bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial
Authors: Koonrungsesomboon Nut , Ngamphaiboon Nuttapong , Townamchai Natavudh , Teeyakasem Pimpisa , Charoentum Chaiyut , Charoenkwan Pimlak , Natesirinilkul Rungrote , Sathitsamitphong Lalita , Ativitavas Touch , Chaiyawat Parunya , Klangjorhor Jeerawan , Hongeng Suradej , Pruksakorn Dumnoensun
Published: March 2020

Background

Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted.

Methods

A total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1–2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4–5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period.

Discussion

This trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development.

Trial registration

This trial was prospectively registered on Thai Clinical Trials Registry (registration number:TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.
CHD4 mediates proliferation and migration of non-small cell lung cancer via the RhoA/ROCK pathway by regulating PHF5A
Authors: Xu Nuo , Liu Fanglei , Wu Shengdi , Ye Maosong , Ge Haiyan , Zhang Meiling , Song Yuanlin , Tong Lin , Zhou Jian , Bai Chunxue
Published: March 2020

Background

Chromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; however, its roles in cancer initiation and progression remain largely unknown. This study aimed to demonstrate the role of CHD4 in the development of non-small cell lung cancer (NSCLC) and determine the potential mechanisms of action.

Methods

By using immunohistochemistry, the expression levels were evaluated in both cancer and non-cancerous tissues. Subsequently, CHD4 knockdown and overexpression strategies were employed to investigate the effects of CHD4 on cell proliferation, migration, along with the growth and formation of tumors in a xenografts mouse model. The protein expression levels of CHD4, PHF5A and ROCK/RhoA markers were determined by Western blot analysis.

Results

Compared with non-cancerous tissues, CHD4 was overexpressed in cancer tissues and CHD4 expression levels were closely related to clinical parameters of NSCLC patients. In H292 and PC-9 cell lines, CHD4 overexpression could promote the proliferative and migratory potential of NSCLC cells. Furthermore, down-regulation of CHD4 could reduce the proliferative and migratory ability in A549 and H1299 cell lines. Meanwhile, knockdown of CHD4 could decrease the tumorigenicity in nude mice. Finally, we demonstrated that one of the mechanisms underlying the promotive effect of CHD4 on NSCLC proliferation and migration may be through its interaction with PHD finger protein 5A (PHF5A) and subsequent activation of the RhoA/ROCK signaling pathway.

Conclusions

CHD4, which is highly expressed in cancer tissue, could be an independent prognostic factor for NSCLC patients. CHD4 plays an important role in regulating the proliferative and migratory abilities of NSCLC via likely the RhoA/ROCK pathway by regulating PHF5A.
Outcomes in patients with chronic uveitis: which factors matter to patients? A qualitative study
Authors: Stolk-Vos Aline C. , Kasigar Hamasa , Nijmeijer Karlijn J. , Missotten Tom O. , Busschbach Jan J. , van de Klundert Joris J. , Kranenburg Leonieke W.
Published: March 2020

Purpose

Outcome measurements currently used in chronic uveitis care fail to cover the full patient perspective. The aim of this study is to develop a conceptual model of the factors that adult patients with chronic uveitis consider to be important when evaluating the impact of their disease and treatment.

Methods

A qualitative study design was used. Twenty chronic uveitis patients were recruited to participate in two focus groups. Data were transcribed verbatim and analysed using thematic analysis in ATLAS.ti.

Results

Coding of the transcripts resulted in a total of 19 codes divided over five themes: 1) disease symptoms and treatment; 2) diagnosis and treatment process; 3) impact on daily functioning; 4) emotional impact; and 5) treatment success factors.

Conclusion

The conceptual model resulting from this study can contribute to the development of future uveitis specific measures in adults.
Individualized treat-and-extend regime for optimization of real-world vision outcome and improved patients’ persistence
Authors: Volkmann Ingo , Knoll Katharina , Wiezorrek Mareile , Greb Oliver , Framme Carsten
Published: March 2020

Background

Intravitreal injections are a mandatory treatment for macular edema due to nAMD, DME and RVO. These chronic diseases usually need chronic treatment using intravitreal injections with anti-VEGF agents. Thus, many trials were performed to define the best treatment interval using pro re nata regimes (PRN), fixed regimes or treat-and-extend regimes (TE). However, real-world studies reveal a high rate of losing patients within a 2-year interval of treatment observation causing worse results. In this study we analyzed retrospectively 2 years of real-world experience with an individualized treat-and-extend injection scheme.

Methods

Since 2015 our treatment scheme for intravitreal injections has been switched from PRN to TE. Out of 102 patients 59 completed a follow up time of 2 years. Every patient received visual acuity testing, SD-OCT and slit lamp examination prior to every injection. At each visit an injection was performed and the treatment interval was adjusted mainly on SD-OCT based morphologic changes by increasing or reducing in 2-week steps. Individual changes of the treatment protocol by face-to-face communication between physician and patient were possible.

