to RIP1-dependent cell death for tailored therapeutic interventions.
DNA methylation microarrays identify epigenetically regulated lipid related genes in obese patients with hypercholesterolemia
Authors: Płatek Teresa , Polus Anna , Góralska Joanna , Raźny Urszula , Gruca Anna , Kieć-Wilk Beata , Zabielski Piotr , Kapusta Maria , Słowińska-Solnica Krystyna , Solnica Bogdan , Malczewska-Malec Małgorzata , Dembińska-Kieć Aldona
Published: October 2020

Background

Epigenetics can contribute to lipid disorders in obesity. The DNA methylation pattern can be the cause or consequence of high blood lipids. The aim of the study was to investigate the DNA methylation profile in peripheral leukocytes associated with elevated LDL-cholesterol level in overweight and obese individuals.

Methods

To identify the differentially methylated genes, genome-wide DNA methylation microarray analysis was performed in leukocytes of obese individuals with high LDL-cholesterol (LDL-CH, ≥ 3.4 mmol/L) versus control obese individuals with LDL-CH, < 3.4 mmol/L. Biochemical tests such as serum glucose, total cholesterol, HDL cholesterol, triglycerides, insulin, leptin, adiponectin, FGF19, FGF21, GIP and total plasma fatty acids content have been determined. Oral glucose and lipid tolerance tests were also performed. Human DNA Methylation Microarray (from Agilent Technologies) containing 27,627 probes for CpG islands was used for screening of DNA methylation status in 10 selected samples. Unpaired t-test and Mann–Whitney U-test were used for biochemical and anthropometric parameters statistics. For microarrays analysis, fold of change was calculated comparing hypercholesterolemic vs control group. The q-value threshold was calculated using moderated Student’s t-test followed by Benjamini–Hochberg multiple test correction FDR.

Results

In this preliminary study we identified 190 lipid related CpG loci differentially methylated in hypercholesterolemic versus control individuals. Analysis of DNA methylation profiles revealed several loci engaged in plasma lipoprotein formation and metabolism, cholesterol efflux and reverse transport, triglycerides degradation and fatty acids transport and β-oxidation. Hypermethylation of CpG loci located in promoters of genes regulating cholesterol metabolism: PCSK9, LRP1, ABCG1, ANGPTL4, SREBF1 and NR1H2 in hypercholesterolemic patients has been found. Novel epigenetically regulated CpG sites include ABCG4, ANGPTL4, AP2A2, AP2M1, AP2S1, CLTC, FGF19, FGF1R, HDLBP, LIPA, LMF1, LRP5, LSR, NR1H2 and ZDHHC8 genes.

Conclusions

Our results indicate that obese individuals with hypercholesterolemia present specific DNA methylation profile in genes related to lipids transport and metabolism. Detailed knowledge of epigenetic regulation of genes, important for lipid disorders in obesity, underlies the possibility to influence target genes by changing diet and lifestyle, as DNA methylation is reversible and depends on environmental factors. These findings give rise for further studies on factors that targets methylation of revealed genes.
TRPM7 silencing attenuates Mg2+ influx in cardiac myoblasts, H9c2 cells
Authors: Tashiro Michiko , Konishi Masato , Kobayashi Ryo , Inoue Hana , Yokoyama Utako
Published: October 2020

