bluuebunny/crossref_metadata_2025 huggingface dataset:
Entangled Impacts of Large-Scale Monsoon Flows and Terrain Circulations on the Diurnal Cycle of Rainfall over the Himalayas
Authors: Zhang Aoqi , Chen Yilun , Pan Xiao , Chen Shumin , Li Weibiao , Fu Yunfei
Published: November 2021

The diurnal features of rainfall over the Himalayas have been widely investigated, but their triggers remain unclear. In this work, we divided the Himalayas and surroundings into four regions, including the plains, foothills, slopes, and plateau, and investigated the above issues. The results show that the rainfall total is controlled by large-scale monsoon flows while its meridional distribution is regulated by terrain circulations. The afternoon rainfall peak in the plains and foothills is linked with the intersection of two monsoon flows. The southward-shifting rainfall peak, which occurs from midnight to early morning in the slopes and foothills, is affected by the nighttime downslope flow and the strong Bay of Bengal monsoon flow in the morning. The evening rainfall peak in the plateau and high-altitude slopes is thought to be a result of the atmospheric layer being at its moistest at that time.

Significance Statement

During the South Asian summer monsoon season, the Himalayas are affected by two large-scale monsoon flows as well as unique topographic circulations. We want to understand how these complex circulations act on diurnal variations of orographic precipitation. The diurnal cycle of rainfall over the Himalayas and surroundings shows three prominent south-to-north peaks, which are caused by significantly different thermodynamic conditions. The southward-shifting diurnal rainfall peak over the Himalayan slopes and foothills, which contributes the most to the arc-shaped orographic rain belt, is triggered by the nighttime downslope flow and strengthened by the strong Bay of Bengal monsoon flow in the morning. The result highlights the entangled impact of monsoon and terrain circulations on orographic precipitation.
In-hand manipulation assessment instruments for children: A scoping review
Authors: Kruger Annelize , Strauss Monique , Visser Marieta
Published: November 2021

Aim

Accurate assessment of in-hand manipulation is imperative when treating children with fine motor delays. A clinically suitable instrument for in-hand manipulation is required to inform the paediatric developmental and rehabilitation context. Critical evaluation of the available instrument is required to make an informed decision and direct future research. The aim of the study was to assess the available literature with a view to writing a scoping review on in-hand manipulation assessment instruments for children.

Methods

The Arskey and O'Malley six-stage scoping review was applied. Fifteen databases were sourced for articles published between 1 January 1990 and 31 December 2020. After identifying 33 eligible articles that met the inclusion criteria, the data obtained from the articles were charted.

Results

Eleven in-hand manipulation assessment instruments were identified and summarised according to (i) the constructs of in-hand manipulation included; (ii) clinical utility aspects of applicability and practicality and (iii) psychometric properties.

Conclusion

At the time of the review, none of the instruments had comprehensively completed the instrument development process to the point of standardisation with evaluated psychometric properties. Further research is recommended for the development of a gold standard in-hand manipulation assessment instrument.
Cancer Warning Symptoms Awareness and Associated Factors Among Individuals Living in Assella Town, Ethiopia
Authors: Gizaw Admasu Belay , Gutema Helina Tadesse , Germossa Gugsa Nemera
Published: November 2021

Introduction

Community awareness about cancer warning symptoms and risk factors in the general population is essential and can be considered as a basis for cancer control programs. Since Patients are rarely aware of the early warning symptoms and cancer risk factors, the burden of disease is increasing everywhere in the world. Evidences has been shown that cancer is highly prevalent in Ethiopia in which the diagnosis is made at later stages of the disease.

Objective

To assess Cancer Warning Symptoms awareness and associated factors among individuals living in Assella Town, Ethiopia.

Methods

A community-based cross-sectional study was employed in Assella town from May 1st to June 1st, 2020 among 410 adult residents 18 years old and above. A systematic random sampling technique was employed to select the households from which the study subjects randomly identified. Data were collected through face-to-face interview by using pre-tested structured questionnaire and entered into Epi data version 3.1 then exported to SPSS version 25.0 for analysis. Logistic regression analyses were used to identify factors associated with outcome variables. Odds ratio and 95% CI at P-values <0.05 was used to determine the presence of association.

Results

The findings of this study revealed that the overall level of awareness of cancer warning symptoms is 214 (52.2% (AOR = 95% CI 47.1, 56.8)). Educational level (AOR = 3.44, 95%CI, 1.50–7.88 (p = 0.003)), awareness of cancer risk factors (AOR = 2.56, 95% CI, 1.67, 3.93, (p < 0.001)) and economic status (AOR = 3.13 (95% CI 1.84, 5.33, p < 0.001)) were identified as factors significantly associated with awareness of cancer warning symptoms among adult populations.

