by Michael Neidlin, Efthymia Chantzi, George Macheras, Mats G. Gustafsson, Leonidas G. AlexopoulosThe pathophysiology of osteoarthritis (OA) involves dysregulation of anabolic and catabolic processes associated with a broad panel of proteins that ultimately lead to cartilage degradation. An increased understanding about these protein interactions with systematic in vitro analyses may give new ideas regarding candidates for treatment of OA related cartilage degradation. Therefore, an ex vivo tissue model of cartilage degradation was established by culturing tissue explants with bacterial collagenase II. Responses of healthy and degrading cartilage were analyzed through protein abundance in tissue supernatant with a 26-multiplex protein profiling assay, after exposing the samples to a panel of 55 protein stimulations present in synovial joints of OA patients. Multivariate data analysis including exhaustive pairwise variable subset selection identified the most outstanding changes in measured protein secretions. MMP9 response to stimulation was outstandingly low in degrading cartilage and there were several protein pairs like IFNG and MMP9 that can be used for successful discrimination between degrading and healthy samples. The discovered changes in protein responses seem promising for accurate detection of degrading cartilage. The ex vivo model seems interesting for drug discovery projects related to cartilage degradation, for example when trying to uncover the unknown interactions between secreted proteins in healthy and degrading tissues.
One of the most severe complications in aesthetic and reconstructive surgeries is the partial or total necrosis of a skin flap. In our experimental study, we demonstrated the use of adipose‐derived stem cells in the increase of skin flap survival rates. Stem cells were isolated from the fat of Wistar rats and genetically modified to permanently produce a green fluorescent protein (GFP). Two random‐pattern skin flaps (2 cm × 8 cm) were elevated on the dorsal area of the spine, and after being separated from the surgical wounds with a thin silicone sheet, they were placed back onto their original location. Then, the autologous GFP‐producing cells were injected intradermally into the dorsal area of the rats. At the seventh day, after the implantation of the stem cells, a clinical and immunohistochemical control was performed. The fluorescence microscopy revealed green vascular formations, suggesting that autologous GFP stromal cells were converted into endothelial cells through neovascularization. In the control skin flaps, where no stromal cells were used, no fluorescence was observed. The statistical analysis showed significantly lower necrosis rates in the right‐sided flaps (i.e., the flaps where adipose‐derived stromal cells were injected) compared with the left‐sided ones. Findings from our study demonstrate that adipose‐derived stem cells play an important role in the improvement of skin flap survival. Neovascularization is an effective way of achieving it.
To identify how social return on investment (SROI) analysis—traditionally used by business consultants—has been interpreted, used and innovated by academics in the health and social care sector and to assess the quality of peer-reviewed SROI studies in this sector.
Community and residential settings.
A wide range of demographic groups and age groups.
The following databases were searched: Web of Science, Scopus, CINAHL, Econlit, Medline, PsychINFO, Embase, Emerald, Social Care Online and the National Institute for Health and Care Excellence. Limited uptake of SROI methodology by academics was found in the health and social care sector. From 868 papers screened, 8 studies met the criteria for inclusion in this systematic review. Study quality was found to be highly variable, ranging from 38% to 90% based on scores from a purpose-designed quality assessment tool. In general, relatively high consistency and clarity was observed in the reporting of the research question, reasons for using this methodology and justifying the need for the study. However, weaknesses were observed in other areas including justifying stakeholders, reporting sample sizes, undertaking sensitivity analysis and reporting unexpected or negative outcomes. Most papers cited links to additional materials to aid in reporting. There was little evidence that academics had innovated or advanced the methodology beyond that outlined in a much-cited SROI guide.
Academics have thus far been slow to adopt SROI methodology in the evaluation of health and social care interventions, and there is little evidence of innovation and development of the methodology. The word count requirements of peer-reviewed journals may make it difficult for authors to be fully transparent about the details of their studies, potentially impacting the quality of reporting in those studies published in these journals.