TRPM7, a member of the melastatin subfamily of transient receptor potential channels, is suggested to be a potential candidate for a physiological Mg2+ channel. However, there is no direct evidence of Mg2+ permeation through endogenous TRPM7. To determine the physiological roles of TRPM7 in intracellular Mg2+ homeostasis, we measured the cytoplasmic free Mg2+ concentration ([Mg2+]i) in TRPM7-silenced H9c2 cells. [Mg2+]i was measured in a cluster of 8–10 cells using the fluorescent indicator, furaptra. TRPM7 silencing did not change [Mg2+]i in Ca2+-free Tyrode’s solution containing 1 mM Mg2+. Increasing the extracellular Mg2+ to 92.5 mM raised [Mg2+]i in control cells (1.56 ± 0.19 mM) at 30 min, while this effect was significantly attenuated in TRPM7-silenced cells (1.12 ± 0.07 mM). The Mg2+ efflux driven by Na+ gradient was unaffected by TRPM7 silencing. These results suggest that TRPM7 regulates the rate of Mg2+ influx in H9c2 cells, although cytoplasmic Mg2+ homeostasis at basal conditions is unaffected by TRPM7 silencing.
Masakari: visualization supported statistical analysis of genome segmentations
Authors: Zeckzer Dirk , Hausdorf Alrik , Hinzmann Nicole , Müller Lydia , Wiegreffe Daniel
Published: October 2020

Background

In epigenetics, the change of the combination of histone modifications at the same genomic location during cell differentiation is of great interest for understanding the function of these modifications and their combinations. Besides analyzing them locally for individual genomic locations or globally using correlations between different cells types, intermediate level analyses of these changes are of interest. More specifically, the different distributions of these combinations for different cell types, respectively, are compared to gain new insights.

Results and discussion

We propose a new tool called ‘Masakari’ that allows segmenting genomes based on lists of ranges having a certain property, e.g., peaks describing histone modifications. It provides a graphical user interface allowing to select all data sets and setting all parameters needed for the segmentation process. Moreover, the graphical user interface provides statistical graphics allowing to assess the quality and suitability of the segmentation and the selected data.

Conclusion

Masakari provides statistics based visualizations and thus fosters insights into the combination of histone modification marks on genome ranges, and the differences of the distribution of these combinations between different cell types.
Integration of anatomy ontology data with protein–protein interaction networks improves the candidate gene prediction accuracy for anatomical entities
Authors: Fernando Pasan C. , Mabee Paula M. , Zeng Erliang
Published: October 2020

Background

Identification of genes responsible for anatomical entities is a major requirement in many fields including developmental biology, medicine, and agriculture. Current wet lab techniques used for this purpose, such as gene knockout, are high in resource and time consumption. Protein–protein interaction (PPI) networks are frequently used to predict disease genes for humans and gene candidates for molecular functions, but they are rarely used to predict genes for anatomical entities. Moreover, PPI networks suffer from network quality issues, which can be a limitation for their usage in predicting candidate genes. Therefore, we developed an integrative framework to improve the candidate gene prediction accuracy for anatomical entities by combining existing experimental knowledge about gene-anatomical entity relationships with PPI networks using anatomy ontology annotations. We hypothesized that this integration improves the quality of the PPI networks by reducing the number of false positive and false negative interactions and is better optimized to predict candidate genes for anatomical entities. We used existing Uberon anatomical entity annotations for zebrafish and mouse genes to construct gene networks by calculating semantic similarity between the genes. These anatomy-based gene networks were semantic networks, as they were constructed based on the anatomy ontology annotations that were obtained from the experimental data in the literature. We integrated these anatomy-based gene networks with mouse and zebrafish PPI networks retrieved from the STRING database and compared the performance of their network-based candidate gene predictions.

Results

According to evaluations of candidate gene prediction performance tested under four different semantic similarity calculation methods (Lin, Resnik, Schlicker, and Wang), the integrated networks, which were semantically improved PPI networks, showed better performances by having higher area under the curve values for receiver operating characteristic and precision-recall curves than PPI networks for both zebrafish and mouse.