Conclusion

Almost one-out-of-two adults residing in Assella town has awareness about cancer warning symptoms. Educational level, awareness of cancer risk factors, and economic status among Assella town residents were identified as factors associated with good level of awareness about cancer warning symptoms.
Tumor‐Associated Macrophages in Vestibular Schwannoma and Relationship to Hearing
Authors: Nisenbaum Eric , Misztal Carly , Szczupak Mikhaylo , Thielhelm Torin , Peña Stefanie , Mei Christine , Goncalves Stefania , Bracho Olena , Ma Ruixuan , Ivan Michael E. , Morcos Jacques , Telischi Fred , Liu Xue‐Zhong , Fernandez‐Valle Cristina , Dinh Christine T.
Published: November 2021

Objective

(1) Characterize the distribution of M1 and M2 macrophages in vestibular schwannomas by hearing status. (2) Develop assays to assess monocyte migration and macrophage polarization in cocultures with vestibular schwannoma cells.

Study Design

Basic and translational science.

Setting

Tertiary care center.

Methods

A retrospective chart review of 30 patients with vestibular schwannoma (VS) was performed. Patients were stratified into serviceable and unserviceable hearing groups. Immunohistochemistry for CD80+ M1 and CD163+ M2 macrophages was conducted. Primary VS cultures (n = 4) were developed and cocultured with monocytes. Immunohistochemistry for macrophage markers was performed to assess monocyte migration and macrophage polarization.

Results

Although tumors associated with unserviceable hearing had higher levels of CD80 and CD163 than those with serviceable hearing, the relationship was only significant with CD163 (P =. 0161). However, CD163 level did not remain a significant predictor variable associated with unserviceable hearing on multivariate analysis when adjusted for other variables. In vitro assays show that VS cells induced monocyte migration and polarization toward CD80+ M1 or CD163+ M2 macrophage phenotypes, with qualitative differences in CD163+ macrophage morphologies between serviceable and unserviceable hearing groups.

Conclusion

Vestibular schwannomas express varying degrees of CD80+ M1 and CD163+ M2 macrophages. We present evidence that higher expression of CD163+ may contribute to poorer hearing outcomes in patients with VS. We also describe in vitro assays in a proof‐of‐concept investigation that VS cells can initiate monocyte migration and macrophage polarization. Future investigations are warranted to explore the relationships between tumor, macrophages, secreted cytokines, and hearing outcomes in patients with VS.
Nrf2 Plays a Key Role in Iron-Overload Cardiomyopathy
Authors: Federti Enrica , Vinchi Francesca , Iatcenko Iana , Ghigo Alessandra , Mattè Alessandro , Cedrick Serge , Siciliano Angela , Chiabrando Deborah , Tolosano Emanuela , Vance S. Zebulon , Riccardi Veronica , Andolfo Immacolata , Iolascon Achille , de Franceschi Lucia
Published: November 2021

Cardiomyopathy due to iron-overload is a severe complication of patients undergoing chronic transfusion regimen such as β-thalassemia and myelodysplastic syndromes. Previous studies have shown the key role of Nrf2, a redox-related transcriptional factor, in both β-thalassemia erythropoiesis and iron homeostasis (Matte A et al. ARS 2018, 2019; Lim PJ et al Nat Metab, 2019). Here, we compared Nrf2 knockout male mice (Nrf2 -/-) and C57BL-6J as wild-type (WT) controls, with a focus on cardiac function. Nrf2 -/- mice were characterized by a mild chronic hemolytic anemia associated with ineffective erythropoiesis, similar to what observed in murineβ-thalassemia (Toya SCM et al., Blood, 2019). Aging Nrf2 -/- mice developed systolic and diastolic dysfunction, associated with increased cardiac oxidative stress, degradation of the calcium-dependent SERCA2A transporter and activation of metalloproteinase MMP9, involved in both SERCA2A degradation and heart remodeling. In Nrf2 -/- mice, we observed increased plasma NTBI, heart iron deposition and elevated expression of cardiac ferroportin when compared to WT animals. Moreover, cardiac Hamp mRNA levels were down-regulated in aging Nrf2 -/- mice when compared to WT mice. This pattern was consistent with progressive cardiac iron overload in absence of Nrf2. Interestingly, activation of TGF-b receptor and PDGF-B-related pathway as well as increased collagen deposition were observed in hearts from 12 months old Nrf2 -/- mice. Taken together our data suggest an aging-associated development of iron-overload cardiomyopathy in mice genetically lacking Nrf2. To evaluate the role of Nrf2 in iron overload cardiomyopathy, Nrf2 -/- and WT mice were exposed to dietary iron supplementation (2.5% w/w carbonyl iron for 28 days). Nrf2 -/- mice developed cardiac hypertrophy which was accompanied by a worsening in collagen deposition and persistent activation of PDGF-B pathway. This was associated with inflammatory vasculopathy. The biologic importance of Nrf2 is supported by the cardiac activation of Nrf2, degradation of SERC2A and activation of TGF-b receptor and PDGF-B pathway in a mouse model of beta thalassemia intermedia, the Hbb3th/+ mice. Collectively our data support the crucial role of Nrf2 in the protection of cardiomyocytes against iron cytotoxicity which significantly develops in aging as well as in β-thalassemia.