Closed incision negative pressure wound therapy (CINPWT) has been shown to be clinically effective compared with the traditional gauze dressing, reducing surgical site infections and wound complications. We evaluated the effect of CINPWT compared with gauze dressing on the need for revision surgery and survival after non‐traumatic major lower amputation. We included 309 patients undergoing 403 major lower amputations in a retrospective study from January 1, 2010 to November 23, 2017. A total of 139 patients received CINPWT, and 170 patients received stump bandage. There was no statistically significant difference between the two groups regarding the need for revision surgery (P = .45). Fourteen stump bandage patients and 15 CINPWT patients died in hospital (P = .57). One year after amputation, 55 CINPWT patients and 66 stump bandage patients had died (P = .82). Survival probabilities adjusted for age and gender 2 years after amputation were .52 (.43‐.61) and .49 (.42‐.58), respectively, and 3 years after amputation were .36 (.25‐.50) and .39 (.32‐.47), respectively. We also found no significant difference in the need for revision surgery in survival probabilities up till 3 years after amputation between patients treated with CINPWT and patients treated with gauze bandage postoperatively.
To determine the proportion of trials published in nursing science journals in 2017 that were prospectively registered.
A review of randomized controlled trials published in a Journal Citation Report nursing science journal in 2017.
Table of contents of included journals.
Randomized controlled trials were identified by manually reviewing the title of all papers published in included journals. Included trials were classified as: (a) Prospectively registered; (b) Retrospectively registered; (c) Registered but registration not reported in the manuscript; (d) Indeterminate registration; and (e) Not registered. Additionally, we recorded if the trial registration number was reported in the manuscript abstract.
Of 151 randomized controlled trials published in nursing science journals in 2017, 17 (11%) were prospectively registered. Thirty‐six (24%) trials were retrospectively and 93 (62%) not registered. We could not determine the registration status of five (3%) trials. The registration number was included in the abstract of two prospectively and eight retrospectively registered studies. Compared with the rest of the world, trial registration rates were significantly lower in Asian countries.
Two included trials were prospectively registered and reported a registration number in the abstract. Compared with other disciplines, rates of prospective trial registration are low. Nurse trialists must ensure that they prospectively register all trials.
We intended to replicate this review in subsequent years with a view to reporting improvements in prospective registration rates over time.
The treatment of chronic functional nausea or nausea due to functional dyspepsia in children is generally symptomatic. Moreover, these disorders pose a risk for worse psychosocial and health outcomes in children. Hypnotherapy (HT), by its ability to positively influence gastrointestinal and psychosocial functioning, may be an effective treatment for chronic nausea.
To test efficacy, this multicentre, parallel, randomised controlled, open label trial evaluates whether gut-directed HT is superior to standard medical treatment (SMT) for reducing nausea. The study will be conducted at eleven academic and non-academic hospitals across the Netherlands. A total of 100 children (8–18 years), fulfilling the Rome IV criteria for chronic idiopathic nausea or functional dyspepsia with prominent nausea, will be randomly allocated (1:1) to receive HT or SMT. Children allocated to the HT group will receive six sessions of HT during 3 months, while children allocated to the SMT group will receive six sessions of SMT+supportive therapy during the same period. The primary outcome will be the difference in the proportion of children with at least 50% reduction of nausea, compared with baseline at 12 months’ follow-up. Secondary outcomes include the changes in abdominal pain, dyspeptic symptoms, quality of life, anxiety, depression, school absences, parental absence of work, healthcare costs and adequate relief of symptoms, measured directly after treatment, 6 and 12 months’ follow-up. If HT proves effective for reducing nausea, it may become a new treatment strategy to treat children with chronic functional nausea or functional dyspepsia with prominent nausea.
Results of the study will be publicly disclosed to the public, without any restrictions, in peer-reviewed journal and international conferences. The study is approved by the Medical Research Ethics Committees United (MEC-U) in the Netherlands.
This study examines the role of age-disparate partnerships on young women’s HIV risk by investigating coital frequency and condom use within age-disparate partnerships involving women aged 15 to 24.
A community-based, cross-sectional study was conducted.
Participants were randomly selected using a two-stage random sampling method in uMgungundlovu district, KwaZulu-Natal, South Africa, between June 2014 and June 2015.