Conclusion

Integration of existing experimental knowledge about gene-anatomical entity relationships with PPI networks via anatomy ontology improved the candidate gene prediction accuracy and optimized them for predicting candidate genes for anatomical entities.
The algal selenoproteomes
Authors: Jiang Liang , Lu Yiqian , Zheng Lin , Li Gaopeng , Chen Lianchang , Zhang Maona , Ni Jiazuan , Liu Qiong , Zhang Yan
Published: October 2020

Background

Selenium is an essential trace element, and selenocysteine (Sec, U) is its predominant form in vivo. Proteins that contain Sec are selenoproteins, whose special structural features include not only the TGA codon encoding Sec but also the SECIS element in mRNA and the conservation of the Sec-flanking region. These unique features have led to the development of a series of bioinformatics methods to predict and research selenoprotein genes. There have been some studies and reports on the evolution and distribution of selenoprotein genes in prokaryotes and multicellular eukaryotes, but the systematic analysis of single-cell eukaryotes, especially algae, has been very limited.

Results

In this study, we predicted selenoprotein genes in 137 species of algae by using a program we previously developed. More than 1000 selenoprotein genes were obtained. A database website was built to record these algae selenoprotein genes (www.selenoprotein.com). These genes belong to 42 selenoprotein families, including three novel selenoprotein gene families.

Conclusions

This study reveals the primordial state of the eukaryotic selenoproteome. It is an important clue to explore the significance of selenium for primordial eukaryotes and to determine the complete evolutionary spectrum of selenoproteins in all life forms.
Interdisciplinary clinical debriefing in the emergency department: an observational study of learning topics and outcomes
Authors: Coggins Andrew , Santos Aaron De Los , Zaklama Ramez , Murphy Margaret
Published: October 2020

Background

Defined as a ‘guided reflective learning conversation’, ‘debriefing’ is most often undertaken in small groups following healthcare simulation training. Clinical debriefing (CD) following experiences in the working environment has the potential to enhance learning and improve performance.

Methods

Prior to the study, a literature review was completed resulting in a standardised approach to CD that was used for training faculty. A pilot study of CD (n = 10) was then performed to derive a list of discussion topics and optimise the faculty training. The resulting debriefing approach was based on the “S.T.O.P.” structure (Summarise the case; Things that went well; Opportunities for improvement; Points of action). A debriefing aid, with suggested scripting, was provided. A subsequent observational study assessed CD within 1-h of clinical events. ‘Significantly distressing’ or ‘violent’ events were excluded. Data was collected on participant characteristics, discussion topics, and team recommendations. Study forms were non-identifiable. Subsequent analysis was performed by two investigators using content analysis of the debriefing forms (n = 71). Discussion topics (learning points) were coded using a modified version of the Promoting Excellence and Reflective Learning in Simulation (PEARLS) framework. One month after completion of the study, ED management staff were surveyed for reports of “harm” as the result of CD.

Results

During the study period, 71 CDs were recorded with a total of 506 participants. Mean debriefing length was 10.93 min (SD 5.6). Mean attendance was 7.13 (SD 3.3) participants. CD topics discussed were divided into ‘plus’ (well-done) and ‘delta’ (need to improve) groupings. 232 plus domains were recorded of which 195 (84.1%) aligned with the PEARLS debriefing framework, suggesting simulation debriefing skills may be translatable to a clinical setting. Topics discussed outside the PEARLS framework included family issues, patient outcome and environmental factors. CD reports led to preventative interventions for equipment problems and to changes in existing protocols. There were no recorded incidents of participant harm resulting from CD.

Conclusions

Topics discussed in CD predominantly aligned to those commonly observed in simulation-based medical education. Collective recommendations from CD can be used as evidence for improving existing protocols and models of care.
Effects of kidney function, serum albumin and hemoglobin on dementia severity in the oldest old people with newly diagnosed Alzheimer’s disease in a residential aged care facility: a cross-sectional study
Authors: Wu Jia-Jyun , Weng Shuo-Chun , Liang Chih-Kuang , Lin Chu-Sheng , Lan Tsuo-Hung , Lin Shih-Yi , Lin Yu-Te
Published: October 2020

Background

Chronic kidney disease (CKD), low serum albumin, and anemia are known risk factors for cognitive decline in older people. We investigated the association between kidney function and cognitive impairment severity in oldest-old people with a diagnosis of Alzheimer’s disease (AD).