Disclosures

Vinchi: Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vifor Pharma: Research Funding; PharmaNutra: Research Funding; Novartis: Research Funding. Ghigo: Kither Biotech: Other: Board member and Co-Founder. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board.
The Compass-COVID19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19
Authors: Van Dreden Patrick , Fraser Douglas D , Voiriot Guillaume , Rousseau Aurélie , Elalamy Ismail , Prassas Ioannis , Terpos Evangelos , Dimopoulos Meletios A. , Grusse Matthieu , Gerotziafas Grigoris
Published: November 2021

Background: In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation or death is un unmet need.

Objective: To derive a prognostic score for the risk of intubation or death in patients with critical COVID-19 by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes.

Methods: We conducted a prospective, observational monocentric study enrolling 118 patients with COVID-19 admitted in the intensive care unit. At the 1st day of ICU admission all patients were assessed for the following biomarkers : protein C, protein S, antithrombin, D-Dimer, fibrin monomers, factors VIIa, V, XII, XII, VIII, von Willebrand antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing tissue factor, IL-6, complement C3a, C5a, thrombin generation, prothrombin time, activated partial thromboplastin time, hemogram, platelet count) and clinical predictors. The clinical outcomes were intubation and mortality during hospitalization in ICU.

Results: The intubation and mortality rate were 70 % and 18% respectively. Multivariate analysis led to the derivation of the COMPASS- COVID19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization. The score predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively).

Conclusions and Relevance: Critical COVID-19 is related with severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID19-ICU score is an accurate predictive model for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The assessment with the COMPASS- COVID-19-ICU score is feasible in tertiary hospitals. In this context it could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

Disclosures

Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria.
Alternate-Day Dosing of Caplacizumab for Immune-Mediated Thrombotic Thrombocytopenic Purpura
Authors: Kühne Lucas , Eichenauer Dennis A. , Knöbl Paul , Völker Linus A. , Kaufeld Jessica , Wendt Ralph , Hägele Holger , Osterholt Thomas , Bieringer Marcus , Buxhofer-Ausch Veronika , Menne Jan , Schoenermarck Ulf , Brinkkoetter Paul
Published: November 2021

Background: The anti-VWF nanobody caplacizumab directly prevents the fatal microthrombi formation in immune-mediated thrombotic thrombocytopenic purpura, thereby adding a new therapeutic principle to the treatment of this autoimmune disorder. However, real-world treatment modalities beyond clinical trials remain heterogeneous.

Methods: Here, we describe the risks and benefits of an alternate-day dosing regimen for caplacizumab, by thoroughly analyzing the timing and outcome of this treatment approach in a retrospective cohort of 25 iTTP patients treated with caplacizumab in Austria and Germany between 2018 and 2021.

Results: Alternate-day dosing of caplacizumab appeared feasible and led to persisting normal platelet counts in the majority of patients, who were converted after a median time of 17 days daily treatment. Four patients experienced iTTP exacerbations or relapses that led to the resumption of daily caplacizumab application and/or other therapies. VWF activity was repeatedly measured in 17 out of 25 patients and documented sufficient suppression by caplacizumab after 24 and 48 hours, in line with published pharmacokinetics.

Conclusion: Extension of caplacizumab injection intervals from daily to alternate-day dosing may be safely considered in selected patients after 30 days of daily treatment. Earlier modifications may be considered in low-risk patients, but require close monitoring for clinical and laboratory features of thrombotic microangiopathy.

Disclosures

Völker: Sanofi-Genzyme: Honoraria, Other: counselling fees.
Genome-Wide CRISPR-Cas9 Screen Identifies Rationally Designed Combination Therapies Relevant for CRLF2-Rearranged Ph-like ALL
Authors: Sasaki Kensuke , Yamauchi Takuji , Semba Yuichiro , Nogami Jumpei , Imanaga Hiroshi , Terasaki Tatsuya , Nakao Fumihiko , Akahane Koshi , Inukai Takeshi , Verhoeyen Els , Akashi Koichi , Maeda Takahiro
Published: November 2021

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL, also known as BCR-ABL1-like ALL) is a disease entity of B-cell ALL that exhibits a gene expression profile, similar to that of Philadelphia chromosome-positive ALL. Ph-like ALL is categorized into two disease subtypes: "ABL-class"- and "CRLF2/JAK pathway"-types, both of which harbor gene alterations that constitutively activate cytokine/growth factor-related signals. Ph-like ALL with the CRLF2 rearrangement exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. Tyrosine kinase inhibitor (TKI)-based treatment regimens are effective in treating ABL-class type Ph-like ALL; however, no standard regimen has been established for the CRLF2/JAK pathway type. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. Thus, novel approaches are needed to treat CRLF2/JAK pathway type Ph-like ALL, in particular for CRLF2-rearranged (CRLF2-r) ALL.

To identify molecules/pathways relevant for CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines (MUTZ5 and KOPN49) that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which, for the first time, enabled highly efficient transduction of human B cell amenable for genome-wide CRSPR/Cas9 screens.

