bluuebunny/crossref_metadata_2025_split huggingface dataset:
A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic
Authors: Klopper Marisa , Heupink Tim Hermanus , Hill-Cawthorne Grant , Streicher Elizabeth Maria , Dippenaar Anzaan , de Vos Margaretha , Abdallah Abdallah Musa , Limberis Jason , Merker Matthias , Burns Scott , Niemann Stefan , Dheda Keertan , Posey James , Pain Arnab , Warren Robin Mark 
Published: February 2020

Abstract
Background
Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations.

Methods
We conducted Illumina sequencing of 211 Beijing genotype M. tuberculosis isolates to facilitate the detection of genomic features that may promote acquisition of drug resistance and restore fitness in highly resistant atypical Beijing forms. Phylogenetic and comparative genomic analysis was done to determine changes that are unique to the resistant strains that also transmit well. Minimum inhibitory concentration (MIC) determination for streptomycin and bedaquiline was done for a limited number of isolates to demonstrate a difference in MIC between isolates with and without certain variants.

Results
Phylogenetic analysis confirmed that two clades of atypical Beijing strains have independently developed resistance to virtually all the potent drugs included in standard (pre-bedaquiline) drug-resistant TB treatment regimens. We show that undetected drug resistance in a progenitor strain was likely instrumental in this resistance acquisition. In this cohort, ethionamide (ethA A381P) resistance would be missed in first-line drug-susceptible isolates, and streptomycin (gidB L79S) resistance may be missed due to an MIC close to the critical concentration. Subsequent inadequate treatment historically led to amplification of resistance and facilitated spread of the strains. Bedaquiline resistance was found in a small number of isolates, despite lack of exposure to the drug. The highly resistant clades also carry inhA promoter mutations, which arose after ethA and katG mutations. In these isolates, inhA promoter mutations do not alter drug resistance, suggesting a possible alternative role.

Conclusion
The presence of the ethA mutation in otherwise susceptible isolates from ethionamide-naïve patients demonstrates that known exposure is not an adequate indicator of drug susceptibility. Similarly, it is demonstrated that bedaquiline resistance can occur without exposure to the drug. Inappropriate treatment regimens, due to missed resistance, leads to amplification of resistance, and transmission. We put these results into the context of current WHO treatment regimens, underscoring the risks of treatment without knowledge of the full drug resistance profile.
Physical integrity and survivorship of long-lasting insecticidal nets distributed to households of the same socio-cultural community in Benin, West Africa
Authors: Ahogni Idelphonse B. , Salako Albert S. , Akinro Bruno , Sovi Arthur , Gnanguenon Virgile , Azondekon Roseric , Dagnon Jean F. , Akogbeto Pamela , Tokponon Filémon , Akogbeto Martin C. 
Published: February 2020

Abstract
Background
Long-lasting insecticidal nets (LLINs) are designed to survive and sustain their physical barrier for 3 years in household conditions. However, studies have shown that most of these nets are usually torn or no longer present in the households in less than 3 years. This study was initiated in Benin to compare the survivorship and physical integrity of seven types of LLINs in a same socio-geographic area.

Methods
In August 2017, 1890 households were selected in 9 villages in the municipality of Zagnanado in central Benin. Each one of the selected households received one of the seven LLIN products: Aspirational®, DawaPlus® 2.0, OlysetNet®, PermaNet® 2.0, PermaNet® 3.0, Royal Sentry® and Yorkool®. Overall, 270 LLINs of each type were freely distributed in Zagnanado, at a rate of 30 LLINs per type per village. These bed nets have been monitored and evaluated every 6 months to identify the most resilient and preferred LLINs in the community. Net survivorship was assessed using the rate of net loss and physical condition.

