bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi
Authors: Borgstein Arabella , Zhang Bo , Lam Colin , Gushu Montfort Bernard , Liomba Alice Wangui , Malenga Albert , Pensulo Paul , Tebulo Andrew , Small Dylan S. , Taylor Terrie , Seydel Karl 
Published: February 2022

Abstract
Background
Cerebral malaria is still a major cause of death in children in sub-Saharan Africa. Among survivors, debilitating neurological sequelae can leave children with permanent cognitive impairments and societal stigma, resulting in taxing repercussions for their families. This study investigated the effect of delay in presentation to medical care on outcome in children with cerebral malaria in Malawi.

Methods
This retrospective study included participants enrolled in a longstanding study of cerebral malaria between 2001 and 2021 and considered coma duration prior to arrival at hospital (with or without anti-malarial treatment), HIV status, blood lactate levels at admission and age as factors that could affect clinical outcome. Outcomes were categorized as full recovery, sequelae at the time of discharge, or death. A multinomial regression was fit and run controlling for coma duration, HIV status, lactate levels and age, to determine the association between each explanatory variable and outcome.

Results
A total of 1663 children with cerebral malaria, aged 6 months to 14 years were included. Longer coma duration (in hours) was associated with greater odds of developing sequelae (OR = 1.023, 95% CI 1.007–1.039, p = 0.006) but not death (OR = 1.00, 95% CI 0.986–1.015, p = 0.961). Younger age (in months) was also correlated with higher rates of sequelae, (OR = 0.990, 95% CI 0.983–0.997, p = 0.004) but not with increased mortality (OR = 0.998, 95% CI 0.993–1.003, p = 0.335). Blood lactate levels on admission were correlated with mortality (OR = 1.125, 95% CI 1.090–1.161, p < 0.001) but not associated with increased rates of sequelae (OR = 1.016, 95% CI 0.973–1.060, p = 0.475). Positive HIV status and treatment with an anti-malarial (artemisinin or non-artemisinin-based) prior to arrival at the hospital were not significantly associated with either adverse outcome.

Conclusions
In Malawian children with cerebral malaria, higher rates of sequelae were significantly associated with extended coma duration prior to admission and younger age. Mortality rates were correlated with increased lactate levels on admission. The differential effects of variables on clinical outcomes suggest that there may be different pathogenic pathways leading to sequelae and death. Actions taken by parents and health care professionals are critical in defining when patients arrive at hospital and determining their ultimate outcome.
Clinical efficacy of different approaches for laparoscopic intersphincteric resection of low rectal cancer: a comparison study
Authors: Ou Wenquan , Wu Xiaohua , Zhuang Jinfu , Yang Yuanfeng , Zhang Yiyi , Liu Xing , Guan Guoxian 
Published: February 2022

Abstract
Background
The operative results of different approaches for the laparoscopic intersphincteric resection (LAISR) of low rectal cancer vary, and the patient characteristics associated with the best outcomes for each procedure have not been reported. We compared the efficacy of different approaches for LAISR of low rectal cancer and discussed the surgical indications for each approach.

Methods
We retrospectively reviewed data from 235 patients with low rectal cancer treated via LAISR from October 2010 to September 2016. Patients underwent either the transabdominal approach for ISR (TAISR, n = 142), the transabdominal perineal approach for ISR (TPAISR, n = 57), or the transanal pull-through approach for ISR (PAISR, n = 36).

Results
The PAISR and TAISR groups exhibited shorter operation times and less intraoperative blood loss than the TPAISR group. The anastomotic distance was shorter in the PAISR and TPAISR groups than in the TAISR group. No differences in the ability to perform radical resection, overall complications, postoperative recovery, Wexner score recorded 12 months after ostomy closure, 3-year disease-free survival, local recurrence-free survival, distant metastasis-free survival, or overall survival (OS) were observed among the three groups.

Conclusions
TAISR, TPAISR, and PAISR have unique advantages and do not differ in terms of operation safety, patient outcomes, or anal function. TPAISR requires a longer time to complete and is associated with more bleeding and a slower recovery of anal function. PAISR should be considered when TAISR cannot ensure a negative distal margin and the tumor and BMI are relatively small; otherwise, TPAISR is required.
Promotion of microRNA-146a by histone deacetylase 4 silencing contributes to radiosensitization of esophageal carcinoma
Authors: Lu Zhonghua , Yun Yifei , Zhang Yutong , Ou Yao , Wang Meihua 
Published: February 2022

Abstract
Background
Histone deacetylases (HDACs) have been identified to be implicated in the carcinogenesis and cancer progression. The present study was performed to probe into the effect of HDAC4 on radioresistance of esophageal carcinoma (EC).