Methods

A cross-sectional study of patients aged 80 years and older was conducted at a veterans’ home in Taiwan between 2012 and 2016. Their estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Diseases (MDRD) equation. Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR).

Results

A total of 84 patients (age mean ± SD, 86.6 ± 3.9 years) had MMSE scores of 10.1 ± 6.7, and CDR scores of 1.6 ± 0.7. The average eGFR was 61.7 ± 21.5 mL/min/1.73m2. The mean hemoglobin concentration was 12.7 ± 1.7 g/dl, and the mean albumin concentration was 4.5 ± 4.8 g/dl. Multivariate regression analyses showed that scores of CDR were significantly correlated with eGFR after adjustment for potential confounders. The scores of MMSE were significantly correlated with serum albumin and hemoglobin after adjustment for potential confounders.

Conclusions

We found dementia severity was significantly associated with kidney function, serum albumin, and hemoglobin in the oldest-old with AD. We recommend that oldest-old people with a diagnosis of AD be evaluated to determine kidney function, as well as nutritional and hematological status. Further study is needed to establish whether prevention of CKD deterioration, and correction of malnutrition and anemia may help to slow cognitive decline in oldest-old people with dementia.
Impact of the implementation of new guidelines on the management of patients with HIV infection at an advanced HIV clinic in Kinshasa, Democratic Republic of Congo (DRC)
Authors: Mangana F. , Massaquoi L. D. , Moudachirou R. , Harrison R. , Kaluangila T. , Mucinya G. , Ntabugi N. , Van Cutsem G. , Burton R. , Isaakidis P.
Published: October 2020

Background

HIV continues to be the main determinant morbidity with high mortality rates in Sub-Saharan Africa, with a high number of patients being late presenters with advanced HIV. Clinical management of advanced HIV patients is thus complex and requires strict adherence to updated, empirical and simplified guidelines. The current study investigated the impact of the implementation of a new clinical guideline on the management of advanced HIV in Kinshasa, Democratic Republic of Congo (DRC).

Methods

A retrospective analysis of routine clinical data of advanced HIV patients was conducted for the periods; February 2016 to March 2017, before implementation of new guidelines, and November 2017 to July 2018, after the implementation of new guidelines. Eligible patients were patients with CD4 < 200 cell/μl and presenting with at least 1 of 4 opportunistic infections. Patient files were reviewed by a medical doctor and a committee of 3 other doctors for congruence. Statistical significance was set at 0.05%.

Results

Two hundred four and Two hundred thirty-one patients were eligible for inclusion before and after the implementation of new guidelines respectively. Sex and age distributions were similar for both periods, and median CD4 were 36 & 52 cell/μl, before and after the new guidelines implementation, respectively. 40.7% of patients had at least 1 missed/incorrect diagnosis before the new guidelines compared to 30% after new guidelines, p < 0.05. Clinical diagnosis for TB and toxoplasmosis were also much improved after the implementation of new guidelines. In addition, only 63% of patients had CD4 count test results before the new guidelines compared to 99% of patients after new guidelines. Death odds after the implementation of new guidelines were significantly lower than before new guidelines in a multivariate regression model that included patients CD4 count and 10 other covariates, p < 0.05.

Conclusions

Simplification and implementation of a new and improved HIV clinical guideline coupled with the installation of laboratory equipment and point of care tests potentially helped reduce incorrect diagnosis and improve clinical outcomes of patients with advanced HIV. Regulating authorities should consider developing simplified versions of guidelines followed by the provision of basic diagnostic equipment to health centers.
MS Spasticity: Take Control (STC) for ambulatory adults: protocol for a randomized controlled trial
Authors: Hugos Cinda L. , Cameron Michelle H.
Published: October 2020

