bluuebunny/crossref_metadata_2025 huggingface dataset:
Barriers to surgery performed by non-physician clinicians in sub-Saharan Africa—a scoping review
Authors: van Heemskerken Phylisha , Broekhuizen Henk , Gajewski Jakub , Brugha Ruairí , Bijlmakers Leon
Published: July 2020

Background

Sub-Saharan Africa (SSA) faces the highest burden of disease amenable to surgery while having the lowest surgeon to population ratio in the world. Some 25 SSA countries use surgical task-shifting from physicians to non-physician clinicians (NPCs) as a strategy to increase access to surgery. While many studies have investigated barriers to access to surgical services, there is a dearth of studies that examine the barriers to shifting of surgical tasks to, and the delivery of safe essential surgical care by NPCs, especially in rural areas of SSA. This study aims to identify those barriers and how they vary between surgical disciplines as well as between countries.

Methods

We performed a scoping review of articles published between 2000 and 2018, listed in PubMed or Embase. Full-text articles were read by two reviewers to identify barriers to surgical task-shifting. Cited barriers were counted and categorized, partly based on the World Health Organization (WHO) health systems building blocks.

Results

Sixty-two articles met the inclusion criteria, and 14 clusters of barriers were identified, which were assigned to four main categories: primary outcomes, NPC workforce, regulation, and environment and resources. Malawi, Tanzania, Uganda, and Mozambique had the largest number of articles reporting barriers, with Uganda reporting the largest variety of barriers from empirical studies only. Obstetric and gynaecologic surgery had more articles and cited barriers than other specialties.

Conclusion

A multitude of factors hampers the provision of surgery by NPCs across SSA. The two main issues are surgical pre-requisites and the need for regulatory and professional frameworks to legitimate and control the surgical practice of NPCs.
Measuring the resilience of health systems in low- and middle-income countries: a focus on community resilience
Authors: Bhandari Sudip , Alonge Olakunle
Published: July 2020

The concept of community resilience has gained considerable attention in the global health discussions since the Ebola outbreak of West Africa in 2014–2015. However, there are no measurement models to quantify community resilience. Without measurement models, it is unclear how to test strategies for building community resilience or to describe their likely intended and unintended results and their impact on health outcomes. We propose a measurement model for community resilience with relevant constructs and indicators to measure these constructs. We conducted a scoping review, systematically searching, screening and selecting relevant articles from two bibliographic databases (PUBMED and Google Scholar) for literature using search terms such as “resilience”, “community resilience” and “health systems resilience”. We screened 500 papers, then completed a full text review of 112 identified as relevant based on their title and abstract. A total of 27 papers and reports were retained for analysis. We then aggregated and synthesised the various definitions of community resilience and the frameworks for understanding these definitions. We identified key constructs from these frameworks and organised these constructs into domains and sub-domains. We proposed indicators to capture aspects of these domains and sub-domains and operationalised these indicators as a measurement model for quantifying community resilience in health systems. We propose a model with 20 indicators to assess community resilience. These indicators tap into various constructs from different theoretical frameworks of community resilience and are useful for assessing the level of knowledge, financial resources, and human, social and physical capital that are needed (or lacking) to respond to any types of shock, including health shock at the community level. This is an initial attempt to describe a multilevel measurement model for quantifying community resilience. This model will help to guide the development and testing of strategies for strengthening community resilience and will require further work to assess its relevance, reliability and validity in different LMIC settings.
Walking with a powered ankle-foot orthosis: the effects of actuation timing and stiffness level on healthy users
Authors: Moltedo Marta , Baček Tomislav , Serrien Ben , Langlois Kevin , Vanderborght Bram , Lefeber Dirk , Rodriguez-Guerrero Carlos
Published: July 2020

Background

In the last decades, several powered ankle-foot orthoses have been developed to assist the ankle joint of their users during walking. Recent studies have shown that the effects of the assistance provided by powered ankle-foot orthoses depend on the assistive profile. In compliant actuators, the stiffness level influences the actuator’s performance. However, the effects of this parameter on the users has not been yet evaluated. The goal of this study is to assess the effects of the assistance provided by a variable stiffness ankle actuator on healthy young users. More specifically, the effect of different onset times of the push-off torque and different actuator’s stiffness levels has been investigated.

Methods

Eight healthy subjects walked with a unilateral powered ankle-foot orthosis in several assisted walking trials. The powered orthosis was actuated in the sagittal plane by a variable stiffness actuator. During the assisted walking trials, three different onset times of the push-off assistance and three different actuator’s stiffness levels were used. The metabolic cost of walking, lower limb muscles activation, joint kinematics, and gait parameters measured during different assisted walking trials were compared to the ones measured during normal walking and walking with the powered orthosis not providing assistance.

Results

This study found trends for more compliant settings of the ankle actuator resulting in bigger reductions of the metabolic cost of walking and soleus muscle activation in the stance phase during assisted walking as compared to the unassisted walking trial. In addition to this, the study found that, among the tested onset times, the earlier ones showed a trend for bigger reductions of the activation of the soleus muscle during stance, while the later ones led to a bigger reduction in the metabolic cost of walking in the assisted walking trials as compared to the unassisted condition.