Methods
The expression of HDAC4 in responders and non-responders to radiotherapy was characterized by RT-qPCR, immunohistochemistry, and Western blot analysis. EC cells were exposed to continuous fractionated X-ray irradiation, and their proliferation and apoptosis were evaluated by means of colony formation assay and flow cytometry based Annexin V-FITC/PI apoptosis assay in response to HDAC4 overexpression or silencing. Mechanistic investigation was conducted by means of in silico analysis and dual-luciferase reporter gene assay. Tumor xenografts derived from radioresistant EC cells were exposed to local X-ray irradiation in vivo for validation.

Results
High expression of HDAC4 was detected in either tumor tissues derived from radiotherapy responders or radioresistant EC cells. Loss of HDAC4 contributed to suppressed proliferation and enhanced apoptosis of radioresistant EC cells. Moreover, our findings revealed that HDAC4 conferred radioresistance of EC by downregulating microRNA-146a (miR-146a). Interleukin-1 receptor-associated kinase 1 (IRAK1) was a target of miR-146a, and its knockdown promoted radiosensitivity. Silencing of HDAC4 radiosensitized EC cells both in vitro and in vivo via the miR-146a/IRAK1 axis.

Conclusion
Hence, loss of HDAC4 upregulated miR-146a to limit radioresistance. This study aids in the better understanding about mechanism responsible for radioresistance of EC.
α-Synuclein-containing erythrocytic extracellular vesicles: essential contributors to hyperactivation of monocytes in Parkinson’s disease
Authors: Liu Zongran , Chan Robin Barry , Cai Zhijian , Liu Xiaodan , Wu Yufeng , Yu Zhenwei , Feng Tao , Yang Ying , Zhang Jing 
Published: February 2022

Abstract
Background
Immune system dysfunction, including higher levels of peripheral monocytes and inflammatory cytokines, is an important feature of Parkinson’s disease (PD) pathogenesis, although the mechanism underlying the process remains to be investigated. In the central nervous system, it is well-known that α-synuclein (α-syn), a key protein involved in PD, activates microglia potently, and it is also reported that α-syn exists in the peripheral system, especially in erythrocytes or red blood cells (RBC) at exceedingly high concentration. The current study focused on the possibility that RBC-derived α-syn mediates the sensitization of peripheral monocytes in PD patients.

Methods
The hyperactivation of monocytes was assessed quantitatively by measuring mRNA levels of typical inflammatory cytokines (including IL-1β, IL-6 and TNF-α) and protein levels of secreted inflammatory cytokines (including pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, IL-8, IFN-γ, IL-2, and IL-12p70 and anti-inflammatory cytokines: IL-4, IL-10, and IL-13). Western blot, nanoparticle tracking analysis and electron microscopy were used to characterize RBC-derived extracellular vesicles (RBC-EVs). Inhibitors of endocytosis and leucine-rich repeat kinase 2 (LRRK2), another key protein involved in PD, were used to investigate how these two factors mediated the process of monocyte sensitization by RBC-EVs.

Results
Increased inflammatory sensitization of monocytes was observed in PD patients and PD model mice. We found that α-syn-containing RBC-EVs isolated from PD model mice or free form oligomeric α-syn induced the inflammatory sensitization of THP-1 cells, and demonstrated that endocytosis was a requirement for this pathophysiological pathway. Furthermore, the hyperactivation of THP-1 cells induced by RBC-EVs was associated with increased LRRK2 production and kinase activity. The phenomenon of inflammatory sensitization of human monocytes and increased LRRK2 were also observed by the treatment of RBC-EVs isolated from PD patients.