Results

After 1 year of treatment visual acuity gain in nAMD was 7.4 ± 2.2 ETDRS letters (n = 34; injection frequency: 7.4 ± 0.4) respectively 6.1 ± 4.7 in DME (n = 9; injection frequency: 8.4 ± 1.1) and 9.7 ± 4.5 in RVO (n = 16; injection frequency: 7.6 ± 0.5). After 2 years of treatment results were as following: nAMD: visual acuity gain 6.9 ± 2.1 (injection frequency: 12.6 ± 0.7); DME: 11.1 ± 5.1 (injection frequency: 14.0 ± 1.0); RVO: 7.5 ± 5.0 (injection frequency: 11.2 ± 0.9). Planned treatment exit after 2 year was achieved in 29.4% of patients in nAMD (0% after 1 year); 0% in DME (0% after 1 year); and 31.3% in RVO (0% after 1 year). Patients’ persistence was 94.1% during the follow-up.

Conclusion

Using a consequent and individualized TE regime in daily practice may lead to a high patients’ persistence and visual acuity gains nearly comparable to those of large prospective clinical trials. Crucial factors are face-to-face communication with the patient as well as a stringent management regime. At this time TE may be the only instrument for proactive therapy which should therefore be regarded as a first-line tool in daily practice.
Enhancing communication, informed consent and recruitment in a paediatric urgent care surgical trial: a qualitative study
Authors: Sherratt Frances C. , Beasant Lucy , Crawley Esther M. , Hall Nigel J. , Young Bridget
Published: March 2020

Background

Recruiting patients to paediatric trials can be challenging, especially in trials that compare markedly different management pathways and are conducted in acute settings. We aimed to enhance informed consent and recruitment in the CONTRACT trial (CONservative TReatment of Appendicitis in Children a randomised controlled Trial; ISRCTN15830435) – a feasibility trial that compared non-operative treatment (antibiotics) versus appendicectomy for uncomplicated acute appendicitis.

Methods

Qualitative study embedded within CONTRACT and conducted across three UK children’s hospitals. Data were transcribed audio-recordings of 85 CONTRACT recruitment consultations with 58 families; and semi-structured interviews with 35 health professionals and 28 families (34 parents, 14 children) invited to participate in CONTRACT. Data analysis drew on thematic approaches. Throughout CONTRACT, we used findings from the ongoing qualitative analysis to inform bespoke communication training for health professionals recruiting to CONTRACT. Before and after training we also examined qualitative changes in communication during consultations and quantitative changes in recruitment rates.

Results

Bespoke communication training focussed on presenting the trial arms in a balanced way, emphasising clinical equipoise, exploring family treatment preferences and managing families’ expectations about the trial’s treatment pathways. Analysis of recruitment consultations indicated that health professionals’ presentation of treatment arms became increasingly balanced following training, (e.g. avoiding imbalanced terminology) and recruitment rose from 38 to 62%. However, they remained reluctant to explore families’ treatment preferences and respond with further information to balance these preferences. Analyses of interviews identified the time constraints of the urgent care setting, concerns about coercion, and reservations about exposing children to conversations about treatment risks as reasons for this reluctance. Interviews with families indicated the importance of clear explanations of trial treatment timings and sensitive communication of treatment allocation for both recruitment and retention.

Conclusions

Following bespoke training based on the qualitative analyses, health professionals presented CONTRACT to families in clearer and more balanced ways and this was associated with an increase in the recruitment rate. Despite training, health professionals remained reluctant to explore families’ treatment preferences. We provide several recommendations to enhance communication, informed consent, recruitment and retention in future trials in urgent care settings.
PEBRA trial – effect of a peer-educator coordinated preference-based ART service delivery model on viral suppression among adolescents and young adults living with HIV: protocol of a cluster-randomized clinical trial in rural Lesotho
Authors: Lejone Thabo Ishmael , Kopo Mathebe , Bachmann Nadine , Brown Jennifer Anne , Glass Tracy Renée , Muhairwe Josephine , Matsela Tebatso , Scherrer Ramona , Chere Lebohang , Namane Tilo , Labhardt Niklaus Daniel , Amstutz Alain
Published: March 2020

Background

Despite tremendous progress in controlling the HIV epidemic in sub-Saharan Africa, HIV-related mortality continues to increase among adolescents and young people living with HIV (AYPLHIV). Globally, sub-Saharan Africa accounts for 85% of the AYPLHIV. Overall outcomes along the HIV care cascade are worse among AYPLHIV as compared to all other age groups due to various challenges in accessing and adhering to antiretroviral therapy (ART). New, innovative multicomponent packages of differentiated service delivery (DSD) models, are required to address the specific needs of AYPLHIV. This study aims to evaluate the feasibility and effectiveness of a multicomponent DSD model (PEBRA model) designed for AYPLHIV and coordinated by a peer-educator.