Conclusions

This study presents a first attempt to show that, together with the assistive torque profile, also the stiffness level of a compliant ankle actuator can influence the assistive performance of a powered ankle-foot orthosis.
Relying on more sense for enhancing lower limb prostheses control: a review
Authors: Tschiedel Michael , Russold Michael Friedrich , Kaniusas Eugenijus
Published: July 2020

Modern lower limb prostheses have the capability to replace missing body parts and improve the patients’ quality of life. However, missing environmental information often makes a seamless adaptation to transitions between different forms of locomotion challenging. The aim of this review is to identify the progress made in this area over the last decade, addressing two main questions: which types of novel sensors for environmental awareness are used in lower limb prostheses, and how do they enhance device control towards more comfort and safety. A literature search was conducted on two Internet databases, PubMed and IEEE Xplore. Based on the criteria for inclusion and exclusion, 32 papers were selected for the review analysis, 18 of those are related to explicit environmental sensing and 14 to implicit environmental sensing. Characteristics were discussed with a focus on update rate and resolution as well as on computing power and energy consumption. Our analysis identified numerous state-of-the-art sensors, some of which are able to “look through” clothing or cosmetic covers. Five control categories were identified, how “next generation prostheses” could be extended. There is a clear tendency towards more upcoming object or terrain prediction concepts using all types of distance and depth-based sensors. Other advanced strategies, such as bilateral gait segmentation from unilateral sensors, could also play an important role in movement-dependent control applications. The studies demonstrated promising accuracy in well-controlled laboratory settings, but it is unclear how the systems will perform in real-world environments, both indoors and outdoors. At the moment the main limitation proves to be the necessity of having an unobstructed field of view.
Oral toxicity of titanium dioxide P25 at repeated dose 28-day and 90-day in rats
Authors: Heo Min Beom , Kwak Minjeong , An Kyu Sup , Kim Hye Jin , Ryu Hyeon Yeol , Lee So Min , Song Kyung Seuk , Kim In Young , Kwon Ji-Hwan , Lee Tae Geol
Published: July 2020

Background

Nanotechnology is indispensable to many different applications. Although nanoparticles have been widely used in, for example, cosmetics, sunscreen, food packaging, and medications, they may pose human safety risks associated with nanotoxicity. Thus, toxicity testing of nanoparticles is essential to assess the relative health risks associated with consumer exposure.

Methods

In this study, we identified the NOAEL (no observed adverse effect level) of the agglomerated/aggregated TiO2 P25 (approximately 180 nm) administered at repeated doses to Sprague-Dawley (SD) rats for 28 and 90 days. Ten of the 15 animals were necropsied for toxicity evaluation after the repeated-dose 90-day study, and the remaining five animals were allowed to recover for 28 days. The agglomerated/aggregated TiO2 P25 dose levels used included 250 mg kg− 1 d− 1 (low), 500 mg kg− 1 d− 1 (medium), and 1000 mg kg− 1 d− 1 (high), and their effects were compared with those of the vehicle control. During the treatment period, the animals were observed for mortality, clinical signs (detailed daily and weekly clinical observations), functional observation battery, weekly body weight, and food and water consumption and were also subjected to ophthalmological examination and urinalysis. After termination of the repeated-dose 28-day, 90-day, and recovery studies, clinical pathology (hematology, blood coagulation time, and serum biochemistry), necropsy (organ weights and gross findings), and histopathological examinations were performed.

Results

No systemic toxicological effects were associated with the agglomerated/aggregated TiO2 P25 during the repeated-dose 28-day, 90-day, and recovery studies in SD rats. Therefore, the NOAEL of the agglomerated/aggregated TiO2 P25 was identified as 1000 mg kg− 1 d− 1, and the substance was not detected in the target organs.

Conclusion

Subacute and subchronic oral administration of the agglomerated/aggregated TiO2 P25 was unlikely to cause side effects or toxic reactions in rats.
Intermittent kangaroo mother care and the practice of breastfeeding late preterm infants: results from four hospitals in different provinces of China
Authors: Zhang Bo , Duan Zhiying , Zhao Yingxi , Williams Sarah , Wall Stephen , Huang Limin , Zhang Xiaoqin , Wu Wenli , Yue Jieya , Zhang Lin , Liu Jun , Zhao Gengli
Published: July 2020

Background

China has an extremely low exclusive breastfeeding rate. Kangaroo mother care (KMC) has been shown to increase the exclusive breastfeeding rate among infants born extremely or very preterm. However, there is limited evidence surrounding intermittent KMC and exclusive breastfeeding in late preterm infants. In our study we investigated the association between the provision of intermittent KMC and breastfeeding practice for late preterm infants in four hospitals in different provinces of China.

Methods

Intermittent KMC was recommended to the mothers of all preterm infants admitted to the postnatal wards of participating hospitals between March 2018 and March 2019. Those who agreed to practice KMC were enrolled in the “KMC group”, those who did not were enrolled in the “No KMC group”. Basic maternal socio-demographic information was collected, feeding practice; outcome and method, were recorded daily whilst in hospital. A follow-up survey of feeding practice was conducted 42 days after discharge. Calculations for feeding practice were performed separately for both groups. Logistics regression was used to analyze the association between KMC and feeding outcome and method, adjusting for socio-demographic covariates.