Conclusions
Our data provided new insight into how hyperactivation of monocytes occurs in PD patients, and identified the central role played by α-syn-containing RBC-EVs in this process.
Advanced HIV disease management practices within inpatient medicine units at a referral hospital in Zambia: a retrospective chart review
Authors: Mbewe Nyuma , Vinikoor Michael J. , Fwoloshi Sombo , Mwitumwa Mundia , Lakhi Shabir , Sivile Suilanji , Yavatkar Mallika , Lindsay Brianna , Stafford Kristen , Hachaambwa Lottie , Mulenga Lloyd , Claassen Cassidy W. 
Published: February 2022

Abstract
Background
Zambia recently achieved UNAIDS 90-90-90 treatment targets for HIV epidemic control; however, inpatient facilities continue to face a large burden of patients with advanced HIV disease and HIV-related mortality. Management of advanced HIV disease, following guidelines from outpatient settings, may be more difficult within complex inpatient settings. We evaluated adherence to HIV guidelines during hospitalization, including opportunistic infection (OI) screening, treatment, and prophylaxis.

Methods
We reviewed inpatient medical records of people living with HIV (PLHIV) admitted to the University Teaching Hospital in Lusaka, Zambia between December 1, 2018 and April 30, 2019. We collected data on patient demographics, antiretroviral therapy (ART), HIV biomarkers, and OI screening and treatment—including tuberculosis (TB), Cryptococcus, and OI prophylaxis with co-trimoxazole (CTX). Screening and treatment cascades were constructed based on the 2017 WHO Advanced HIV Guidelines.

Results
We reviewed files from 200 charts of patients with advanced HIV disease; of these 92% (184/200) had been on ART previously; 58.1% (107/184) for more than 12 months. HIV viral load (VL) testing was uncommon but half of VL results were high. 39% (77/200) of patients had a documented CD4 count result. Of the 172 patients not on anti-TB treatment (ATT) on admission, TB diagnostic tests (either sputum Xpert MTB/RIF MTB/RIF or urine TB-LAM) were requested for 105 (61%) and resulted for 60 of the 105 (57%). Nine of the 14 patients (64%) with a positive lab result for TB died before results were available. Testing for Cryptococcosis was performed predominantly in patients with symptoms of meningitis. Urine TB-LAM testing was rarely performed.

Conclusions
At a referral hospital in Zambia, CD4 testing was inconsistent due to laboratory challenges and this reduced recognition of AHD and implementation of AHD guidelines. HIV programs can potentially reduce mortality and identify PLHIV with retention and adherence issues through strengthening inpatient activities, including reflex VL testing, TB-LAM and serum CrAg during hospitalization.
Using natural history to guide supervised machine learning for cryptic species delimitation with genetic data
Authors: Derkarabetian Shahan , Starrett James , Hedin Marshal 
Published: February 2022

AbstractThe diversity of biological and ecological characteristics of organisms, and the underlying genetic patterns and processes of speciation, makes the development of universally applicable genetic species delimitation methods challenging. Many approaches, like those incorporating the multispecies coalescent, sometimes delimit populations and overestimate species numbers. This issue is exacerbated in taxa with inherently high population structure due to low dispersal ability, and in cryptic species resulting from nonecological speciation. These taxa present a conundrum when delimiting species: analyses rely heavily, if not entirely, on genetic data which over split species, while other lines of evidence lump. We showcase this conundrum in the harvester Theromaster brunneus, a low dispersal taxon with a wide geographic distribution and high potential for cryptic species. Integrating morphology, mitochondrial, and sub-genomic (double-digest RADSeq and ultraconserved elements) data, we find high discordance across analyses and data types in the number of inferred species, with further evidence that multispecies coalescent approaches over split. We demonstrate the power of a supervised machine learning approach in effectively delimiting cryptic species by creating a “custom” training data set derived from a well-studied lineage with similar biological characteristics as Theromaster. This novel approach uses known taxa with particular biological characteristics to inform unknown taxa with similar characteristics, using modern computational tools ideally suited for species delimitation. The approach also considers the natural history of organisms to make more biologically informed species delimitation decisions, and in principle is broadly applicable for taxa across the tree of life.
Effects of transcranial magnetic stimulation in modulating cortical excitability in patients with stroke: a systematic review and meta-analysis
Authors: Bai Zhongfei , Zhang Jiaqi , Fong Kenneth N. K. 
Published: February 2022