Methods

PEBRA (Peer-Educator Based Refill of ART) is a cluster randomized, open-label, superiority trial conducted at 20 health facilities in three districts of Lesotho, Southern Africa. The clusters (health facilities) are randomly assigned to either the PEBRA model or standard of care in a 1:1 ratio, stratified by district. AYPLHIV aged 15–24 years old in care and on ART at one of the clusters are eligible. In the PEBRA model, a peer-educator coordinates the antiretroviral therapy (ART) services - such as medication pick-up, SMS notifications and support options - according to the preferences of the AYPLHIV. The peer-educator delivers this personalized model using a tablet-based application called PEBRApp. The control clusters continue to offer standard of care: ART services coordinated by the nurse. The primary endpoint is viral suppression at 12 months. Secondary endpoints include self-reported adherence to ART, quality of life, satisfaction with care and engagement in care. The target sample size is 300 AYPLHIV. Statistical analyses are conducted and reported in line with CONSORT guidelines for cluster randomized trials.

Discussion

The PEBRA trial will provide evidence on the feasibility and effectiveness of an inclusive, holistic and preference-based DSD model for AYPLHIV that is coordinated by a peer-educator. Many countries in SSA have an existing peer-educator program. If proven effective, the PEBRA model and PEBRApp have the potential to be scaled up to similar settings.

Trial registration

Clinicaltrials.gov, NCT03969030. Registered on 31 May 2019. More information: www.pebra.info
Comparing hemoglobin distributions between population-based surveys matched by country and time
Authors: Hruschka Daniel J. , Williams Anne M. , Mei Zuguo , Leidman Eva , Suchdev Parminder S. , Young Melissa F. , Namaste Sorrel
Published: March 2020

Background

Valid measurement of hemoglobin is important for tracking and targeting interventions. This study compares hemoglobin distributions between surveys matched by country and time from The Demographic and Health Survey (DHS) Program and the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.

Methods

Four pairs of nationally representative surveys measuring hemoglobin using HemoCue® with capillary (DHS) or venous (BRINDA) blood were matched by country and time. Data included 17,719 children (6–59 months) and 21,594 non-pregnant women (15–49 y). Across paired surveys, we compared distributional statistics and anemia prevalence.

Results

Surveys from three of the four countries showed substantial differences in anemia estimates (9 to 31 percentage point differences) which were consistently lower in BRINDA compared to DHS (2 to 31 points for children, 1 to 16 points for women).

Conclusion

We identify substantial differences in anemia estimates from surveys of similar populations. Further work is needed to identify the cause of these differences to improve the robustness of anemia estimates for comparing populations and tracking improvements over time.
Study protocol of a co-created primary organizational-level intervention with the aim to improve organizational and social working conditions and decrease stress within the construction industry – a controlled trial
Authors: Cedstrand Emma , Nyberg Anna , Bodin Theo , Augustsson Hanna , Johansson Gun
Published: March 2020

Background

Within construction industry, physical work exposures have long been recognized as possible determinants for musculoskeletal disorders, but less attention has been given the increasing organizational and social work hazards and stress within this industry. There is to date a lack of knowledge about how to improve organizational and social working conditions and decrease stress within the construction industry.

Methods

This paper outlines the design of a controlled trial to evaluate the effectiveness of a co-created organizational-level intervention with the aim to improve role clarity, quantitative demands, staffing, planning, team effectiveness, psychosocial safety climate and stress. Two regions (> 700 employees) within one large construction company in Sweden will participate as intervention and control group. Further we present the design of the process evaluation assessing fidelity, support from managers, readiness for change and contextual factors. We will utilize questionnaires, semi-structured interviews, observations and documentation as means for data collection, hence a mixed methods approach is applied.

Discussion

The study is expected to contribute to the understanding of how adverse organizational and social working conditions and stress can be improved within the construction industry. By applying co-creation we wish to develop an intervention and implementation strategies that fit to the context, are in line with the needs of end-users and are supported by all management levels - all of which are highlighted features in successful workplace interventions.

Trial registration

ISRCTN, ISRCTN16548039. Registered 12/02/20. Retrospectively registered
Cost-effectiveness of mandatory bicycle helmet use to prevent traumatic brain injuries and death
Authors: Reuvers Rick , Over Eelco A. B. , Suijkerbuijk Anita W. M. , Polder Johan J. , de Wit G. Ardine , van Gils Paul F.
Published: March 2020

Background

Traumatic brain injury (TBI) is the main cause of mortality and severe morbidity in cyclists admitted to Dutch emergency departments (EDs). Although the use of bicycle helmets is an effective way of preventing TBI, this is uncommon in the Netherlands. An option to increase its use is through a legal enforcement. However, little is known about the cost-effectiveness of such mandatory use of helmets in the Dutch context.

The current study aimed to assess the cost-effectiveness of a law that enforces helmet use to reduce TBI and TBI-related mortality.