Background

Spasticity affects 60–80% of people with multiple sclerosis (MS), impacting activity, participation and quality of life. We developed the group delivered spasticity self-management program, “MS Spasticity: Take Control” (STC), with DVDs for education and lower extremity stretching. STC is based on an international guideline and recommendations from systematic reviews and emphasizes the importance of stretching with specific stretching exercises. Our pilot trial (n = 38) compared STC followed by one month of home stretching practice to unguided use of the National MS Society (NMSS) brochure titled “Stretching for People with MS: An Illustrated Manual,” also followed by one month of home stretching practice. In this pilot trial, STC showed promising effects on the impact of spasticity (MS Spasticity Scale-88) and other self-report and physical performance measures. We will now carry out a fully-powered trial to evaluate the effect of STC compared to a comparably delivered control program on the impact and severity of spasticity in people with MS and self-reported lower extremity spasticity.

Methods

Two hundred-twenty ambulatory adults with MS self-reported spasticity interfering with daily activities will be randomized 1:1 to STC or control, using the same NMSS brochure used in the pilot study, with both programs delivered in groups with trained facilitators. Outcomes are the impact of spasticity with the MS Spasticity Scale-88, the severity of spasticity with the Numeric Rating Scale for Spasticity, other self-report questionnaires, and physical performance walking measures at baseline and one and 6 months after the interventions.

Discussion

Stretching is the cornerstone of spasticity management. Stretching takes time and energy every day. Unfortunately, beyond the logical expectation that regular stretching should help prevent muscle shortening and contractures in the presence of spasticity, there is very little data on the effects of stretching on spasticity in people with MS or any other condition. Our pilot trial of STC suggested that education and stretching help reduce the impact of spasticity. To definitively determine if this education and instructional program with daily stretching practice is effective, a fully powered trial with a comparable control intervention and facilitators who did not create STC is needed. Here we report the protocol for this trial.

Trial registration

NCT03166930 May 25, 2017.
Rationale and design of ePPOP-ID: a multicenter randomized controlled trial using an electronic-personalized program for obesity in pregnancy to improve delivery
Authors: Deruelle Philippe , Lelorain Sophie , Deghilage Sylvie , Couturier Emmanuelle , Guilbert Elodie , Berveiller Paul , Sénat Marie Victoire , Vayssière Christophe , Sentilhes Loïc , Perrotin Franck , Gallot Denis , Chauleur Céline , Sananes Nicolas , Roth Emmanuel , Luton Dominique , Caputo Marie , Lorio Elodie , Chatelet Carla , Couster Julien , Timbely Oumar , Doret-Dion Muriel , Duhamel Alain , Pigeyre Marie
Published: October 2020

Background

Pre-pregnancy obesity and excessive gestational weight gain (GWG) are established risk factors for adverse pregnancy, delivery and birth outcomes. Pregnancy is an ideal moment for nutritional interventions in order to establish healthier lifestyle behaviors in women at high risk of obstetric and neonatal complications.

Methods

Electronic-Personalized Program for Obesity during Pregnancy to Improve Delivery (ePPOP-ID) is an open multicenter randomized controlled trial which will assess the efficacy of an e-health web-based platform offering a personalized lifestyle program to obese pregnant women in order to reduce the rate of labor procedures and delivery interventions in comparison to standard care. A total of 860 eligible pregnant women will be recruited in 18 centers in France between 12 and 22 weeks of gestation, randomized into the intervention or the control arm and followed until 10 weeks of postpartum.