Results
The survivorship of all types of LLIN was estimated at 92% (95% CI 90.33–92.96) after 6 months and 70% (95% CI 67.25–71.81) after a year of use. At 12 months, all bed nets monitored were below the NetCalc model threshold of 92.8% for an LLIN with a lifespan of 3 years. Only 1.73% of all types of LLIN had a visible loss of integrity after 6 months with a median proportionate hole index (PHI) estimated at zero. The percentage significantly increased after 12 months with 10.41% of damaged nets (all types of LLINs). The median PHI for each brand of net was 23, 196, 141, 23, 23, 121 and 72, respectively for Aspirational®, DawaPlus® 2.0, OlysetNet®, PermaNet® 2.0, PermaNet® 3.0, Royal Sentry® and Yorkool®. A significant difference was noted between the PHI at 6 and 12 months (p < 0.0001). After 12 months, the DawaPlus®2.0, OlysetNet® and Royal Sentry® suffered significantly more damage compared to the others (p < 0.001).

Conclusion
The results of this study showed that after a year of use, the survivorship of the 7 LLIN products in households was lower than expected. However, all the LLIN products successfully met WHO standards for physical integrity after 12 months of use. The monitoring continues. The next steps will help to identify the most sustainable LLINs.
Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization
Authors: Liu Wei , Rong Yuluo , Wang Jiaxing , Zhou Zheng , Ge Xuhui , Ji Chengyue , Jiang Dongdong , Gong Fangyi , Li Linwei , Chen Jian , Zhao Shujie , Kong Fanqi , Gu Changjiang , Fan Jin , Cai Weihua 
Published: February 2020

AbstractBackgroundSpinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism.MethodsElectron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms.ResultsOur results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain- and loss-of-function experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p.ConclusionHypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.
HIV treatment in Guinea-Bissau: room for improvement and time for new treatment options
Authors: Jespersen S. , Månsson F. , Lindman J. , Wejse C. , Medina C. , da Silva Z. J. , Te DdS , Medstrand P. , Esbjörnsson J. , Hønge B. L. 
Published: February 2020

AbstractDespite advances in the treatment quality of HIV throughout the world, several countries are still facing numerous obstacles in delivering HIV treatment at a sufficiently high quality, putting patients’ lives in jeopardy. The aim of this status article is to give an overview of HIV treatment outcomes in the West African country, Guinea-Bissau, and to assess how newer treatment strategies such as long-acting injectable drugs or an HIV cure may limit or stop the HIV epidemic in this politically unstable and low-resource setting. Several HIV cohorts in Guinea-Bissau have been established and are used as platforms for epidemiological, virological, immunological and clinical studies often with a special focus on HIV-2, which is prevalent in the country. The Bandim Health Project, a demographic surveillance site, has performed epidemiological HIV surveys since 1987 among an urban population in the capital Bissau. The Police cohort, an occupational cohort of police officers, has enabled analyses of persons seroconverting with estimated times of seroconversion among HIV-1 and HIV-2-infected individuals, allowing incidence measurements while the Bissau HIV Cohort and a newer Nationwide HIV Cohort have provided clinical data on large numbers of HIV-infected patients. The HIV cohorts in Guinea-Bissau are unique platforms for research and represent real life in many African countries. Poor adherence, lack of HIV viral load measurements, inadequate laboratory facilities, high rates of loss to follow-up, mortality, treatment failure and resistance development, are just some of the challenges faced putting the goal of “90–90–90″ for Guinea-Bissau well out of reach by 2020. Maintaining undetectable viral loads on treatment as a prerequisite of a cure strategy seems not possible at the moment. Thinking beyond one-pill-once-a-day, long-acting antiretroviral treatment options such as injectable drugs or implants may be a better treatment option in settings like Guinea-Bissau and may even pave the way for an HIV cure. If the delivery of antiretroviral treatment in sub-Saharan Africa in a sustainable way for the future should be improved by focusing on existing treatment options or through focusing on new treatment options remains to be determined.
LncRNA Gm12664–001 ameliorates nonalcoholic fatty liver through modulating miR-295-5p and CAV1 expression
Authors: Zhang Qiao , Wang Jiemei , Li Hongyin , Zhang Yuan , Chu Xia , Yang Jianjun , Li Ying 
Published: February 2020

Abstract
Background
Our study aims to investigate the mechanisms of lncRNA Gm12664–001 improved hepatic lipid accumulation-initiated NAFLD via regulating miR-295-5p and CAV1 in AML12 cells.