Methods

The cost-effectiveness was estimated through decision tree modelling. In this study, wearing bicycle helmets enforced by law was compared with the current situation of infrequent voluntary helmet use. The total Dutch cycling population, consisting of 13.5 million people, was included in the model. Model data and parameters were obtained from Statistics Netherlands, the National Road Traffic Database, Dutch Injury Surveillance System, and literature. Effects included were numbers of TBI, death, and disability-adjusted life years (DALY). Costs included were healthcare costs, costs of productivity losses, and helmet costs. Sensitivity analysis was performed to assess which parameter had the largest influence on the incremental cost-effectiveness ratio (ICER).

Results

The intervention would lead to an estimated reduction of 2942 cases of TBI and 46 deaths.

Overall, the incremental costs per 1) death averted, 2) per TBI averted, and 3) per DALY averted were estimated at 1) € 2,002,766, 2) € 31,028 and 3) € 28,465, respectively. Most favorable were the incremental costs per DALY in the 65+ age group: € 17,775.

Conclusions

The overall costs per DALY averted surpassed the Dutch willingness to pay threshold value of € 20,000 for cost-effectiveness of preventive interventions. However, the cost per DALY averted for the elderly was below this threshold, indicating that in this age group largest effects can be reached. If the price of a helmet would reduce by 20%, which is non-hypothetical in a situation of large-scale purchases and use of these helmets, the introduction of this regulation would result in an intervention that is almost cost-effective in all age groups.
Cumulative lifetime violence severity scale: development and initial testing among men
Authors: Scott-Storey Kelly , O’Donnell Sue , Wuest Judith , MacIntosh Judith , Merritt-Gray Marilyn
Published: March 2020

Background

Knowledge of the relationship between men’s health and violence is flawed by narrow and faulty conceptualization and measurement of violence that often results in attribution of health problems to one form or type of violence without consideration of other exposures. Our purpose is to describe the development and initial testing of the Cumulative Lifetime Violence Severity scale designed for use in health research to measure men’s perceptions of the severity of their cumulative lifetime violence.

Methods

We framed the dimensions of violence severity as: type (physical, psychological, sexual), timing (childhood, adulthood), focus (perpetrator, target), context, frequency, and degree of distress. Items reflecting these dimensions were vetted by local experts including individuals who identified as men, with particular attention to meaningful language for men. The measure was pretested, revised to 64 items, and tested for test-retest reliability prior to use in a study of 685 English-speaking Eastern Canadian men, ages 19 to 65 years. We used Principal Components Analysis to illuminate the underlying dimensionality of the items.

Results

Principal Components Analysis yielded a 44-item 11 component solution that accounted for 64.06% of variance with good model fit and a Cronbach’s alpha of .92. All dimensions of our conceptualization of violence severity were reflected in the components, except Adult Target Sexual Violence. Convergent validity between the Cumulative Lifetime Violence Severity-44 Scale and a global lifetime violence rating scale was r = .750 (p < .001) and concurrent validity was moderate and significant between the Cumulative Lifetime Violence Severity-44 scale and measures of mental health problems commonly experienced by people with violence histories.

Conclusions

The Cumulative Lifetime Violence Severity-44 scale shows promise as the first comprehensive measure of cumulative lifetime violence for health research that considers gender, individual distress and experiences as both perpetrator and target. Next steps include further exploratory analysis with a more diverse sample of men and confirmatory factor analysis.
Single-stage repair of contaminated hernias using a novel antibiotic-impregnated biologic porcine submucosa tissue matrix
Authors: Minor Samuel , Brown Carl J. , Rooney Paul S. , Hodde Jason P. , Julien Lisa , Scott Tracy M. , Karimuddin Ahmer A. , Raval Manoj J. , Phang P. Terry
Published: March 2020

Background

Single-stage repair of incisional hernias in contaminated fields has a high rate of surgical site infection (30–42%) when biologic grafts are used for repair. In an attempt to decrease this risk, a novel graft incorporating gentamicin into a biologic extracellular matrix derived from porcine small intestine submucosa was developed.

Methods

This prospective, multicenter, single-arm observational study was designed to determine the incidence of surgical site infection following implantation of the device into surgical fields characterized as CDC Class II, III, or IV.

Results

Twenty-four patients were enrolled, with 42% contaminated and 25% dirty surgical fields. After 12 months, 5 patients experienced 6 surgical site infections (21%) with infection involving the graft in 2 patients (8%). No grafts were explanted.

Conclusions

The incorporation of gentamicin into a porcine-derived biologic graft can be achieved with no noted gentamicin toxicity and a low rate of device infection for patients undergoing single-stage repair of ventral hernia in contaminated settings.