The intervention is based on nutrition, eating behavior, physical activity, motivation and well-being advices in which personalization is central, as well as the use of a mobile/tablet application. Inputs includes data from the medical record of participants (medical history, anthropometric data), from the web platform (questionnaires on dietary habits, eating behavior, physical activity and motivation in both groups), and adherence to the program (time of connection for the intervention group only). Data are collected at inclusion, 32 weeks, delivery and 10 weeks postpartum. As primary outcome, we will use a composite endpoint score of obstetrical interventions during labor and delivery, defined as caesarean section and instrumental delivery (forceps and vacuum extractor). Secondary outcomes will consist of data routinely collected as part of usual antenatal and perinatal care, such as GWG, hypertension, preeclampsia, as well as fetal and neonatal outcomes including premature birth, gestational age at birth, birth weight, macrosomia, Apgar score, arterial umbilical cord pH, neonatal traumatism, hyperbilirubinemia, respiratory distress syndrome, transfer in neonatal intensive care unit, and neonatal adiposity. Post-natal outcomes will be duration of breastfeeding, maternal weight retention and child weight at postnatal visit.

Discussion

The findings of the ePPOP-ID trial will help design e-health intervention program for obese women in pregnancy.

Trial registration

ClinicalTrials.govIdentifier:NCT02924636/ October 5th 2016.
Mitochondrial apurinic/apyrimidinic endonuclease 1 enhances mtDNA repair contributing to cell proliferation and mitochondrial integrity in early stages of hepatocellular carcinoma
Authors: Bazzani Veronica , Barchiesi Arianna , Radecka Dorota , Pravisani Riccardo , Guadagno Antonio , Di Loreto Carla , Baccarani Umberto , Vascotto Carlo
Published: October 2020

Background

Hepatocellular carcinoma (HCC) is the leading cause of primary liver cancers. Surveillance of individuals at specific risk of developing HCC, early diagnostic markers, and new therapeutic approaches are essential to obtain a reduction in disease-related mortality. Apurinic/apyrimidinic endonuclease 1 (APE1) expression levels and its cytoplasmic localization have been reported to correlate with a lower degree of differentiation and shorter survival rate. The aim of this study is to fully investigate, for the first time, the role of the mitochondrial form of APE1 in HCC.

Methods

As a study model, we analyzed samples from a cohort of patients diagnosed with HCC who underwent surgical resection. Mitochondrial APE1 content, expression levels of the mitochondrial import protein Mia40, and mtDNA damage of tumor tissue and distal non-tumor liver of each patient were analyzed. In parallel, we generated a stable HeLa clone for inducible silencing of endogenous APE1 and re-expression of the recombinant shRNA resistant mitochondrially targeted APE1 form (MTS-APE1). We evaluated mtDNA damage, cell growth, and mitochondrial respiration.

Results

APE1’s cytoplasmic positivity in Grades 1 and 2 HCC patients showed a significantly higher expression of mitochondrial APE1, which accounted for lower levels of mtDNA damage observed in the tumor tissue with respect to the distal area. In the contrast, the cytoplasmic positivity in Grade 3 was not associated with APE1’s mitochondrial accumulation even when accounting for the higher number of mtDNA lesions measured. Loss of APE1 expression negatively affected mitochondrial respiration, cell viability, and proliferation as well as levels of mtDNA damage. Remarkably, the phenotype was efficiently rescued in MTS-APE1 clone, where APE1 is present only within the mitochondrial matrix.

Conclusions

Our study confirms the prominent role of the mitochondrial form of APE1 in the early stages of HCC development and the relevance of the non-nuclear fraction of APE1 in the disease progression. We have also confirmed overexpression of Mia40 and the role of the MIA pathway in the APE1 import process. Based on our data, inhibition of the APE1 transport by blocking the MIA pathway could represent a new therapeutic approach for reducing mitochondrial metabolism by preventing the efficient repair of mtDNA.
Swept-source OCT findings in shaken baby syndrome: case report
Authors: Ksiaa Imen , Ghachem Mohamed , Besbes Habib , Khochtali Sana , Chouchane Slaheddine , Khairallah Moncef
Published: October 2020

Background

Our purpose was to document the swept source optical coherence tomography (SSOCT) findings in a patient with Shaken baby syndrome (SBS).