While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that the JAK-STAT axis is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL and FLT3 depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that reduces CRKL activity, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status.

Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

Disclosures

No relevant conflicts of interest to declare.
Conservative approach for the treatment of urethral prolapse in children: case report and literature review of 278 pediatric cases
Authors: Kacimi Salah Eddine Oussama , Aloulou Mohammad , Naoum Ranim , Moumeni Mohammed , Kaddour Abdallah , ElSheemy Mohammed Said
Published: November 2021

Background

Urethral prolapse (UP) is a rare, benign condition that often goes misdiagnosed and mistreated. It consists of the eversion of the distal urethral mucosa through the outer urethral meatus, leading to vascular obstruction and prolapsed tissue edema, which aggravates the prolapse. Although many review articles were reported on this condition, none of them focused on the conservative approach nor targeted the pediatric population. In this paper, we present successful medical management of UP in a 13-month-old Caucasian female and perform an extensive review of the literature to include articles that reported a conservative approach in patients under 18-years-old. We also suggested a practical algorithm for both diagnosis and management of this condition.

Case presentation

A 13-month-old Caucasian white female was presented with a urinary tract infection and vaginal bleeding. Genital examination showed a hyperemic donut-shaped mass covering the urinary meatus, of 0.7 cm diameter, with an actively bleeding open center. After confirming the diagnosis of UP with catheterization, a conservative approach was decided; antibiotics associated with topical corticosteroids including betamethasone 1% cream. The first-week outcome showed regression of the prolapsed tissue and the examination after four months showed normal vaginal mucosa with no evidence of relapse.

Conclusions

20 studies were retained after PubMed search with a total of 278 female patients aged between 1 month and 15 years old. The main reasons for referral were vaginal bleeding and mass, urinary symptoms followed by sexual abuse. Non-surgical treatment was tried for 162 patients. 53 of them were successfully managed, while 92 reported unsuccessful outcomes. The conservative approach was successful in 19% of all patients and raised to 32.7% in the portion of children selected for the initial conservative approach. Even though this review showed good results with medical treatment in children with UP, additional comparative studies are required to evaluate the effectiveness of conservative treatment in comparison with surgical interventions. In addition, Long-term follow-up is required as recurrence was reported up to 2 years following conservative treatment.
Benchmarking different approaches for Norovirus genome assembly in metagenome samples
Authors: Fuentes-Trillo Azahara , Monzó Carolina , Manzano Iris , Santiso-Bellón Cristina , Andrade Juliana da Silva Ribeiro de , Gozalbo-Rovira Roberto , García-García Ana-Bárbara , Rodríguez-Díaz Jesús , Chaves Felipe Javier
Published: November 2021

Background

Genome assembly of viruses with high mutation rates, such as Norovirus and other RNA viruses, or from metagenome samples, poses a challenge for the scientific community due to the coexistence of several viral quasispecies and strains. Furthermore, there is no standard method for obtaining whole-genome sequences in non-related patients. After polyA RNA isolation and sequencing in eight patients with acute gastroenteritis, we evaluated two de Bruijn graph assemblers (SPAdes and MEGAHIT), combined with four different and common pre-assembly strategies, and compared those yielding whole genome Norovirus contigs.

Results

Reference-genome guided strategies with both host and target virus did not present any advantages compared to the assembly of non-filtered data in the case of SPAdes, and in the case of MEGAHIT, only host genome filtering presented improvements. MEGAHIT performed better than SPAdes in most samples, reaching complete genome sequences in most of them for all the strategies employed. Read binning with CD-HIT improved assembly when paired with different analysis strategies, and more notably in the case of SPAdes.

Conclusions

Not all metagenome assemblies are equal and the choice in the workflow depends on the species studied and the prior steps to analysis. We may need different approaches even for samples treated equally due to the presence of high intra host variability. We tested and compared different workflows for the accurate assembly of Norovirus genomes and established their assembly capacities for this purpose.
Enzymatically-crosslinked gelatin hydrogels containing paenipeptin and clarithromycin against carbapenem-resistant pathogen in murine skin wound infection
Authors: Moon Sun Hee , Kaufmann Yihong , Fujiwara Ryoichi , Huang En
Published: November 2021

Background

The recent rise and spread of carbapenem-resistant pathogens pose an urgent threat to public health and has fueled the search for new therapies. Localized delivery of topical antibiotics is an alternative for the treatment of infected wounds caused by drug-resistant pathogens. In this study, we aimed to develop antimicrobial-loaded hydrogels for topical treatment of wound infections in a murine skin wound infection.