Trial registration

The study was registered March 27, 2015 at www.clinicaltrials.gov as NCT02401334.
Pharmacists’ knowledge and counselling on fall risk increasing drugs in a tertiary teaching hospital in Nigeria
Authors: Akande-Sholabi Wuraola , Ogundipe Francis S. , Adisa Rasaq
Published: March 2020

Background

Falls and fall-related injuries are a foremost health concern among older adults aged 60 years and above. Fall-risk-increasing drugs (FRIDs) use by older adults is one related cause of falling, and it is frequently used among older adults. Pharmacist-led counselling is an aspect of patient education that has been associated with improved therapeutic outcome and quality of life in high income countries with scarcity of information in low-middle income countries. This study therefore aims to assess hospital pharmacists’ knowledge and counselling on fall-related medications using the list compiled by the Swedish National Board of Health and Welfare on FRIDs and orthostatic drugs (ODs).

Methods

A cross-sectional survey was carried out among 56 pharmacists working in a teaching hospital in Nigeria, between July and August 2019, using a self-administered questionnaire. Data were summarized with descriptive statistics while chi-square test was used for categorical variables at p < 0.05.

Results

Thirty-five (62.5%) were within 10 years of practice experience. Two-third (62.5%) of the pharmacists possessed an additional qualification to Bachelor of Pharmacy degree. Twenty-two (40.0%) were aware of the FRIDs and ODs list. In all, (89.3%) had “unsatisfactory” knowledge of classes of medications and specific medicines that could cause a fall. Most pharmacists 42 (80.8%) focused counsel on appropriate medication use, adverse effects of drugs and storage of medications. Knowledge score of both FRIDs and ODs were neither significantly associated with pharmacists’ years of qualification (χ2 = 1.282; p = 0.733), (χ2 = 2.311; p = 0.510) nor with possession of additional qualification (χ2 = 0.854; p = 0.836), (χ2 = 2.996; p = 0.392). Majority, 53 (98.1%) believed that patients will benefit from effective counselling on FRIDs and ODs. About half (25; 51.0%) suggested training through seminar presentation as a measure for FRIDs and ODs sensitization.

Conclusion

A substantial gap in knowledge and awareness of FRIDs and ODs was noted among the hospital pharmacists. However, engagement of pharmacists on counsel that focus on medication use, adverse effect and storage was relatively better. Thus, there is a general need to create awareness about fall-risk-increasing drugs among hospital pharmacists, so as to help improve the therapeutic outcome particularly in the older adults.
Effects of various mastitis treatments on the reproductive performance of cows
Authors: Smulski Sebastian , Gehrke Marek , Libera Kacper , Cieslak Adam , Huang Haihao , Patra Amlan Kumar , Szumacher-Strabel Malgorzata
Published: March 2020

Background

The purpose of the study described here was to evaluate the effects of different supportive treatments - such as antioxidants, immunomodulators, and nonsteroidal anti-inflammatory drugs (NSAIDs) - in mastitic cows treated with intramammary antibiotics on the efficacy of mastitis therapy and fertility indices. Fertility indices, including time to first insemination, conception rate, time between calving and conception (open days), and number of services per conception (insemination index), were evaluated for 300 dairy cows. Sixty cows without apparent clinical signs of mastitis were assigned 100 days after calving to a Control group. Another 240 cows with clinical mastitis were systematically divided into four experimental groups (I–IV) of 60 cows each. All mastitic cows were treated with approved intramammary antibiotics in recommended doses. Cows in Group I were treated with intramammary antibiotics only. Cows in Groups II, III, and IV, received intramammary antibiotic therapy and a single injection with antioxidants, an immunomodulator (lysozyme dimer), or an NSAID (flunixin meglumine), respectively.

Results

The lowest treatment efficacy of mastitic quarters and cows was noted in Group I (51.6 and 53.3%; p > 0.05). The best recovery rate was noted in Group II (63.3 and 66.7%; p > 0.05), followed by Group III (58.3 and 60.9%) and Group IV (58.3 and 58.0%; p > 0.05). The above data did not differ statistically (p > 0.05). The animals with mastitis (Groups I–IV) showed prolonged time to first insemination, more open days, higher insemination index, and lower conception rate than the control cows (p <  0.05). The conception rate of healthy cows and of successfully treated cows was insignificantly lower than that of cows required prolonged antibiotic therapy. Supportive treatments improved the mastitis recovery rate compared with intramammary antibiotics only. The efficacy of mastitis treatments affected the reproduction indices: in cows requiring prolonged treatment with antioxidants, a shorter time to first insemination was needed than in other groups (p <  0.05). Fewer days open were observed between the group with antioxidants and the control group (p <  0.05).

Conclusions

Clinical mastitis negatively affects reproductive indices (days open, pregnancy rate after first AI, NSC) in dairy cows. Different types of supportive medicine, such as antioxidants (vitamin C and E, and β-carotene), lysozyme dimer, or NSAID can be useful in improving fertility in mastitis cows treated with antibiotic only. It has been proven that each supportive treatment improved antibiotics efficiency and the antibiotic combined with the antioxidants was the most effective treatment.
Enhancing the bioconversion of phytosterols to steroidal intermediates by the deficiency of kasB in the cell wall synthesis of Mycobacterium neoaurum
Authors: Xiong Liang-Bin , Liu Hao-Hao , Zhao Ming , Liu Yong-Jun , Song Lu , Xie Zhi-Yong , Xu Yi-Xin , Wang Feng-Qing , Wei Dong-Zhi
Published: March 2020

Background

The bioconversion of phytosterols into high value-added steroidal intermediates, including the 9α-hydroxy-4-androstene-3,17-dione (9-OHAD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC), is the cornerstone in steroid pharmaceutical industry. However, the low transportation efficiency of hydrophobic substrates into mycobacterial cells severely limits the transformation. In this study, a robust and stable modification of the cell wall in M. neoaurum strain strikingly enhanced the cell permeability for the high production of steroids.