AbstractBackgroundTranscranial magnetic stimulation (TMS) has attracted plenty of attention as it has been proved to be effective in facilitating motor recovery in patients with stroke. The aim of this study was to systematically review the effects of repetitive TMS (rTMS) and theta burst stimulation (TBS) protocols in modulating cortical excitability after stroke.MethodsA literature search was carried out using PubMed, Medline, EMBASE, CINAHL, and PEDro, to identify studies that investigated the effects of four rTMS protocols—low and high frequency rTMS, intermittent and continuous TBS, on TMS measures of cortical excitability in stroke. A random-effects model was used for all meta-analyses.ResultsSixty-one studies were included in the current review. Low frequency rTMS was effective in decreasing individuals’ resting motor threshold and increasing the motor-evoked potential of the non-stimulated M1 (affected M1), while opposite effects occurred in the stimulated M1 (unaffected M1). High frequency rTMS enhanced the cortical excitability of the affected M1 alone. Intermittent TBS also showed superior effects in rebalancing bilateral excitability through increasing and decreasing excitability within the affected and unaffected M1, respectively. Due to the limited number of studies found, the effects of continuous TBS remained inconclusive. Motor impairment was significantly correlated with various forms of TMS measures.ConclusionsExcept for continuous TBS, it is evident that these protocols are effective in modulating cortical excitability in stroke. Current evidence does support the effects of inhibitory stimulation in enhancing the cortical excitability of the affected M1.
Breastfeeding experiences during the COVID-19 pandemic in Spain:a qualitative study
Authors: Rodríguez-Gallego Isabel , Strivens-Vilchez Helen , Agea-Cano Irene , Marín-Sánchez Carmen , Sevillano-Giraldo María Dolores , Gamundi-Fernández Concepción , Berná-Guisado Concepción , Leon-Larios Fatima 
Published: February 2022

Abstract
Background
The pandemic caused by COVID-19 has affected reproductive and perinatal health both through the infection itself and, indirectly, as a consequence of changes in medical care, social policy or social and economic circumstances.
The objective of this study is to explore the impact of the pandemic and of the measures adopted on breastfeeding initiation and maintenance.

Methods
A qualitative descriptive study was conducted by means in-depth semi-structured interviews, until reaching data saturation. The study was conducted between the months of January to May 2021. Participants were recruited by midwives from the Primary Care Centres of the Andalusian provinces provinces of Seville, Cádiz, Huelva, Granada, and Jaén. The interviews were conducted via phone call and were subsequently transcribed and analysed by means of reflexive inductive thematic analysis, using Braun and Clarke’s thematic analysis.

Results
A total of 30 interviews were conducted. Five main themes and ten subthemes were developed, namely: Information received (access to the information, figure who provided the information), unequal support from the professionals during the pandemic (support to postpartum hospitalization, support received from Primary Health Care during the postpartum period), social and family support about breastfeeding (support groups, family support), impact of confinement and of social restriction measures (positive influence on breastfeeding, influence on bonding with the newborn), emotional effect of the pandemic (insecurity and fear related to contagion by coronavirus, feelings of loneliness).

Conclusion
The use of online breastfeeding support groups through applications such as WhatsApp®, Facebook® or Instagram® has provided important breastfeeding information and support sources. The main figure identified that has provided formal breastfeeding support during this period was that of the midwife. In addition, the social restrictions inherent to the pandemic have exerted a positive effect for women in bonding and breastfeeding, as a consequence of the increase in the time spent at their homes and in the family nucleus co-living.
Translational framework for implementation evaluation and research: a normalisation process theory coding manual for qualitative research and instrument development
Authors: May Carl R. , Albers Bianca , Bracher Mike , Finch Tracy L. , Gilbert Anthony , Girling Melissa , Greenwood Kathryn , MacFarlane Anne , Mair Frances S. , May Christine M. , Murray Elizabeth , Potthoff Sebastian , Rapley Tim 
Published: February 2022

AbstractBackgroundNormalisation Process Theory (NPT) is frequently used to inform qualitative research that aims to explain and evaluate processes that shape late-stage translation of innovations in the organisation and delivery of healthcare. A coding manual for qualitative researchers using NPT will facilitate transparent data analysis processes and will also reduce the cognitive and practical burden on researchers.Objectives(a) To simplify the theory for the user. (b) To describe the purposes, methods of development, and potential application of a coding manual that translates normalisation process theory (NPT) into an easily usable framework for qualitative analysis. (c) To present an NPT coding manual that is ready for use.MethodQualitative content analysis of papers and chapters that developed normalisation process theory, selection and structuring of theory constructs, and testing constructs against interview data and published empirical studies using NPT.ResultsA coding manual for NPT was developed. It consists of 12 primary NPT constructs and conforms to the Context-Mechanism-Outcome configuration of realist evaluation studies. Contexts are defined as settings in which implementation work is done, in which strategic intentions, adaptive execution, negotiating capability, and reframing organisational logics are enacted. Mechanisms are defined as the work that people do when they participate in implementation processes and include coherence-building, cognitive participation, collective action, and reflexive monitoring. Outcomes are defined as effects that make visible how things change as implementation processes proceed and include intervention mobilisation, normative restructuring, relational restructuring, and sustainment.ConclusionThe coding manual is ready to use and performs three important tasks. It consolidates several iterations of theory development, makes the application of NPT simpler for the user, and links NPT constructs to realist evaluation methods. The coding manual forms the core of a translational framework for implementation research and evaluation.
A prospective comparison of adaptive and fixed boost plans in radiotherapy for glioblastoma
Authors: Matsuyama Tomohiko , Fukugawa Yoshiyuki , Kuroda Junichiro , Toya Ryo , Watakabe Takahiro , Matsumoto Tadashi , Oya Natsuo 
Published: February 2022