Results

Paenipeptin analogue 1, a linear lipopeptide, potentiated clarithromycin against multidrug-resistant Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, and Klebsiella pneumoniae. Enzymatically-crosslinked gelatin hydrogels were developed to encapsulate paenipeptin analogue 1 and clarithromycin. The encapsulated antimicrobials were gradually released from hydrogels during incubation, reaching 75.43 and 53.66% for paenipeptin and clarithromycin, respectively, at 24 h. The antimicrobial-loaded hydrogels containing paenipeptin and clarithromycin synergistically resulted in 5-log reduction in carbapenem-resistant A. baumannii within 6 h in vitro. Moreover, the antimicrobial-loaded hydrogels reduced 3.6- and 2.5-log of carbapenem-resistant A. baumannii when treated at 4 or 20 h post infection, respectively, in a murine skin wound infection.

Conclusions

Enzymatically-crosslinked gelatin hydrogels loaded with paenipeptin analogue 1 and clarithromycin exhibited potent therapeutic efficacy against carbapenem-resistant A. baumannii in murine skin wound infection.
Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats
Authors: Chu Zheng , Han Wei , Liu Peng , Liu Fei , Lei Gang , Deng Lisha , Yang Liu , Dang Yonghui
Published: November 2021

Background

Previous studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation.

Results

Data showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What’s more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats.

Conclusions

These results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.
Survival-associated N6-adenosine methyltransferase signatures in lung squamous cell carcinoma and clinical verification
Authors: Qu Jialin , Wang Li , Jiang Man , Wei Zhimin , Fu Guangming , Zhang Xiaochun
Published: November 2021

Background

N6-methyladenine (m6A) is the most common modification of mRNA and IncRNA in higher organisms. m6A has been confirmed to be related to the formation and progression of tumors and m6A-related genes can be used as prognostic biomarkers in a variety of tumors. However, there have been no similar studies on lung squamous cell carcinoma. The main purpose of this study was aimed to explore the differential expression of m6A-related genes in lung squamous cell carcinoma tissues and its relationship with patient clinical prognosis.

Methods

We integrated three m6A writers that catalyze the methylation of adenine on mRNA molecules. The training set including 501 patients with LUSC was collected from The Cancer Genome Atlas (TCGA) database and the test set including 181 patients with LUSC was collected from the Gene Expression Omnibus (GEO) database. Based on the expression level of the m6A methylase gene, we established a tumor subgroup and risk-prognosis model to quantify the risk index and long-term patient prognosis, which were confirmed by principal component analysis (PCA) and receiver operating characteristic (ROC) curve analysis. After lung squamous cell carcinoma tissue specimens were obtained during surgery, immunohistochemistry (IHC) was used to verify the results in vitro.

Results

The results of the study showed that the expression of the three m6A methylases in tumor tissues and normal tissues was significantly different (P < 0.05). The survival-prognostic model based on METTL3 gene expression showed better predictive performance (AUC: 0.706). Patients in the high-risk and low-risk groups exhibited significant differences in terms of survival time and 5-year and 10-year survival rates. Immunohistochemistry revealed that patients with high METTL3 expression exhibited a longer survival time than those with low METTL3 expression.

Conclusions

Our study showed that the molecular phenotype based on the expression of METTL3 may be an independent risk factor affecting the prognosis of lung squamous cell carcinoma. These findings not only prove the important role of m6A methylase in lung squamous cell carcinoma, but are also expected to provide more accurate prognostic assessment and individualized treatment for patients with lung squamous cell carcinoma.
Funding patterns for biomedical research and infectious diseases burden in Gabon
Authors: Adegnika Olouyomi Scherif , Honkpehedji Yabo Josiane , Mougeni Lotola Fabrice , Agnandji Selidji Todagbe , Adegnika Ayola Akim , Lell Bertrand , Sicuri Elisa
Published: November 2021

Background

Biomedical research plays an important role in improving health. There seems to exist a negative correlation between the amount of biomedical research funding and disease burden from all Sub-Saharan African countries. In this study, we describe funding patterns for biomedical research, explore the correlation between funding and burden of diseases, and quantify inequalities in funds distribution across diseases in Gabon over the period 2005–2015.

Methods

Data on medical research funds from 2005 to 2015 were retrieved through a structured questionnaire distributed to Gabonese biomedical research institutions and by consulting online databases. Data on the burden of diseases were gathered from the World Health Organization and the Institute for Health Metrics and Evaluation. We used Kendall rank correlation coefficient to explore the correlation between cumulative funds over time and the burden of disease. The inequality distribution of funding across diseases was assessed through Gini coefficient and Lorenz curve.

Results

Biomedical research funding was characterized by a remarkable growth from 2005 to 2010 and a decline from 2010 to 2014. Funds were mostly from external sources and from partnerships. There was inequality in research funds allocation across diseases and malaria was far the most funded disease. There was a significant negative correlation between cumulative funding and the burden of HIV, tuberculosis, and of Helminthiasis (from 2006 to 2010) suggesting that research may be contributing to the management of such diseases. A positive, although not significant, correlation was found between cumulative funds and malaria burden.