Results

Among the 844 mothers participating in the study, 627 (74.3%) chose to perform KMC. More of the mothers who provided KMC were exclusively breast milk feeding their infants in the 24 h before hospital discharge (54.6%) and at follow-up (57.3%), compared to mothers who did not provide KMC (34.6% at discharge and 33.2% at follow-up,). Mothers in the KMC group were more likely to be breastfeeding (method) than mothers in the No KMC group (65.3% vs. 52.1% at discharge, and 83.1% vs. 67.3% at follow up). Logistic regression indicated that compared with the No KMC group, mothers who provided KMC were twice as likely to be exclusively breast milk feeding their infants at discharge (OR = 2.15 (95% CI 1.53, 3.02)), use breastfeeding method at discharge as opposed to other means such as bottle or cup feeding (OR = 1.61 (95% CI 1.15, 2.25)), be exclusive breast milk feeding at follow-up (OR = 2.55 (95% CI 1.81, 3.61)), and use breastfeeding method at follow-up (OR = 2.09 (95% CI 1.44, 3.02)).

Conclusions

Intermittent KMC was associated with a nearly doubled increase in exclusive breast milk feeding (outcome) and breastfeeding (method) at both discharge and 42 days after discharge for late preterm infants. This is especially important in China where exclusive breastfeeding rates are low, intermittent KMC provides a feasible means to increase the likelihood of these vulnerable infants receiving the benefits of exclusive breastmilk.
The relationship between perceived milk supply and exclusive breastfeeding during the first six months postpartum: a cross-sectional study
Authors: Sandhi Ayyu , Lee Gabrielle T. , Chipojola Roselyn , Huda Mega Hasanul , Kuo Shu-Yu
Published: July 2020

Background

Perceived milk supply is an important modifiable factor for optimal breastfeeding. However, little is known about maternal perception of milk supply or how it impacts breastfeeding practices. The aim of this study was to examine relationships of perceived milk supply, maternal breastfeeding self-efficacy, and skin-to-skin contact with early initiation and exclusive breastfeeding among mothers of infants less than 6 months of age in Indonesia.

Methods

This was a cross-sectional study conducted in Yogyakarta City, Indonesia between August and October 2015. Maternal perception of milk supply was assessed using the Hill and Humenick Lactation Scale. Data on breastfeeding practices, and maternal and infant factors were collected using a structured questionnaire. Multiple regression and multivariate logistic regression analyses were performed to obtain estimates of associations.

Results

Thirty four percent of mothers had initiated breastfeeding within an hour after birth, and 62.4% of mothers were exclusively breastfeeding. High levels of perceived breast milk supply were reported in mothers who practiced skin-to-skin contact or rooming-in with their infants, experienced positive infant sucking behavior, or had high breastfeeding self-efficacy (p < 0.05). Mothers with a higher level of perceived milk production (Odds Ratio [OR] 3.20; 95% Confidence Interval [CI] 1.76, 5.83) or practicing skin-to-skin contact (OR 2.36; 95% CI 1.13, 4.91) were more likely to exclusively breastfeed, while employed mothers were less likely to breastfeed their infants exclusively (OR 0.47; 95% CI 0.24, 0.93).

Conclusions

In this study, skin-to-skin contact and breastfeeding self-efficacy are important determinants of perceived milk supply. Higher perception of milk supply was positively linked with exclusive breastfeeding. Our study highlights the importance of the assessment for mother’s perception of milk supply, maternal breastfeeding self-efficacy, and skin-to-skin contact in achieving optimal breastfeeding outcomes.
Clubfoot treatment with Ponseti method—parental distress during plaster casting
Authors: Walter Christian , Sachsenmaier Saskia , Wünschel Markus , Teufel Martin , Götze Marco
Published: July 2020

Background

Clubfoot is one of the most prevalent musculoskeletal congenital defects. Gold standard treatment of idiopathic clubfoot is the conservative Ponseti method, including the reduction of deformity with weekly serial plaster casting and percutaneous Achilles tenotomy. It is well known that parents of children with severe and chronic illnesses are mentally stressed, but in recent studies regarding clubfoot treatment, parents were only asked about their satisfaction with the treatment. Largely unknown is parental distress before and during plaster casting in clubfoot.

Therefore, we want to determinate first, how pronounced the parents’ worries are before treatment and if they decrease during the therapy. Second, we hypothesized that parents faced with an extreme deformity (high Pirani score), reveal more distress, than parents whose children have a less pronounced deformity (low Pirani score). Therefore, we wanted to investigate whether the Pirani score correlates with the parents’ mental resilience in relation to the therapy of the child as a global distress parameter.

Methods

To answer this question, we developed a questionnaire with the following emphases: Physical capacity, mental resilience, motion score, parents score, and child score with point scores 1 (not affected) to 6 (high affected). Subsequently, we interviewed 20 parents whose children were treated with clubfeet and determined the Pirani score of the infants at the beginning (T0) and at the end (TE) of the treatment with plaster casting.

Results

High values were obtained in child score (Mean (M) = 3.11), motion score (M= 2.63), and mental resilience (M= 2.25). During treatment, mental resilience improved (p= 0.015) significantly. Spearman correlation coefficient between Pirani score (T0) and mental resilience (T0) is 0.21, so the initial hypothesis had to be rejected.