Case presentation

SSOCT was obtained without sedation in a six-month-old girl with bilateral multilayered retinal hemorrhages due to SBS. It documented vitreoretinal interface abnormalities, including internal limiting membrane (ILM) detachment with retinal traction, in association with other specific changes in the inner and outer retinal layers. Six weeks later, retinal hemorrhages had substantially resolved, and there was optic disc pallor. OCT showed ILM reattachment with release of retinal traction and the development of severe diffuse retinal atrophy involving the fovea.

Conclusions

SS OCT can provide useful information in SBS, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up.
Limbal stem cell deficiency secondary to systemic paclitaxel (Taxol) for breast cancer: a case report
Authors: Sekhon Amardeep , Wang Jeff Y. F. , Tan Johnson C. H. , Holland Simon P. , Yeung Sonia N.
Published: October 2020

Background

Paclitaxel (PTX) is an antineoplastic drug widely used in treatments for ovarian, breast, and small-cell lung cancer. Although ocular effects associated with PTX have been previously described, very few studies have specifically reported systemic PTX as a contributing factor for limbal stem cell deficiency (LSCD), which is characterized by the loss of stem cell and barrier function of the limbus leading to progressive pain and reduction in visual acuity. Described here is a unique case where a patient was diagnosed with LSCD secondary to PTX use for the treatment of breast cancer, at doses of PTX far lower than what is reported in current literature.

Case presentation

A 73-year-old woman with a previous diagnosis of breast cancer with liver metastasis presented with a complaint of increasing pain in the left eye more than the right, along with decreasing visual acuity in both eyes following 3 months of PTX therapy for recurrent liver metastases. Upon examination, best-corrected visual acuity was 20/100 in the right eye and counting fingers on the left. Peripheral neovascularization, stromal scarring, and features of limbal stem cell deficiency (LSCD) were noted on the right cornea. A central neurotrophic ulcer with thinning to 50% and 360 degrees of conjunctivalization were noted on the left. After the discontinuation PTX with doxorubicin as the substitute, there was no further progression of her LSCD, and stabilization of her ocular surface was achieved.

Conclusion

Although chemotherapy induced LSCD is a relatively rare adverse event, it is essential for clinicians starting new chemotherapy agents to consider the potential ocular toxicities that may result in their use. Ophthalmology review is recommended for patients after starting PTX therapy to assess for signs of LSCD, particularly in patients where drug toxicity can be aggravated due to impaired hepatic function.
Assessment of optometrists’ knowledge, skills and practice on cataract: a cross-sectional study from Kisumu County, Western Kenya
Authors: Muma Shadrack , Obonyo Stephen
Published: October 2020

Background

The quality of life can be impacted negatively by blindness arising from cataract. The total prevalence of blindness in Kenya is estimated at 0.7%, however cataract contributes almost half (43%) of the total blindness in Kenya. Optometrists are well placed to assess and refer cataract patients. However, little is known on optometrists’ skills, practice and knowledge. Therefore, this study was designed to assess optometrists’ knowledge, skill and practice on cataract in Kisumu, Kenya.

Methods

A cross-sectional study design was used. The study was conducted from June 2019 to August 219 using self-administered questionnaire. Basic socio-demographic characteristics were collected and participants’ knowledge, skills and practice on cataract were investigated. The primary outcome measure was the proportions of participants who identified the questions related to knowledge, skills and practice on cataract. Chi-square analysis was performed to assess the association between demographic characteristics of participants with practice, knowledge and skills.

Results

A total of 49 optometrists with a mean age of 30.4 years and mean duration of practice of 1–10 years were interviewed. Most optometrists had good knowledge on various aspects of cataract. For example (98%) had a good knowledge on the types of cataract. Almost three quarter (75.5%) of the optometrists reported that they could diagnose cataract correctly based on skills. However, half (57.1%) of the optometrists could not identify nuclear cataract. Being a self reported practice and not an observed practice, most optometrists (61.2%) reported that they did not screen patients aged 40 years and above for cataract. Almost half (52.6%) of the optometrists reported that they did a routine eye examination however, they could not justify the significance of examining the crystalline lens for patient above 40 years.