Methods
The animals were divided into normal control (NC) group and high fat diet (HFD) group (20 mice per group) for 8w. The steatotic liver was measured by hematoxylin eosin (HE) staining and kits. We performed systematical analyses on hepatic expression profiles of long noncoding RNAs (lncRNAs) and microRNAs in a high-fat diet (HFD)-induced steatotic animal model. The expression profile of targets was confirmed by bioinformatics analysis, luciferase assay, RT-PCR and western blot in AML12 cells.

Results
HFD treatment markedly observed hepatic fatty degeneration with primarily fat vacuoles, and increased TG level compared with control. According to microarray data, we found that transfection of Gm12664–001 siRNA (siRNA-118,306) obviously enhanced TG accumulation and repressed CAV1 in AML12 cells. Furthermore, the TG accumulation markedly increased by siRNA-mediated knockdown of CAV1 in AML12 cells. By bioinformatics prediction, AML12 cells were transfected of siRNA-118,306 obviously upregulated miR-295-5p. Transfection of miR-295-5p mimics significantly increased TG accumulation and obviously suppressed the target CAV1.

Conclusions
The results revealed that lncRNA Gm12664–001 attenuated hepatic lipid accumulation through negatively regulating miR-295-5p and enhancing CAV1 expression in AML12 cells.
A case-series of patients with musculoskeletal conditions in an underserved community in Moca, Dominican Republic
Authors: da Silva-Oolup Sophia , Nordin Margareta , Stern Paula , Outerbridge Geoff , Côté Pierre 
Published: February 2020

Abstract
Purpose
To describe characteristics and activity limitations of new patients with musculoskeletal conditions presenting to the World Spine Care (WSC) clinic located in the underserved community of Moca, Dominican Republic.

Methods
We conducted a prospective case series of consecutive adults between October 12 and December 5, 2015. A survey of valid and reliable measures including: Body pain diagram, Wong-Baker FACES® pain rating scale, Spine Functional Index (SFI), Lower Limb Functional Index (LLFI), Upper Limb Functional Index (ULFI) and the 12-item Short Form Health Survey (SF-12v2) was administered to collect socio-demographics, expectation of recovery, comorbidities, and self-reported health status data.

Results
Forty-two patients (23 females and 19 males) were included. The most common primary complaint was lower back pain (40.5%; 17/42) and 57% (24/42) of individuals reported pain that interfered with their ability to function and engage in daily activities. Half of the patients presented with two complaints. Complaints were similar between genders. Most patients (64%; 27/42) reported chronic pain (> 6 months) and 97% (41/42) reported believing that they would recover. Twenty-one percent (9/42) self-reported being diagnosed with depression and/or anxiety at some point in their life. In addition, most (57%; 24/42) individuals reported below average physical and mental health related quality of life.

Conclusions
This study is the first to describe characteristics of patients seeking care at the WSC clinic in Moca, Dominican Republic. Most patients attending the clinic suffer from persistent spine complaints that interfere with their ability to function and engage in daily activities. Nevertheless, the patients have positive expectations of recovery.
The role of CD68+ macrophage in classical Hodgkin lymphoma patients from Egypt
Authors: Mohamed Osama , El Bastawisy Ahmed , Allahlobi Nasr , Abdellateif Mona S. , Zekri Abdel Rahman N. , Shaarawy Sabry , Korany Zeinab , Mohanad Marwa , Bahnassy Abeer A. 
Published: February 2020

Abstract
Background
CD68+ tumor-associated macrophages (TAM) play an important role in the progression of classical Hodgkin lymphoma (cHL). We assessed the role of CD20 and CD68 + TAM in a cohort of cHL patients from Egypt and correlated the number of CD68 + cells with patients’ characteristics, response to treatment, overall and progression free survival rates (OS & PFS).

Methods
CD20 expression and CD68 + TAM numbers were assessed in representative tumor tissues obtained from 81 cHL patients using flowcytometry (FCM), immunohistochemistry (IHC), and Rt-PCR techniques.