Conclusions

The negative correlation between HIV and tuberculosis cumulative funding and burden suggests that research may be contributing to the management of such diseases but further research is needed to assess the causal direction of such as relationship. As the burden of non-communicable diseases is increasing, more research funds should be focused on those. While research partnerships have been and will remain fundamental, Gabon should increase the amount of national funds to overcome periods of reduced research funding flows from abroad.
Particulate matter (PM10) prediction based on multiple linear regression: a case study in Chiang Rai Province, Thailand
Authors: Kliengchuay Wissanupong , Srimanus Rachodbun , Srimanus Wechapraan , Niampradit Sarima , Preecha Nopadol , Mingkhwan Rachaneekorn , Worakhunpiset Suwalee , Limpanont Yanin , Moonsri Kamontat , Tantrakarnapa Kraichat
Published: November 2021

Background

The northern regions of Thailand have been facing haze episodes and transboundary air pollution every year in which particulate matter, particularly PM10, accumulates in the air, detrimentally affecting human health. Chiang Rai province is one of the country’s most popular tourist destinations as well as an important economic hub. This study aims to develop and compare the best-fitted model for PM10prediction for different seasons using meteorological factors.

Method

The air pollution and weather data acquired from the Pollution Control Department (PCD) spanned from the years 2011 until 2018 at two stations on an hourly basis. Four different stepwise Multiple Linear Regression (MLR) models for predicting the PM10concentration were then developed, namely annual, summer, rainy, and winter seasons.

Results

The maximum daily PM10concentration was observed in the summer season for both stations. The minimum daily concentration was detected in the rainy season. The seasonal variation of PM10was significantly different for both stations. CO was moderately related to PM10in the summer season. The PM10summer model was the best MLR model to predict PM10during haze episodes. In both stations, it revealed an R2of 0.73 and 0.61 in stations 65 and 71, respectively. Relative humidity and atmospheric pressure display negative relationships, although temperature is positively correlated with PM10concentrations in summer and rainy seasons. Whereas pressure plays a positive relationship with PM10in the winter season.

Conclusions

In conclusion, the MLR models are effective at estimating PM10concentrations at the local level for each seasonal. The annual MLR model at both stations indicates a good prediction with an R2of 0.61 and 0.52 for stations 65 and 73, respectively.
Patient empowerment through a user-centered design of an electronic personal health record: a qualitative study of user requirements in chronic kidney disease
Authors: Toni Esmaeel , Pirnejad Habibollah , Makhdoomi Khadijeh , Mivefroshan Azam , Niazkhani Zahra
Published: November 2021

Background

To improve chronic disease outcomes, self-management is an effective strategy. An electronic personal health record (ePHR) is a promising tool with the potential to support chronic patient’s education, counseling, and self-management. Fitting ePHRs within the daily practices of chronic care providers and chronic patients requires user-centered design approaches. We aimed to understand users’ needs and requirements in chronic kidney disease (CKD) care to consider in the design of an ePHR to facilitate its implementation, adoption, and use.

Methods

A qualitative study was conducted in a major Iranian nephrology center including inpatient and outpatient settings in 2019. We conducted 28 semi-structured interviews with CKD patients, nurses, and adult nephrologists. To confirm or modify the requirements extracted from the interviews, a focus group was also held. Data were analyzed to extract especially those requirements that can facilitate implementation, adoption, and sustained use based on the PHR adoption model and the unified theory of acceptance and use of technology.

Results

Participants requested an ePHR that provides access to up to date patient information, facilitates patient-provider communication, and increases awareness about patient individualized conditions. Participants expected a system that is able to cater to low patient e-health literacy and high provider workload. They requested the ePHR to include purposeful documentation of medical history, diagnostic and therapeutic procedures, tailored educational content, and scheduled care reminders. Messaging function, tailored educational content to individual patients’ conditions, and controlled access to information were highly valued in order to facilitate its implementation, adoption, and use.

Conclusions

We focused on the ePHR’s content and functionalities in the face of facilitators and/or barriers envisioned for its adoption in nephrology care. Designers and implementers should value CKD patients’ needs and requirements for self-management such as providing personalized education and counseling (on the basis of their condition and risk factors), health literacy, and disease progression levels. The socio-technical aspects of care also need further attention to facilitate ePHR’s adoption.
Adherence to the Mediterranean diet assessed by a novel dietary biomarker score and mortality in older adults: the InCHIANTI cohort study
Authors: Hidalgo-Liberona Nicole , Meroño Tomás , Zamora-Ros Raul , Rabassa Montserrat , Semba Richard , Tanaka Toshiko , Bandinelli Stefania , Ferrucci Luigi , Andres-Lacueva Cristina , Cherubini Antonio
Published: November 2021

Background

Dietary biomarkers may complement dietary intake assessment made by dietary questionnaires. We developed an a-posteriori dietary biomarkers score based on Mediterranean diet food groups and evaluated its association with mortality.