Conclusion

The issues of the children are in the focus of parental worries concerning clubfoot treatment, especially the assumed future motion and the assumed ability to play with other children. Particular emphasis should be placed on educating parents about the excellent long-term results in the function of the treated feet especially as this topic shows the greatest parental distress.
Overexpression of programmed cell death ligand 1 in patients with CIN and its correlation with human papillomavirus infection and CIN persistence
Authors: Sancakli Usta Ceyda , Altun Eren , Afsar Selim , Bulbul Cagla Bahar , Usta Akin , Adalı Ertan
Published: July 2020

Backround

HPV causes specific cell-mediated immunity in the cervix. Mononuclear cells such as helper T cells (CD4+), cytotoxic T cells (CD8+), and dendritic cells play a critical role in the initiation of the HPV-specific immune response and destruction of virus-infected cervical epithelial cells. The programmed cell death ligand 1 (PD-L1) gene encodes an immune inhibitory receptor ligand and overexpression of PD-L1 inhibits T-cell activation and cytokine production. The aim of this study was to investigate the expression of PD-L1 in cervical tissue and its correlation with clinicopathological findings.

Methods

In this cross-sectional study, a total of 94 women who were referred for colposcopy due to abnormal Papanicolaou (PAP) test results and/or HPV positivity were evaluated. The presence of HR-HPV–DNA was analyzed using type- and gene-specific primers along with commercial real-time polymerase chain reaction. The cervical examination was done with a colposcope. Cervical biopsies were obtained from the areas that were evaluated as abnormal during the colposcopy. Histopathological result of cervical biopsies were defined as no intraepithelial neoplasia (CIN 0), mild CIN (CIN I), and moderate-to-high CIN (CIN II-III). All women were classified into four groups based on their HR-HPV positivity and cervical biopsy results: Group I (controls; n = 29), HR-HPV (−) CIN 0; Group II (n = 21), HR-HPV (+) CIN 0; Group III (n = 20), HR-HPV (+) CIN I; and Group IV (n = 24), HR-HPV (+) CIN II-III. A semi-quantitative scoring system was used to evaluate the degree of Ki-67, p16, and PD-L1 immunoreactivity in the cervical tissue samples.

Results

We found that PD-L1 expression in both mononuclear cells and in cervical epithelial cells gradually increases from the HR-HPV (−), CIN 0 group to the HR-HPV (+), CIN II-III group (p = 0.0003 and p = 0.0394, respectively) and mononuclear PD-L1 expression was correlated with HPV type, initial Pap test results, HPV persistence, and CIN persistence or recurrence (p = 0.0180, p = 0.0109, p = 0.0042, and p = 0.0189, respectively). Moreover, mononuclear PD-L1 expression was also correlated with Ki-67 and p16 immunoreactivity (p = 0.0432 and p = 0.0166, respectively). Epithelial PD-L1 expression was only correlated with HPV type and the presence of HPV persistence (p = 0.0122 and p = 0.0292, respectively).

Conclusion

During the initial evaluation of the cervical histology results, the assessment of PD-L1 expression—especially in mononuclear cells in cervical tissue samples—may provide more information on the progression of HR-HPV infection and its persistence.
Fasciola gigantica excretory-secretory products (FgESPs) modulate the differentiation and immune functions of buffalo dendritic cells through a mechanism involving DNMT1 and TET1
Authors: Mei Xuefang , Shi Wei , Zhao Wenping , Luo Honglin , Zhang Yaoyao , Wang Yurui , Sheng Zhaoan , Wang Dongying , Zhu Xing-Quan , Huang Weiyi
Published: July 2020

Background

Fasciola gigantica infection threatens the health of both humans and animals in the world. The excretory/secretory products (ESPs) of this fluke has been reported to impair the activation and maturation of immune cells. We have previously shown the influence of F. gigantica ESPs (FgESPs) on the maturation of buffalo dendritic cells (DCs). However, the underlying mechanisms remain unclear. The objective of this study was to investigate the potency of FgESPs in shifting the differentiation and immune functions of buffalo DCs.

Methods

Buffalo DCs were incubated with FgESPs directly or further co-cultured with lymphocytes in vitro. qRT-PCR was employed to determine the gene expression profile of DCs or the mixed cells, and an ELISA was used to measure cytokine levels in the supernatants. Hoechst and Giemsa staining assays, transmission electron microscopy, caspase-3/7 activity test and histone methylation test were performed to determine DC phenotyping, apoptosis and methylation. To investigate the mechanism involved with DNA methylation, a Co-IP assay and immunofluorescent staining assay were performed to observe if there was any direct interaction between FgESPs and DNMT1/TET1 in buffalo DCs, while RNAi technology was employed to knockdown DNMT1 and TET1 in order to evaluate any different influence of FgESPs on DCs when these genes were absent.

Results

qRT-PCR and ELISA data together demonstrated the upregulation of DC2 and Th2/Treg markers in DCs alone and DCs with a mixed lymphocyte reaction (MLR), suggesting a bias of DC2 that potentially directed Th2 differentiation in vitro. DC apoptosis was also found and evidenced morphologically and biochemically, which might be a source of tolerogenic DCs that led to Treg differentiation. In addition, FgESPs induced methylation level changes of histones H3K4 and H3K9, which correlate with DNA methylation. Co-IP and immunofluorescent subcellular localization assays showed no direct interaction between the FgESPs and DNMT1/TET1 in buffalo DCs. The productions of IL-6 and IL-12 were found separately altered by the knockdown of DNMT1 and TET1 in DCs after FgESPs treatment.