Results
The expression levels of CD68 protein by IHC was high in 27 (33.3%), moderate in 15 (18.5%), low in 15 (18.5%), and negative in 24 (29.6%) patients (p = 0.13). CD68-mRNA expression was high in 43/81(53.1%), and low in 38(46.9%) patients (p = 0.6). The number of CD68 + TAM (by FCM) was low (< 20 cells) in 42/81 (51.9%), and high (≥20 cells) in 39/81 (48.1%) patients (p = 0.74). CD68 expression (by FCM, IHC& Rt-PCR) associated significantly with poor response to treatment, decreased CD20 expression, reduced OS and PFS rates (p < 0.001 for all). CD68 expression (by Rt-PCR only) associated significantly with advanced disease stage (p = 0.04). The age of the patients, high CD20 expression & high CD68+ macrophage number were independent prognostic factors for OS (p= 0.02, p = 0.008 & p = 0.009; respectively). However, the age of the patient, high CD20, and high CD68+ macrophage expression (by FCM&IHC) were independent prognostic factors for DFS (p. = 0.004, p. = 0.01, p. = 0.007 and p. = 0.01; respectively).

Conclusion
CD68 + TAM expression (by Rt-PCR, FCM and/or IHC) can identify patients with poor response to treatment and reduced survival rates (OS& PFS). Assessment of CD68 + positive macrophages by FCM is superior to other methods (Rt-PCR and IHC) as a prognostic factor for DFS and OS rates.
Exclusive breastfeeding cessation and associated factors among employed mothers in Dukem town, Central Ethiopia
Authors: Kebede Tolossa , Woldemichael Kifle , Jarso Habtemu , Bekele Bayu Begashaw 
Published: February 2020

Abstract
Background
Employed women tend to exclusively breastfeed less than non-employed women. Early returning to work has been major reason why employed women stop exclusive breastfeeding. The aim of this study was to investigate exclusive breastfeeding (EBF) cessation and associated factors among employed mothers in Dukem town, Central Ethiopia.

Methods
A cross-sectional study was conducted from February to March 2015 using total sample of 313 randomly selected permanently employed women. Information regarding participants’ work-related factors, health service and sociodemographic factors were collected by face to face interview using structured questionnaire. Data were checked for completeness, entered and analyzed by SPSS version 20. Binary logistic regression was done to identify factors associated with exclusive breastfeeding cessation. The strength of association was measured using odds ratio with 95% confidence intervals.

Results
Prevalence of exclusive breastfeeding cessation was 75.7% (95% CI 71.0, 80.5%). Having a short duration of maternity leave (AOR 9.3; 95% CI 3.8, 23), being a full time employee (AOR 3.5; 95% CI 1.7, 11), being private organization employee (AOR=2.1, 95% CI(1, 4.3)), lack of flexible work time (AOR 3.0; 95% CI 1.2, 7.5), not pumping breast milk (AOR 4.3; 95% CI 1.7, 11), lack of a lactation break (AOR 6.7; 95% CI 3,14.5) and work place far away from her child (AOR 3.1; 95% CI 3.1, 6.3), were significantly associated with cessation of EBF among employed mothers.

Conclusion
Prevalence of exclusive breastfeeding cessation was much higher than the international and national expectation. The concerned governmental bodies should consider improving the legislation of the 3 months postpartum maternity leave to reduce employed mother’s exclusive breastfeeding cessation.
Addressing low-value pharmacological prescribing in primary prevention of CVD through a structured evidence-based and theory-informed process for the design and testing of de-implementation strategies: the DE-imFAR study
Authors: Sanchez Alvaro , Pijoan Jose Ignacio , Pablo Susana , Mediavilla Marta , de Rozas Rita Sainz , Lekue Itxasne , Gonzalez-Larragan Susana , Lantaron Gaspar , Argote Jon , García-Álvarez Arturo , Latorre Pedro Maria , Helfrich Christian D. , Grandes Gonzalo 
Published: February 2020

Abstract
Background
De-implementation or abandonment of ineffective or low-value healthcare is becoming a priority research field globally due to the growing empirical evidence of the high prevalence of such care and its impact in terms of patient safety and social inefficiency. Little is known, however, about the factors, barriers, and facilitators involved or about interventions that are effective in promoting and accelerating the de-implementation of low-value healthcare. The De-imFAR study seeks to carry out a structured, evidence-based, and theory-informed process involving the main stakeholders (clinicians, managers, patients, and researchers) for the design, deployment, and assessment of de-implementation strategies for reducing low-value pharmacological prescribing.