A total of 1306 15–24-year-old women in an ongoing heterosexual partnership were included in the analysis. Participants had to be a resident in the area for 12 months, and able to provide informed consent and speak one of the local languages (Zulu or English).
Sexual frequency was assessed by asking participants how many times they had sex with each partner in the past 12 months. The degree of condomless sex within partnerships was assessed in the survey by asking participants how often they used a condom with their partners.
Age-disparate partnerships were associated with a higher order category (once, 2–5, 6–10, 11–20, >20) of coital frequency (adjusted OR (aOR) 1.32, p
The finding that increased sexual activity is positively associated with age-disparate partnerships adds to the evidence that age-disparate partnerships pose greater HIV risk for young women. Our study results indicate that interventions to reduce risky sexual behaviour within age-disparate partnerships remain relevant to reducing the high HIV incidence rates among adolescent girls and young women.
Asthma and chronic obstructive pulmonary disease (COPD) are common respiratory conditions, which result in significant morbidity worldwide. These conditions are associated with a range of non-specific symptoms, which in themselves are a target for health research. Such research is increasingly being conducted using electronic health records (EHRs), but computable phenotype definitions, in the form of code sets or code lists, are required to extract structured data from these large routine databases in a systematic and reproducible way. The aim of this protocol is to specify a systematic review to identify code sets for respiratory symptoms in EHRs research.
MEDLINE and Embase databases will be searched using terms relating to EHRs, respiratory symptoms and use of code sets. The search will cover all English-language studies in these databases between January 1990 and December 2017. Two reviewers will independently screen identified studies for inclusion, and key data will be extracted into a uniform table, facilitating cross-comparison of codes used. Disagreements between the reviewers will be adjudicated by a third reviewer. This protocol has been produced in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol guidelines.
As a review of previously published studies, no ethical approval is required. The results of this review will be submitted to a peer-reviewed journal for publication and can be used in future research into respiratory symptoms that uses electronic healthcare databases.
by Yvonne J. Rosenberg, George K. Lewis, David C. Montefiori, Celia C. LaBranche, Mark G. Lewis, Lori A. Urban, Jonathan P. Lees, Lingjun Mao, Xiaoming JiangRecombinant antibodies play increasingly important roles as immunotherapeutic treatments for human cancers as well as inflammatory and infectious diseases and have revolutionized their management. In addition, their therapeutic potential may be enhanced by the introduction of defined mutations in the crystallizable fragment (Fc) domains eg YTE (M252Y/S254T/T256E) and LS (M428L/N434S), as a consequence of increased half-lives and prolonged duration of protection. However, the functional properties of any biologic may be compromised by unanticipated immunogenicity in humans, rendering them ineffective. Several potent broadly neutralizing HIV monoclonal antibodies (bnAbs) have been identified that protect against SHIV challenge in macaque models and reduce HIV viremia in HIV-infected individuals. In the present study, the pharmacokinetics and immunogenicity of one or more 5mg/kg subcutaneous (SC) injections in naïve macaques of the HIV bnAb PGT121 and its PGT121-YTE mutant, both produced in plants, have been compared towards prolonging efficacy. Induction of anti-drug/anti-idiotypic antibodies (ADA, anti-id) has been monitored using both binding ELISAs and more functional inhibition of virus neutralization (ID50) assays. Timing of the anti-Id responses and their impact on pharmacokinetic profiles (clearance) and efficacy (protection) have also been assessed. The results indicate that ADA induction in naïve macaques may result both from injection of the previously non-immunogenic PGT121 into pre-primed animals and also by the introduction of the YTE mutation. Binding ADA antibody levels, induced in 7/10 macaques within two weeks of a first or second PGT121-YTE injection, were closely associated with both reduced pharmacokinetic profiles and loss of protection. However no correlation was observed with inhibitory ADA activity. These studies provide insights into both the structural features of bnAb and the immune status of the host which may contribute to the development of ADA in macaques and describe possible YTE-mediated changes in structure/orientation of HIV bnAbs that trigger such responses.