Methods

642 participants (56% female), aged ≥65 years, with complete data on dietary biomarkers were followed during 20 years in the InCHIANTI cohort study (Tuscany, Italy). The main outcomes were all-cause, cardiovascular, and cancer mortality. Dietary biomarkers were selected from literature and from correlation analyses with dietary intakes of Mediterranean diet food groups in the study. The baseline levels of the following dietary biomarkers were chosen: urinary total polyphenols and resveratrol metabolites, and plasma carotenoids, selenium, vitamin B12, linolenic, eicosapentaenoic and docosahexaenoic acids, and the mono-unsaturated/saturated fatty acid ratio. Associations of the Mediterranean diet score using dietary biomarkers and a validated food frequency questionnaire (FFQ) (as tertiles) with mortality were assessed through Cox regression.

Results

During the 20-year follow-up [median (Q1–Q3), 14 (8–18) years], and 435 deaths occurred (139 from cardiovascular diseases and 89 from cancer-related causes). In the fully adjusted models, the dietary biomarker-Mediterranean diet score was inversely associated with all-cause (HRT3vs.T1 0.72; 95%CI 0.56–0.91) and cardiovascular (HRT3vs.T1 0.60; 95%CI 0.38–0.93), but not with cancer mortality. Associations between the FFQ-Mediterranean diet score and mortality were not statistically significant.

Conclusions

A greater adherence at baseline to a Mediterranean diet assessed by a dietary biomarker score was associated with a lower risk of mortality in older adults during a 20-year follow-up. The measurement of dietary biomarkers may contribute to guide individualized dietary counseling to older people.

Trial registration

NCT01331512
Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
Authors: van den Heuvel Guus R. M. , Kroeze Leonie I. , Ligtenberg Marjolijn J. L. , Grünberg Katrien , Jansen Erik A. M. , von Rhein Daniel , de Voer Richarda M. , van den Heuvel Michel M.
Published: November 2021

Background

Lung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. The development of predictive and prognostic biomarkers is of great importance. Mutational signatures harbor potential clinical value as predictors of therapy response in cancer. Here we set out to investigate particular mutational processes by assessing mutational signatures and associations with clinical features, tumor mutational burden (TMB) and targetable mutations.

Methods

In this retrospective study, we studied tumor DNA from patients with non-small cell lung cancer (NSCLC) irrespective of stage. The samples were sequenced using a 2 megabase (Mb) gene panel. On each sample TMB was determined and defined as the total number of single nucleotide mutations per Mb (mut/Mb) including non-synonymous mutations. Mutational signature profiling was performed on tumor samples in which at least 30 somatic single base substitutions (SBS) were detected.

Results

In total 195 samples were sequenced. Median total TMB was 10.3 mut/Mb (range 0–109.3). Mutational signatures were evaluated in 76 tumor samples (39%; median TMB 15.2 mut/Mb). SBS signature 4 (SBS4), associated with tobacco smoking, was prominently present in 25 of 76 samples (33%). SBS2 and/or SBS13, both associated with activity of the AID/APOBEC family of cytidine deaminases, were observed in 11 of 76 samples (14%). SBS4 was significantly more present in early stages (I and II) versus advanced stages (III and IV;P = .005).

Conclusion

In a large proportion of NSCLC patients tissue panel sequencing with a 2 Mb panel can be used to determine the mutational signatures. In general, mutational signature SBS4 was more often found in early versus advanced stages of NSCLC. Further studies are needed to determine the clinical utility of mutational signature analyses.
Identification and clinical validation of EMT-associated prognostic features based on hepatocellular carcinoma
Authors: Xu Dafeng , Wang Yu , Wu Jincai , Lin Shixun , Chen Yonghai , Zheng Jinfang
Published: November 2021

Background

The aim of this study was to construct a model based on the prognostic features associated with epithelial–mesenchymal transition (EMT) to explore the various mechanisms and therapeutic strategies available for the treatment of metastasis and invasion by hepatocellular carcinoma (HCC) cells.

Methods

EMT-associated genes were identified, and their molecular subtypes were determined by consistent clustering analysis. The differentially expressed genes (DEGs) among the molecular subtypes were ascertained using the limma package and they were subjected to functional enrichment analysis. The immune cell scores of the molecular subtypes were evaluated using ESTIMATE, MCPcounter, and GSCA packages of R. A multi-gene prognostic model was constructed using lasso regression, and the immunotherapeutic effects of the model were analyzed using the Imvigor210 cohort. In addition, immunohistochemical analysis was performed on a cohort of HCC tissue to validate gene expression.

Results

Based on the 59 EMT-associated genes identified, the 365—liver hepatocellular carcinoma (LIHC) samples were divided into two subtypes, C1 and C2. The C1 subtype mostly showed poor prognosis, had higher immune scores compared to the C2 subtype, and showed greater correlation with pathways of tumor progression. A four-gene signature construct was fabricated based on the 1130 DEGs among the subtypes. The construct was highly robust and showed stable predictive efficacy when validated using datasets from different platforms (HCCDB18 and GSE14520). Additionally, compared to currently existing models, our model demonstrated better performance. The results of the immunotherapy cohort showed that patients in the low-risk group have a better immune response, leading to a better patient’s prognosis. Immunohistochemical analysis revealed that the expression levels of the FTCD, PON1, and TMEM45A were significantly over-expressed in 41 normal samples compared to HCC samples, while that of the G6PD was significantly over-expressed in cancerous tissues.