Results

The deletion of the nonessential kasB, encoding a β-ketoacyl-acyl carrier protein synthase, led to a disturbed proportion of mycolic acids (MAs), which is one of the most important components in the cell wall of Mycobacterium neoaurum ATCC 25795. The determination of cell permeability displayed about two times improvement in the kasB-deficient strain than that of the wild type M. neoaurum. Thus, the deficiency of kasB in the 9-OHAD-producing strain resulted in a significant increase of 137.7% in the yield of 9α-hydroxy-4-androstene-3,17-dione (9-OHAD). Ultimately, the 9-OHAD productivity in an industrial used resting cell system was reached 0.1135 g/L/h (10.9 g/L 9-OHAD from 20 g/L phytosterol) and the conversion time was shortened by 33%. In addition, a similar self-enhancement effect (34.5%) was realized in the 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC) producing strain.

Conclusions

The modification of kasB resulted in a meaningful change in the cell wall mycolic acids. Deletion of the kasB gene remarkably improved the cell permeability, leading to a self-enhancement of the steroidal intermediate conversion. The results showed a high efficiency and feasibility of this construction strategy.
Expression profile analysis identifies key genes as prognostic markers for metastasis of osteosarcoma
Authors: Guan Xiaoqing , Guan Zhiyuan , Song Chunli
Published: March 2020

Background

OS is the most common malignant tumor of bone which was featured with osteoid or immature bone produced by the malignant cells, and biomarkers are urgently needed to identify patients with this aggressive disease.

Methods

We downloaded gene expression profiles from GEO and TARGET datasets for OS, respectively, and performed WGCNA to identify the key module. Whereafter, functional annotation and GSEA demonstrated the relationships between target genes and OS.

Results

In this study, we discovered four key genes—ALOX5AP, HLA-DMB, HLA-DRA and SPINT2 as new prognostic markers and confirmed their relationship with OS metastasis in the validation set.

Conclusions

In conclusion, ALOX5AP, HLA-DMB, HLA-DRA and SPINT2 were identified by bioinformatics analysis as possible prognostic markers for OS metastasis.
Identification of novel biomarkers affecting the metastasis of colorectal cancer through bioinformatics analysis and validation through qRT-PCR
Authors: Lian Wenping , Jin Huifang , Cao Jingjing , Zhang Xinyu , Zhu Tao , Zhao Shuai , Wu Sujun , Zou Kailu , Zhang Xinyun , Zhang Mingliang , Zheng Xiaoyong , Peng Mengle
Published: March 2020

Background

Tumor progression and distant metastasis are the main causes of deaths in colorectal cancer (CRC) patients, and the molecular mechanisms in CRC metastasis have not been completely discovered.

Methods

We identified differentially expressed genes (DEGs) and lncRNAs (DELs) of CRC from The Cancer Genome Atlas (TCGA) database. Then we conducted the weighted gene co-expression network analysis (WGCNA) to investigate co-expression modules related with CRC metastasis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, DEG-DEL co-expression network and survival analyses of significant modules were also conducted. Finally, the expressions of selected biomarkers were validated in cell lines by quantitative real-time PCR (qRT-PCR).

Results

2032 DEGs and 487 DELs were involved the construction of WGCNA network, and greenyellow, turquoise and brown module were identified to have more significant correlation with CRC metastasis. GO and KEGG pathway analysis of these three modules have proven that the functions of DEGs were closely involved in many important processes in cancer pathogenesis. Through the DEG-DEL co-expression network, 12 DEGs and 2 DELs were considered as hub nodes. Besides, survival analysis showed that 30 DEGs were associated with the overall survival of CRC. Then 10 candidate biomarkers were chosen for validation and the expression of CA2, CHP2, SULT1B1, MOGAT2 and C1orf115 were significantly decreased in CRC cell lines when compared to normal human colonic epithelial cells, which were consistent with the results of differential expression analysis. Especially, low expression of SULT1B1, MOGAT2 and C1orf115 were closely correlated with poorer survival of CRC.