Abstract
Purpose
To analyze the efficacy of adaptive radiotherapy (ART) for glioblastoma.

Methods
Sixty-one glioblastoma patients who received ART were prospectively evaluated. The initial clinical target volume (CTVinitial) was represented by T2 hyperintensity on postoperative MRIs (pre-RT MRI [MRIpre])plus 10 mm. The initial planning target volume (PTVinitial) was the CTVinitial plus a 5-mm margin. The PTVinitial received 40 Gy. An MRI and a second planning CT were performed during radiotherapy (MRImid). Two types of boost CTVs (the resection cavity and residual tumor on enhanced T1-weighted MRI plus 10 mm) were created based on the MRIpre and MRImid (CTVboost-pre and -mid). The boost PTV (PTVboost) was the CTVboost plus 5 mm. Two types of boost plans (fixed and adaptive boost plans in the first and second planning CT, respectively) of 20 Gy were created. The PTV based on the post-RT MRI (PTVboost-post) was created, and the dose-volume histograms of the PTVboost-post in the fixed and adaptive boost plans were compared. Additionally, the conformity indices (CIs) of the fixed and adaptive boost plans were compared.

Results
The median V95 of the PTVboost-post of the fixed and adaptive boost plans (V95pre and V95mid) were 95.6% and 98.3%, respectively (P < 0.01). The median V95pre and V95mid of patients after gross total resection (GTR) were 97.4% and 98.8%, respectively (P = 0.41); in contrast, the median values of patients after non-GTR were 91.9% and 98.2%, respectively (P < 0.01). The median CIs of the fixed and adaptive boost plans in all patients were 1.45 and 1.47, respectively (P = 0.31). The median CIs of the fixed and adaptive boost plans in patients after GTR were 1.61 and 1.48, respectively (P = 0.01); in contrast, those in patients after non-GTR were 1.36 and 1.44, respectively (P = 0.13).

Conclusion
ART for glioblastoma improved the target coverage and dose reduction for the normal brain. By analyzing the results according to the resection rate, we can expect a decrease in normal brain dose in patients with GTR and an increase in coverage in those with partial resection or biopsy.
Cucurbitacin E inhibits cellular proliferation and induces apoptosis in melanoma by suppressing HSDL2 expression
Authors: Liu Wen-Bei , Wang He-Li , Chen Lei , Tang Biao , Ke Guolin , Wang Shuai , Sun Yin-Qiao , Ma Junting , Lyu Da-Lun 
Published: February 2022

Abstract
Background
Melanoma is among the most aggressive types of skin malignancy and can have an unpredictable clinical course. Exploration of novel therapeutic targets and their regulators remains essential for the prevention and treatment of melanoma.

Methods
HSDL2 protein levels were examined by immunohistochemistry. The roles of HSDL2 in cell proliferation and apoptosis were identified by CCK-8 and colony formation assays. The function of HSDL2 in cell apoptosis was analysed by flow cytometry. Western blotting, cell proliferation and apoptosis and a xenograft tumour model were utilized to explore the inhibitory functions and mechanisms of CuE in melanoma.

Results
HSDL2 is overexpressed in melanoma and promotes melanoma progression by activating the ERK and AKT pathways. CuE could inhibit the ERK and AKT pathways by decreasing HSDL2 expression; therefore, CuE could inhibit melanoma growth in vitro and in vivo.

Conclusion
HSDL2 may be a promising therapeutic target against melanoma, and CuE can inhibit melanoma by downregulating HSDL2 expression.