Conclusions

The four-gene signature construct fabricated based on the EMT-associated genes provides valuable information to further study the pathogenesis and clinical management of HCC.
Anopheles drivers of persisting malaria transmission in Guna Yala, Panamá: an operational investigation
Authors: Ávila Mario I. , Vajda Élodie A. , Gutiérrez Eileen Jeffrey , Gibson Daragh A. , Renteria Mariela Mosquera , Presley Nicholas , O’Reilly Daniel , Burton Timothy A. , Tatarsky Allison , Lobo Neil F.
Published: November 2021

Background

Though most of Panamá is free from malaria, localized foci of transmission persist, including in the Guna Yala region. Government-led entomological surveillance using an entomological surveillance planning tool (ESPT) sought to answer programmatically-relevant questions that would enhance the understanding of both local entomological drivers of transmission and gaps in protection that result in persisting malaria transmission to guide local vector control decision-making.

Methods

The ESPT was used to design a sampling plan centered around the collection of minimum essential indicators to investigate the relevance of LLINs and IRS in the communities of Permé and Puerto Obaldía, Guna Yala, as well as to pinpoint any remaining spaces and times where humans are exposed to Anopheles bites (gaps in protection). Adult Anopheles were collected at three time points via human landing catches (HLCs), CDC Light Traps (LT), and pyrethrum spray catches (PSCs) during the rainy and dry seasons. Mosquitoes were identified to species via molecular methods. Insecticide susceptibility testing of the main vector species to fenitrothion was conducted.

Results

In total, 7537 adult Anopheles were collected from both sites. Of the 493 specimens molecularly confirmed to species, two thirds (n = 340) were identified as Nyssorhynchus albimanus, followed by Anopheles aquasalis. Overall Anopheles human biting rates (HBRs) were higher outdoors than indoors, and were higher in Permé than in Puerto Obaldía: nightly outdoor HBR ranged from 2.71 bites per person per night (bpn) (Puerto Obaldía), to 221.00 bpn (Permé), whereas indoor nightly HBR ranged from 0.70 bpn (Puerto Obaldía) to 81.90 bpn (Permé). Generally, peak biting occurred during the early evening. The CDC LT trap yields were significantly lower than that of HLCs and this collection method was dropped after the first collection. Pyrethrum spray catches resulted in only three indoor resting Anopheles collected. Insecticide resistance (IR) of Ny. albimanus to fenitrothion was confirmed, with only 65.5% mortality at the diagnostic time.

Conclusion

The early evening exophagic behaviour of Anopheles vectors, the absence of indoor resting behaviours, and the presence of resistance to the primary intervention insecticide demonstrate limitations of the current malaria strategy, including indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs), and point to both gaps in protection and to the drivers of persisting malaria transmission in Guna Yala. These findings highlight the need for continued and directed entomological surveillance, based on programmatic questions, that generates entomological evidence to inform an adaptive malaria elimination strategy.
Self-reported arm and shoulder problems in breast cancer survivors in Sub-Saharan Africa: the African Breast Cancer-Disparities in Outcomes cohort study
Authors: Boucheron Pauline , Anele Angelica , Zietsman Annelle , Galukande Moses , Parham Groesbeck , Pinder Leeya F. , Andersson Therese M.-L. , Anderson Benjamin O. , Foerster Milena , Schüz Joachim , dos Santos Silva Isabel , McCormack Valerie
Published: November 2021

Background

Arm and shoulder problems (ASP), including lymphedema, were common among women with breast cancer in high-income countries before sentinel lymph node biopsy became the standard of care. Although ASP impair quality of life, as they affect daily life activities, their frequency and determinants in Sub-Saharan Africa remain unclear.

Methods

All women newly diagnosed with breast cancer at the Namibian, Ugandan, Nigerian, and Zambian sites of the African Breast Cancer-Disparities in Outcomes (ABC-DO) cohort study were included. At each 3-month follow-up interview, women answered the EORTC-QLQ-Br23 questionnaire, including three ASP items: shoulder/arm pain, arm stiffness, and arm/hand swelling. We estimated the cumulative incidence of first self-reported ASP, overall and stratified by study and treatment status, with deaths treated as competing events. To identify determinants of ASP, we estimated cause-specific hazard ratios using Cox models stratified by study site.

Results

Among 1476 women, up to 4 years after diagnosis, 43% (95% CI 40–46), 36% (33–38) and 23% (20–25), respectively, self-reported having experienced arm/shoulder pain, stiffness and arm/hand swelling at least once. Although risks of self-reported ASP differed between sites, a more advanced breast cancer stage at diagnosis, having a lower socioeconomic position and receiving treatment increased the risk of reporting an ASP.

Conclusion

ASP are very common in breast cancer survivors in Sub-Saharan Africa. They are influenced by different factors than those observed in high-income countries. There is a need to raise awareness and improve management of ASP within the African setting.