Conclusions

FgESPs may induce the DC2 phenotype or the apoptosis of buffalo DCs to induce the downstream Th2/Treg response of T cells, possibly through a DNMT1- or TET1-dependent manner(s).
Histone N-alpha terminal modifications: genome regulation at the tip of the tail
Authors: Demetriadou Christina , Koufaris Costas , Kirmizis Antonis
Published: July 2020

Histone proteins are decorated with numerous post-(PTMs) or co-(CTMs) translational modifications mainly on their unstructured tails, but also on their globular domain. For many decades research on histone modifications has been focused almost solely on the biological role of modifications occurring at the side-chain of internal amino acid residues. In contrast, modifications on the terminal N-alpha amino group of histones—despite being highly abundant and evolutionarily conserved—have been largely overlooked. This oversight has been due to the fact that these marks were being considered inert until recently, serving no regulatory functions. However, during the past few years accumulating evidence has drawn attention towards the importance of chemical marks added at the very N-terminal tip of histones and unveiled their role in key biological processes including aging and carcinogenesis. Further elucidation of the molecular mechanisms through which these modifications are regulated and by which they act to influence chromatin dynamics and DNA-based processes like transcription is expected to enlighten our understanding of their emerging role in controlling cellular physiology and contribution to human disease. In this review, we clarify the difference between N-alpha terminal (Nt) and internal (In) histone modifications; provide an overview of the different types of known histone Nt-marks and the associated histone N-terminal transferases (NTTs); and explore how they function to shape gene expression, chromatin architecture and cellular phenotypes.
New generalized fractional versions of Hadamard and Fejér inequalities for harmonically convex functions
Authors: Qiang Xiaoli , Farid Ghulam , Yussouf Muhammad , Khan Khuram Ali , Rahman Atiq Ur
Published: July 2020

The aim of this paper is to establish new generalized fractional versions of the Hadamard and the Fejér–Hadamard integral inequalities for harmonically convex functions. Fractional integral operators involving an extended generalized Mittag-Leffler function which are further generalized via a monotone increasing function are utilized to get these generalized fractional versions. The results of this paper give several consequent fractional inequalities for harmonically convex functions for known fractional integral operators deducible from utilized generalized fractional integral operators.
Molecular analysis of methicillin-resistant Staphylococcus aureus isolates from four teaching hospitals in Iran: the emergence of novel MRSA clones
Authors: Firoozeh Farzaneh , Omidi Mitra , Saffari Mahmood , Sedaghat Hossein , Zibaei Mohammad
Published: July 2020

Background

The global spread of methicillin-resistant Staphylococcus aureus (MRSA) infections necessitates the use of validated methods for the identification and typing of this bacterium. This study aimed to determine the distribution of main molecular types of MRSA strain circulating among hospitalized patients in teaching hospitals in Isfahan and Kashan.

Methods

A total of 146 Staphylococcus aureus strains were isolated from patients in four teaching hospitals in Isfahan and Kashan during June 2017 to September 2018. The antimicrobial resistance patterns of Staphylococcus aureus strains were performed by disc diffusion method. The MRSA strains were identified phenotypically and confirmed by PCR assay. The prevalence of microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) genes among MRSA strains was evaluated by multiplex PCR. The genotypes of MRSA strains were determined by multilocus sequence typing and SCCmec typing.

Results

Of 146 Staphylococcus aureus isolates, 24 (16.4%) isolates were identified as MRSA strains. According to antimicrobial susceptibility testing the highest resistance rates were seen for tetracycline, erythromycin, ciprofloxacin and gentamicin. All of Staphylococcus aureus isolates were susceptible to vancomycin whereas 3 (2.1%) isolates were resistant to linezolid. Three different SCCmec types were obtained among MRSA strains including 16 (66.7%) SCCmec type V, 3 (12.5%) SCCmec type III and 5 (20.8%) SCCmec type II. Of 24 MRSA isolates 20 (83.3%) carried MSCRAMMs genes including eno (70.8%), fib (54.1%), cna (25.0%), fnbB (16.6%), ebps 5 (20.8%), and the fnbA, bbp and clfA genes were not detected in any MRSA isolate. MLST analysis revealed 11 sequence types among MRSA isolates as follows: ST239, ST291, ST22, ST861, ST889, ST8, ST59, ST343, ST772, ST6 and ST1465. Also seven MLST-based clonal complexes (CCs) were identified among MRSA strains including: CC8, CC7, CC398, CC59, CC22, CC1 and CC5.

Conclusions

A relatively high diversity was found in MRSA genotypes in Kashan and Isfahan hospitals, and seven clonal complexes were identified. Pandemic MRSA clones including CC8 and CC22 were the most prevalent clones and the novel ST types including ST1465, ST861, ST 889 and ST772 are reported for the first time in Iran in the present study. In addition the high prevalence of MSCRAMMs genes in MRSA isolates demonstrates the high potential of these strains for pathogenicity.
Plasma circulating tumor DNA assessment reveals KMT2D as a potential poor prognostic factor in extranodal NK/T-cell lymphoma
Authors: Li Qiong , Zhang Wei , Li Jiali , Xiong Jingkang , Liu Jia , Chen Ting , Wen Qin , Zeng Yunjing , Gao Li , Gao Lei , Zhang Cheng , Kong Peiyan , Peng Xiangui , Liu Yao , Zhang Xi , Rao Jun
Published: July 2020

Background

The early detection of tumors upon initial diagnosis or during routine surveillance is important for improving survival outcomes. Here, we investigated the feasibility and clinical significance of circulating tumor DNA (ctDNA) detection for Extranodal NK/T-cell lymphoma, nasal type (ENTKL).