Conclusion

This study identified 5 genes as new biomarkers affecting the metastasis of CRC. Besides, SULT1B1, MOGAT2 and C1orf115 might be implicated in the prognosis of CRC patients.
District-level approach for tailoring and targeting interventions: a new path for malaria control and elimination
Authors: Gosling Roly , Chimumbwa John , Uusiku Petrina , Rossi Sara , Ntuku Henry , Harvard Kelly , White Chris , Tatarsky Allison , Chandramohan Daniel , Chen Ingrid
Published: March 2020

Despite huge investments and implementation of effective interventions for malaria, progress has stalled, with transmission being increasingly localized among difficult-to-reach populations and outdoor-biting vectors. Targeting difficult pockets of transmission will require the development of tailored and targeted approaches suited to local context, drawing from insights close to the frontlines. Districts are best placed to develop tailored, locally appropriate approaches. We propose a reorganization of how malaria services are delivered. Firstly, enabling district health officers to serve as conduits between technical experts in national malaria control programmes and local community leaders with knowledge specific to local, at-risk populations; secondly, empowering district health teams to make malaria control decisions. This is a radical shift that requires the national programme to cede some control. Shifting towards a district or provincial level approach will necessitate deliberate planning, and repeated, careful assessment, starting with piloting and learning through experience. Donors will need to alter current practice, allowing for flexible funding to be controlled at sub-national levels, and to mix finances between case management, vector control and surveillance, monitoring and evaluation. System-wide changes proposed are challenging but may be necessary to overcome stalled progress in malaria control and elimination and introduce targeted interventions tailored to the needs of diverse malaria affected populations.
Amplicon deep sequencing of kelch13 in Plasmodium falciparum isolates from Senegal
Authors: Gaye Amy , Sy Mouhamad , Ndiaye Tolla , Siddle Katherine J. , Park Daniel J. , Deme Awa B. , Mbaye Aminata , Dieye Baba , Ndiaye Yaye Die , Neafsey Daniel E. , Early Angela , Farrell Timothy , Yade Mamadou Samb , Diallo Mamadou Alpha , Diongue Khadim , Bei Amy , Ndiaye Ibrahima Mbaye , Volkman Sarah K. , Badiane Aida Sadikh , Ndiaye Daouda
Published: March 2020

Background

In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy (ACT) with artemether–lumefantrine as the first-line treatment for uncomplicated Plasmodium falciparum malaria. To date, multiple mutations associated with artemisinin delayed parasite clearance have been described in Southeast Asia in the Pfk13 gene, such as Y493H, R539T, I543T and C580Y. Even though ACT remains clinically and parasitologically efficacious in Senegal, the spread of resistance is possible as shown by the earlier emergence of resistance to chloroquine in Southeast Asia that subsequently spread to Africa. Therefore, surveillance of artemisinin resistance in malaria endemic regions is crucial and requires the implementation of sensitive tools, such as next-generation sequencing (NGS) which can detect novel mutations at low frequency.

Methods

Here, an amplicon sequencing approach was used to identify mutations in the Pfk13 gene in eighty-one P. falciparum isolates collected from three different regions of Senegal.

Results

In total, 10 SNPs around the propeller domain were identified; one synonymous SNP and nine non-synonymous SNPs, and two insertions. Three of these SNPs (T478T, A578S and V637I) were located in the propeller domain. A578S, is the most frequent mutation observed in Africa, but has not previously been reported in Senegal. A previous study has suggested that A578S could disrupt the function of the Pfk13 propeller region.

Conclusion

As the genetic basis of possible artemisinin resistance may be distinct in Africa and Southeast Asia, further studies are necessary to assess the new SNPs reported in this study.
Rapid shifts in the age-specific burden of malaria following successful control interventions in four regions of Uganda
Authors: Kigozi Simon P. , Kigozi Ruth N. , Epstein Adrienne , Mpimbaza Arthur , Sserwanga Asadu , Yeka Adoke , Nankabirwa Joaniter I. , Halliday Katherine , Pullan Rachel L. , Rutazaana Damian , Sebuguzi Catherine M. , Opigo Jimmy , Kamya Moses R. , Staedke Sarah G. , Dorsey Grant , Greenhouse Bryan , Rodriguez-Barraquer Isabel
Published: March 2020

Background

Malaria control using long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) has been associated with reduced transmission throughout Africa. However, the impact of transmission reduction on the age distribution of malaria cases remains unclear.

Methods

Over a 10-year period (January 2009 to July 2018), outpatient surveillance data from four health facilities in Uganda were used to estimate the impact of control interventions on temporal changes in the age distribution of malaria cases using multinomial regression. Interventions included mass distribution of LLINs at all sites and IRS at two sites.

Results

Overall, 896,550 patient visits were included in the study; 211,632 aged < 5 years, 171,166 aged 5–15 years and 513,752 > 15 years. Over time, the age distribution of patients not suspected of malaria and those malaria negative either declined or remained the same across all sites. In contrast, the age distribution of suspected and confirmed malaria cases increased across all four sites. In the two LLINs-only sites, the proportion of malaria cases in < 5 years decreased from 31 to 16% and 35 to 25%, respectively. In the two sites receiving LLINs plus IRS, these proportions decreased from 58 to 30% and 64 to 47%, respectively. Similarly, in the LLINs-only sites, the proportion of malaria cases > 15 years increased from 40 to 61% and 29 to 39%, respectively. In the sites receiving LLINs plus IRS, these proportions increased from 19 to 44% and 18 to 31%, respectively.