Methods
A phase I formative study using a systematic and comprehensive framework based on theory and evidence for the design of implementation strategies—specifically, the Behavior Change Wheel (BCW)—will be conducted to design and model de-implementation strategies to favor reductions in low-value pharmacological prescribing of statins in primary prevention of cardiovascular disease (CVD) by main stakeholders (clinicians, managers, patients, and researchers) in a collegiate way. Subsequently, a phase II comparative hybrid trial will be conducted to assess the feasibility and potential effectiveness of at least one active de-implementation strategy to reduce low-value pharmacological prescribing of statins in primary prevention of CVD compared to the usual procedures for dissemination of clinical practice guidelines (“what-not-to-do” recommendations). A mixed-methods evaluation will be used: quantitative for the results of the implementation at the professional level (e.g., adoption, reach and implementation or execution of the recommended clinical practice); and qualitative to determine the feasibility and perceived impact of the de-implementation strategies from the clinicians’ perspective, and patients’ experiences related to the clinical care received.

Discussion
The DE-imFAR study aims to generate valid scientific knowledge about the design and development of de-implementation strategies using theory- and evidence-based methodologies suggested by implementation science. It will explore the effectiveness of these strategies and their acceptability among clinicians, policymakers, and patients. Its ultimate goal is to maximize the quality and efficiency of our health system by abandoning low-value pharmacological prescribing.

Trial registration
Clinicaltrials.gov identifier: NCT04022850. Registered 17 July 2019
Stereotactic body radiotherapy (SBRT) for adrenal metastases of oligometastatic or oligoprogressive tumor patients
Authors: König Laila , Häfner Matthias F. , Katayama Sonja , Koerber Stefan A. , Tonndorf-Martini Eric , Bernhardt Denise , von Nettelbladt Bastian , Weykamp Fabian , Hoegen Philipp , Klüter Sebastian , Susko Matthew S. , Debus Jürgen , Hörner-Rieber Juliane 
Published: February 2020

Abstract
Introduction
Local ablative treatment strategies are frequently offered to patients diagnosed with oligometastatic disease. Stereotactic body radiotherapy (SBRT), as ablative treatment option, is well established for lung and liver metastases, whereas for isolated adrenal gland metastases the level of evidence is scarce.

Material and methods
This single-institution analysis of oligometastatic or oligoprogressive disease was limited to patients who received SBRT to adrenal metastasis between 2012 and 2019. Patient, tumor, treatment characteristics, and dosimetric parameters were analyzed for evaluation of their effect on survival outcomes.

Results
During the period of review 28 patients received ablative SBRT to their adrenal gland metastases. Most common primary tumors were non-small cell lung cancers (46%) with most patients diagnosed with a single adrenal gland metastasis (61%), which occurred after a median time of 14 months. SBRT was delivered to a median biological effective dose at α/β of 10 (BED10) of 75 Gy (range: 58–151 Gy). Median gross tumor volume (GTV) and median planning target volume (PTV) were 42 and 111 mL, respectively. The homogeneity and conformity indices were 1.17 (range: 1.04–1.64) and 0.5 (range: 0.4.0.99), respectively, with the conformity index being affected by dose restrictions to organs at risk (OARs) in 50% of the patients. Overall response rate based on RECIST criteria was 86% (CR = 29%, PR = 57%) with 2-year local control (LC) of 84.8%, 2-year progression-free survival (PFS) of 26.3%, and 1-and 2-year overall survival (OS) of 46.6 and 32.0%, respectively. During follow up, only two local recurrences occurred. A trend for superior LC was seen if BED10 was ≥75Gy (p = 0.101) or if the PTV was < 100 ml (p = 0.072). SBRT was tolerated well with only mild toxicity.

Conclusion
SBRT for adrenal metastases resulted in promising LC with low toxicity. Treatment response appeared to be superior, if SBRT was applied with higher BED. As the close proximity of OARs often limits the application of sufficiently high doses, further dose escalations strategies and techniques should be investigated in future.