Methods

The plasma ctDNA assessment was based on blood specimens collected from 65 newly diagnosed patients with ENKTL in the hematology medical center of Xinqiao Hospital. Longitudinal samples collected under chemotherapy were also included. The gene mutation spectrum of ENKTL was analyzed via next generation sequencing.

Results

We found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%) and NOTCH1 (7.7%). The mutation allele frequencies of ATM and JAK3 were significantly correlated with the disease stage, and mutated KMT2D, ASXL3 and JAK3 were positively correlated with the metabolic tumor burden of the patients. Compared with the tumor tissue, ctDNA profiling showed good concordance (93.75%). Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequencies of the genes. Compared with PET/CT, ctDNA has more advantages in tracking residual disease in patients. In addition, patients with mutated KMT2D had higher expression compared with those with wild type, and mutated KMT2D predicted poor prognosis.

Conclusion

Our results unveil the mutation spectrum of ENKTL patients’ plasma, which can be used to monitor the disease status of the patients exactly, and KMT2D is the most frequently mutated gene with prognosis prediction value. The application of ctDNA sequencing can provide precision treatment strategies for patients.

Trial registration

This study is registered with chictr.org (ChiCTR1800014813, registered 7 February, 2018-Retrospectively registered).
Unrealized potential of drug repositioning in Europe during COVID-19 and beyond: a physician's perspective
Authors: Bayoumy A. B. , de Boer N. K. H. , Ansari A. R. , Crouwel F. , Mulder C. J. J.
Published: July 2020

Drug repositioning is the scientific strategy of investigating existing drugs for additional clinical indications. The advantages of drug repositioning are that it benefits patients and that it adds new indications to existing drugs for lower costs compared to de novo drug development. Clinical research groups recognizing efficacy of these “old” drugs for a new indications often face an uphill struggle due to a lack of funding and support because of poor structural and regulatory support for clinical drug development. The current framework for drug repositioning allows “venture capital” companies to abuse loopholes in the legislation to gain long-term market authorization among with excessive high pricing. A new regulatory framework is needed to prevent abuse of the legislation and promote clinical investigator-driven drug repositioning. The COVID-19 pandemic has boosted funding and regulatory support for drug repositioning. The lessons learned from the COVID-19 pandemic should be implemented in a new clear blueprint for drug repositioning. This blueprint should guide clinicians through legislation for drug repositioning in the EU. This review summarizes the routes for registration and discusses the current state of drug repositioning in Europe.
Preoperative balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension led to successful anesthetic management for total hysterectomy under general anesthesia: a case report
Authors: Ota Tomoko , Kawai Kazumi , Niihata Tomoko , Fukuda Hideki
Published: July 2020

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease of obstructive pulmonary artery remodeling as a consequence of major vessel thromboembolism. Balloon pulmonary angioplasty (BPA) is an alternative treatment for patients with inoperable CTEPH. We report a case of CTEPH which improved following preoperative BPA intervention, allowing total hysterectomy to be performed.

Case presentation

A 48-year-old woman was transferred to our hospital to undergo total hysterectomy for endometrial cancer. She developed pulmonary embolism 7 months ago at another hospital, and a diagnosis of CTEPH was made based on multiple pulmonary emboli and pulmonary hypertension at our institute. Two BPA sessions for seven branches of the bilateral pulmonary arteries were conducted, resulting in a decrease of mean pulmonary artery pressure from 54 to 33 mmHg. Total hysterectomy was successfully performed under general anesthesia without any complications.

Conclusions

BPA could be effective for reducing PH in patients with CTEPH undergoing noncardiac surgery.
Flipped classroom in a therapeutic modality course: students’ perspective
Authors: Bates Dana , Ludwig Genevieve
Published: July 2020

The use of flipped classrooms has gained momentum and involves the instructor replacing the passive reception of material found in common lectures, so class time may be used for hands-on practical application, discussion, or assignments. The purpose of this paper is to explore students’ perceptions of a flipped therapeutic modality course. Focus group interviews were conducted with sixteen participants (14 female, 2 male) who completed a therapeutic modality course. Data were collected through 4 focus group interviews, which were digitally recorded and transcribed. Data were analyzed to uncover dominant themes—first by organizing the data, then summarizing data into codes, and finally interpreting. Credibility was secured through peer review, member checks, and investigator triangulation. The analysis resulted in three common themes: the flipped classroom (1) was perceived as valuable by students, (2) led to active participation in class, and (3) helped students feel better prepared for the class. Athletic training students, particularly in a flipped therapeutic modality course, valued this pedagogical approach.
Classifying the diagnosis of study participants in clinical trials: a structured and efficient approach
Authors: van Engelen Tjitske S. R. , Kanglie Maadrika M. N. P. , van den Berk Inge A. H. , Bouwman Merel L. J. , Suhooli Hind J. M. , Heckert Sascha L. , Stoker Jaap , Bossuyt Patrick M. M. , Prins Jan M. ,   For the OPTIMACT Study Group, Annema Jouke , Beenen Ludo F. M. , van den Berk Inge A. H. , Bipat Shandra , Bossuyt Patrick M. M. , Bresser Paul , Dijkgraaf Marcel , Donker Jos , van Engelen Tjitske S. R. , Frankemölle Betty , Groenink Maarten , Hochheimer Suzanne M. R. , Holleman Frits , Hulzebosch Dorine , Kanglie Maadrika M. N. P. , Keijzers Mitran , van der Lee Ivo , Leenhouts Peter , Luitse Jan , Meijboom Lilian J. , Middeldorp Saskia , Montauban van Swijndregt Alexander , de Monyé Wouter , Otker Jacqueline , Ridderikhof Milan , Romijn Johannes A. , Schoonderwoerd Antoinet J. N. , Sprengers Ralf W. , Stoker Jaap , Taal Elizabeth M. , Winter Michiel , Prins Jan M.
Published: July 2020

Background

A challenge in imaging research is a diagnostic classification of study participants. We hypothesised that a structured approach would be efficient and that classification by medical students, residents, and an expert panel whenever necessary would be as valid as classification of all patients by experts.