Conclusions

These findings demonstrate a shift in the burden of malaria from younger to older individuals following implementation of successful control interventions, which has important implications for malaria prevention, surveillance, case management and control strategies.
“We have this, with my husband, we live in harmony”: exploring the gendered decision-making matrix for malaria prevention and treatment in Nampula Province, Mozambique
Authors: Hildon Zoe Jane-Lara , Escorcio-Ymayo Maria , Zulliger Rose , Arias de Aramburú Rosario , Lewicky Nan , Harig Hunter , Chidassicua Jose Braz , Underwood Carol , Pinto Liliana , Figueroa Maria Elena
Published: March 2020

Background

Conceptualizing gender dynamics and ways of bridging entrenched gender roles will contribute to better health promotion, policy and planning. Such processes are explored in relation to malaria in Mozambique.

Methods

A multi-method, qualitative study using focus group discussions (FGDs) and in-depth interviews (IDIs) explored the perspectives of community members, leaders and stakeholders on malaria. The study was conducted in Nampula Province, in an intervention district for the Tchova Tchova Stop Malaria (TTSM) gender-sensitive community dialogues, and in a non-intervention district.

Results

Participants (n = 106) took part in six FGDs and five IDIs in each district. Those exposed to TTSM commonly stated that the programme influenced more equalitarian gender roles, attitudes and uptake of protective malaria-related practices. These positive changes occurred within the context of an observed, gendered decision-making matrix, which aligns inward- or outward-facing decisions with malaria prevention or treatment. Decisions more dependent on male or elder sanctioning at community level are outward-facing decisions, while decisions falling within women’s domain at household level are inward-facing decisions. Related to prevention, using bed nets was largely an inward-facing prevention decision for women, who were generally tasked with hanging, washing and making nets usable. Net purchase and appropriation for malaria prevention (rather than for instance for fishing) was men’s prerogative. Regular net use was associated with sleeping together more regularly, bringing couples closer. Attending antenatal care to access intermittent preventive treatment during pregnancy was often an outward-facing prevention decision, under the purview of older, influential women and ultimately needing sanctioning by men. With respect to seeking care for malaria symptoms, women typically sought help from traditional healers first. This inward-facing treatment decision was within their control, in contrast to the frequently transport-dependent, outward-facing decision to attend a health facility. Sharing decisions was described as a feature of a “harmonious household,” something that was said to be encouraged by the TTSM intervention and that was both lived and aspirational.

Conclusions

TTSM community dialogues helped communication on both interpersonal (couple) and community levels, ultimately encouraging malaria-related behaviours. Leveraging ways of bringing men and women together to share decision making will improve malaria intervention success.
Immunization with virus-like particles conjugated to CIDRα1 domain of Plasmodium falciparum erythrocyte membrane protein 1 induces inhibitory antibodies
Authors: Harmsen Charlotte , Turner Louise , Thrane Susan , Sander Adam F. , Theander Thor G. , Lavstsen Thomas
Published: March 2020

Background

During the erythrocytic cycle, Plasmodium falciparum malaria parasites express P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) that anchor the infected erythrocytes (IE) to the vascular lining of the host. The CIDRα1 domain of PfEMP1 is responsible for binding host endothelial protein C receptor (EPCR), and increasing evidence support that this interaction triggers severe malaria, accounting for the majority of malaria-related deaths. In high transmission regions, children develop immunity to severe malaria after the first few infections. This immunity is believed to be mediated by antibodies targeting and inhibiting PfEMP1, causing infected erythrocytes to circulate and be cleared in the spleen. The development of immunity to malaria coincides with acquisition of broad antibody reactivity across the CIDRα1 protein family. Altogether, this identifies CIDRα1 as an important vaccine target. However, the antigenic diversity of the CIDRα1 domain family is a challenge for vaccine development.

Methods

Immune responses in mice vaccinated with Virus-Like Particles (VLP) presenting CIDRα1 antigens were investigated. Antibody reactivity was tested to a panel of recombinant CIDRα1 domains, and the antibodies ability to inhibit EPCR binding by the recombinant CIDRα1 domains was tested in Luminex-based multiplex assays.

Results

VLP-presented CIDRα1.4 antigens induced a rapid and strong IgG response capable of inhibiting EPCR-binding of multiple CIDRα1 domains mainly within the group A CIDRα1.4–7 subgroups.

Conclusions

The study observations mirror those from previous CIDRα1 vaccine studies using other vaccine constructs and platforms. This suggests that broad CIDRα1 antibody reactivity may be achieved through vaccination with a limited number of CIDRα1 variants. In addition, this study suggest that this may be achieved through vaccination with a human compatible VLP vaccine platform.