Conclusion

The study established that despite the good level of knowledge among optometrist on cataract, there exist a gap on skills and practice. The results of this study calls for more clinical based activities among optometrists. This will eases diagnosis of cataract and its management with an aim to reduce the burden in Kenya.
Association between increased neutrophil-to-lymphocyte ratio and postoperative delirium in elderly patients with total hip arthroplasty for hip fracture
Authors: He Rui , Wang Fei , Shen Huarui , Zeng Yong , LijuanZhang
Published: October 2020

Background

Delirium is a common complication in elderly patients with total hip arthroplasty (THA) for hip fracture. The mechanism of postoperative delirium (POD) is associated with the neuroinflammatory process. The aim of this study was to the incidence and perioperative risk factors of POD and investigate whether NLR could serve as a potential marker for POD in elderly patients with THA for hip fracture.

Methods

This was a multicenter prospective study, we included elderly patients with THA for hip fracture under general anesthesia. Receiver operating characteristic (ROC) curve was performed to identify the optimal cut point of NLR for POD. The relationship between NLR and POD was analyzed by multivariable analysis.

Results

Seven hundred eighty patients (mean age 73.33 ± 7.66) were eligible for inclusion in the study. 23.33% (182/780) of patients had POD. ROC curve analysis showed that the optimal cut point of NLR for POD was NLR ≥ 3.5. Compared with no POD, higher NLR, older age, diabetes, and higher neutrophil count were more likely in patients with POD(P < 0.05). Multivariate logistic regression analysis showed that NLR ≥ 3.50 [adjusted odds ratio(aOR), 3.93; confidence interval (CI), 2.47–6.25; P < 0.001)], older age (aOR, 1.04; 95%CI, 1.02–1.07; P = 0.001), diabetes (aOR, 1.58; 95% CI, 1.06–2.36; P = 0.025),higher neutrophil count (aOR, 1.25; 95%CI, 1.15–1.35; P < 0.001) were associated with increased risk of POD.

Conclusions

Older age, diabetes, higher neutrophil count, and NLR ≥ 3.5 were independent risk factors for POD, and NLR can be used as a potential marker for prediction of delirium in elderly patients with THA for hip fracture.
Consensus of potential modifiable prognostic factors for persistent pain after a first episode of nonspecific idiopathic, non-traumatic neck pain: results of nominal group and Delphi technique approach
Authors: Verwoerd Martine , Wittink Harriet , Maissan Francois , Smeets Rob
Published: October 2020

Background

Identify and establish consensus regarding potential prognostic factors for the development of chronic pain after a first episode of idiopathic, non-traumatic neck pain.

Design

This study used two consensus group methods: a modified Nominal Group (m-NGT) and a Delphi Technique.

Methods

The goal of the m-NGT was to obtain and categorize a list of potential modifiable prognostic factors. These factors were presented to a multidisciplinary panel in a two-round Delphi survey, which was conducted between November 2018 and January 2020. The participants were asked whether factors identified are of prognostic value, whether these factors are modifiable, and how to measure these factors in clinical practice. Consensus was a priori defined as 70% agreement among participants.

Results

Eighty-four factors were identified and grouped into seven categories during the expert meeting using the modified NGT. A workgroup reduced the list to 47 factors and grouped them into 12 categories. Of these factors, 26 were found to be potentially prognostic for chronification of neck pain (> 70% agreement). Twenty-one out of these 26 factors were found to be potentially modifiable by physiotherapists based on a two-round Delphi survey.

Conclusion

Based on an expert meeting (m-NGT) and a two-round Delphi survey, our study documents consensus (> 70%) on 26 prognostic factors. Twenty-one out of these 26 factors were found to be modifiable, and most factors were psychological in nature.