Methods

OPTIMACT is a randomised trial designed to evaluate the effectiveness of replacing chest x-ray for ultra-low-dose chest computed tomography (CT) at the emergency department. We developed a handbook with diagnostic guidelines and randomly selected 240 cases from 2,418 participants enrolled in OPTIMACT. Each case was independently classified by two medical students and, if they disagreed, by the students and a resident in a consensus meeting. Cases without consensus and cases classified as complex were assessed by a panel of medical specialists. To evaluate the validity, 60 randomly selected cases not referred to the panel by the students and the residents were reassessed by the specialists.

Results

Overall, the students and, if necessary, residents were able to assign a diagnosis in 183 of the 240 cases (76% concordance; 95% confidence interval [CI] 71–82%). We observed agreement between students and residents versus medical specialists in 50/60 cases (83% concordance; 95% CI 74–93%).

Conclusions

A structured approach in which study participants are assigned diagnostic labels by assessors with increasing levels of medical experience was an efficient and valid classification method, limiting the workload for medical specialists. We presented a viable option for classifying study participants in large-scale imaging trials (Netherlands National Trial Register number NTR6163).
Adoption of Immune Checkpoint Inhibitors and Patterns of Care at the End of Life
Authors: Riaz Fauzia , Gan Geliang , Li Fangyong , Davidoff Amy J. , Adelson Kerin B. , Presley Carolyn J. , Adamson Blythe J. , Shaw Pooja , Parikh Ravi B. , Mamtani Ronac , Gross Cary P.
Published: July 2020

PURPOSE:

As immune checkpoint inhibitors (ICIs) have transformed the care of patients with cancer, it is unclear whether treatment at the end of life (EOL) has changed. Because aggressive therapy at the EOL is associated with increased costs and patient distress, we explored the association between the Food and Drug Administration (FDA) approvals of ICIs and treatment patterns at the EOL.

METHODS:

We conducted a retrospective, observational study using patient-level data from a nationwide electronic health record–derived database. Patients had advanced melanoma, non–small-cell lung cancer (NSCLC; cancer types with an ICI indication), or microsatellite stable (MSS) colon cancer (a cancer type without an ICI indication) and died between 2013 and 2017. We calculated annual proportions of decedents who received systemic cancer therapy in the final 30 days of life, using logistic regression to model the association between the post-ICI FDA approval time and use of systemic therapy at the EOL, adjusting for patient characteristics. We assessed the use of chemotherapy or targeted/biologic therapies at the EOL, before and after FDA approval of ICIs using Pearson chi-square test.

RESULTS:

There was an increase in use of EOL systemic cancer therapy in the post-ICI approval period for both melanoma (33.9% to 43.2%; P < .001) and NSCLC (37.4% to 40.3%; P < .001), with no significant change in use of systemic therapy in MSS colon cancer. After FDA approval of ICIs, patients with NSCLC and melanoma had a decrease in the use of chemotherapy, with a concomitant increase in use of ICIs at the EOL.

CONCLUSION:

The adoption of ICIs was associated with a substantive increase in the use of systemic therapy at the EOL in melanoma and a smaller yet significant increase in NSCLC.
Considerations and Caveats when Applying Global Sensitivity Analysis Methods to Physiologically Based Pharmacokinetic Models
Authors: Liu Dan , Li Linzhong , Rostami-Hodjegan Amin , Bois Frederic Y. , Jamei Masoud
Published: July 2020

Three global sensitivity analysis (GSA) methods (Morris, Sobol and extended Sobol) are applied to a minimal physiologically based PK (mPBPK) model using three model drugs given orally, namely quinidine, alprazolam, and midazolam. We investigated how correlations among input parameters affect the determination of the key parameters influencing pharmacokinetic (PK) properties of general interest, i.e., the maximal plasma concentration (Cmax) time at which Cmax is reached (Tmax), and area under plasma concentration (AUC). The influential parameters determined by the Morris and Sobol methods (suitable for independent model parameters) were compared to those determined by the extended Sobol method (which considers model parameter correlations). For the three drugs investigated, the Morris method was as informative as the Sobol method. The extended Sobol method identified different sets of influential parameters to Morris and Sobol. These methods overestimated the influence of volume of distribution at steady state (Vss) on AUC24h for quinidine and alprazolam. They also underestimated the effect of volume of liver (Vliver) for all three drugs, the impact of enzyme intrinsic clearance of CYP2C9 and CYP2E1 for quinidine, and that of UGT1A4 abundance for midazolam. Our investigation showed that the interpretation of GSA results is not straightforward. Dismissing existing model parameter correlations, GSA methods such as Morris and Sobol can lead to biased determination of the key parameters for the selected outputs of interest. Decisions regarding parameters’ influence (or otherwise) should be made in light of available knowledge including the model assumptions, GSA method limitations, and inter-correlations between model parameters, particularly in complex models.
TCR-Seq Identifies Distinct Repertoires of Distant-Metastatic and Nondistant-Metastatic Thyroid Tumors
Authors: Lan Xiabin , Cao Jun , Ye Ke , Zhang Chao , Zhang Qihong , Ge Xinyang , Wang Changxi , Zhang Chunliu , Tai Zaixian , Wei Wei , Huang Yi , Yi Xin , Tan Zhuo , Zheng Chuanming , Chen Chao , Zhu Xin , Wang Jiafeng , Xu Jiajie , Zhu Xuhang , Ge Minghua
Published: July 2020

Context

Malignant thyroid tumor with distant metastasis is associated with poor outcome. Early detection of distant metastasis is of great clinical importance.

Objective

Thyroid tumor infiltrated with T cells can serve as a biomarker for monitoring metastasis.

Design

A retrospective analysis was performed of patient clinical samples collected between 2012 to 2018, using T-cell receptor sequencing (TCR-seq) for clinical exploration.

Setting

This study took place at Zhejiang Cancer Hospital.

Patients

Sixty-eight patients with papillary thyroid cancer (PTC) (distinct metastatic status) and 21 patients with benign nodules were enrolled. All patients had not received any treatment before surgery.

Main Outcome Measure

The characteristics of TCRβ complementary-determining region 3 (CDR3) for each patient were determined by high-throughput sequencing.

Results

The TCRβ diversity of malignant tumors is significantly higher than benign nodules both in blood and tumor samples (Shannon index, blood, P < .01; tumor, P < .001). The malignant tumors with distant metastasis or invasiveness showed lower TCRβ diversity than nonmetastasis (Shannon index, P < .01) or noninvasive (Shannon index, P < .01) malignant tumors. Analysis of the Morisita-Horn similarity index indicated significant TCRβ repertoire similarity between tumor and blood in distant-metastatic patients (comparison with nonmetastasis, P < .05). According to the discrepancy of the CDR3 among patients with different clinicopathological status, the classifier was constructed to discriminate distant-metastatic individuals. A promising area under the curve value of 83.8% was obtained with the number of overlapping CDR3 clonotypes.

Conclusion

The availability and reliability of TCR-seq render it prospective to translate these intrinsic attributes into clinical practice for monitoring distant metastasis in PTC patients.
Catecholamine-Sparing Effect of Angiotensin II in an Anephric Patient With Mixed Shock After Cardiac Revascularization Surgery: A Case Report
Authors: Cutler Nathan S. , Khanna Ashish K.
Published: July 2020

Vasodilatory shock is common following cardiac surgery, caused by an inflammatory response to cardiopulmonary bypass (CPB). Some cases are refractory to volume resuscitation, high-dose catecholamines, arginine vasopressin, and established adjunctive therapies. Angiotensin II (ANG-2), an endogenous hormone in the renin–angiotensin–aldosterone system (RAAS), has several direct and indirect vasoconstrictive properties that make it a promising potential treatment. This case describes the successful use of ANG-2 in an anephric patient who suffered from severe refractory shock following CPB, offering a unique potential mechanism of benefit in a broader population of patients with baseline impaired RAAS.
A Case Report of a Successful Percutaneous Trial and Surgical Placement of a Spinal Cord Stimulator in a Patient With Severe Thoracolumbar Scoliosis
Authors: Cheng Jenny Zhao , Bao Mike H. , Shen Shiqian
Published: July 2020

Spinal cord stimulation has been demonstrated as a therapeutic option for patients with persistent lumbar radicular pain secondary to failed back surgery syndrome. This case report demonstrates a successful percutaneous spinal cord stimulator (SCS) trial followed by surgical placement of a permanent SCS to treat lumbar radicular pain and axial low back pain in a patient with severe thoracolumbar scoliosis status after laminectomy and spinal fusion surgery. Currently, there is a paucity of literature on this topic.
Assessing the Economic Consequences of Disarmament
Authors: Button Kenneth
Published: July 2020

This article looks at how a group of diverse economic experts tackled a major macroeconomic question and managed to reach a consensus conclusion. This was despite being confronted with limited data, embryonic general-equilibrium methodologies, and limited computing power. The realization, in the early 1960s, that the procession of nuclear weapons would shortly extend beyond the USA, Britain, France, and Russia led to increased fears of catastrophic global warfare. The economic concern with disarmament was along Keynesian lines, namely that reduced public expenditure on defense (“conversion”) could lead to a serious economic depression. The focus here is on a United Nations Consultative Group which had the remit of estimating the economic and social consequences of global disarmament. Using information from documents of the time, substantially supplemented with personal commentaries of committee members, both published and from archives, the paper examines how the committee managed to reconcile very divergent economic views to produce a unanimous report. These basic matters of political economy are as germane today as they were nearly sixty years ago. Indeed, probably more so with the challenges of sustainable development being added to those of global peace.
Words, Not Bombs
Authors: Rahmani Sina
Published: July 2020

The introduction to this special issue of boundary 2 examines W. G. Sebald’s rapid and sudden transformation from controversial and curmudgeonly Germanist to literary superstar as a case study in the “global valences of the critical.” The massive success of Sebald’s strange and variegated oeuvre among critics highlights a pervasive and troubling provincialism afflicting this supposedly global moment in world cultural history. Using Sebald’s The Rings of Saturn, the author links the emergence of “distant” modes of reading to drone warfare and concludes by calling for greater emphasis on literary translation.