Emergency intubation of children with abnormal respiratory or cardiac physiology is a high-risk procedure and associated with a high incidence of adverse events including hypoxemia. Successful emergency intubation is dependent on inter-related patient and operator factors. Preoxygenation has been used to maximise oxygen reserves in the patient and to prolong the safe apnoeic time during the intubation phase. Transnasal Humidified Rapid Insufflation Ventilatory Exchange (THRIVE) prolongs the safe apnoeic window for a safe intubation during elective intubation. We designed a clinical trial to test the hypothesis that THRIVE reduces the frequency of adverse and hypoxemic events during emergency intubation in children and to test the hypothesis that this treatment is cost-effective compared with standard care.
The Kids THRIVE trial is a multicentre randomised controlled trial performed in participating emergency departments and paediatric intensive care units. 960 infants and children aged 0–16 years requiring emergency intubation for all reasons will be enrolled and allocated to THRIVE or control in a 1:1 allocation with stratification by site, age (7 years) and operator (junior and senior). Children allocated to THRIVE will receive weight appropriate transnasal flow rates with 100% oxygen, whereas children in the control arm will not receive any transnasal oxygen insufflation. The primary outcomes are defined as follows: (1) hypoxemic event during the intubation phase defined as SpO2
Ethics approval for the protocol and consent process has been obtained (HREC/16/QRCH/81). The trial has been actively recruiting since May 2017. The study findings will be submitted for publication in a peer-reviewed journal.
by Emmalee J. Northrop, Jerica J. J. Rich, Jim R. Rhoades, George A. PerryBlood tests for early detection of pregnancy in cattle based on pregnancy-associated glycoproteins (PAGs) are commercially available. The objective of these studies were to compare the accuracy of blood tests to transrectal ultrasonography in detecting AI pregnancies, and to compare the accuracy of blood tests in predicting pregnancy loss. Beef cattle from 6 herds were synchronized using a recommended CIDR based protocol (Study 1: n = 460; Study 2: n = 472). Pregnancy status was determined by transrectal ultrasonography between days 28–40 following AI, blood samples were collected at this time. In study 2 a final pregnancy determination was performed at the end of the breeding season to determine pregnancy loss. Each serum sample was examined for PAG concentrations using a microtiter plate reader and/or scored by two technicians blind to pregnancy status and pregnancy loss. For study 1 Cohen’s kappa statistics were calculated to assess the agreement between each test and transrectal ultrasonography. For study 2 data was analyzed using the GLIMMIX procedure of SAS with herd as a random effect, and loss, age, and their interaction included in the model. Agreement was good to very good for each test. There was no difference (P = 0.79) in sensitivity, but a difference (PP = 0.04), age (P = 0.0002), and their interaction (P = 0.06) on PAG concentrations. In conclusion both pregnancy tests were accurate at detecting AI pregnancies, and were in very good agreement with transrectal ultrasonography. Both tests detected differences in PAGs among females that maintained and lost pregnancy; however, prediction proved to be difficult as most females were above the threshold and would have been considered pregnant on the day of testing.
The aim of this study was to provide guidance to improve the completeness and clarity of meta‐ethnography reporting.
Evidence‐based policy and practice require robust evidence syntheses which can further understanding of people's experiences and associated social processes. Meta‐ethnography is a rigorous seven‐phase qualitative evidence synthesis methodology, developed by Noblit and Hare. Meta‐ethnography is used widely in health research, but reporting is often poor quality and this discourages trust in and use of its findings. Meta‐ethnography reporting guidance is needed to improve reporting quality.
The eMERGe study used a rigorous mixed‐methods design and evidence‐based methods to develop the novel reporting guidance and explanatory notes.
The study, conducted from 2015 ‐ 2017, comprised of: (1) a methodological systematic review of guidance for meta‐ethnography conduct and reporting; (2) a review and audit of published meta‐ethnographies to identify good practice principles; (3) international, multidisciplinary consensus‐building processes to agree guidance content; (4) innovative development of the guidance and explanatory notes.
Recommendations and good practice for all seven phases of meta‐ethnography conduct and reporting were newly identified leading to 19 reporting criteria and accompanying detailed guidance.
The bespoke eMERGe Reporting Guidance, which incorporates new methodological developments and advances the methodology, can help researchers to report the important aspects of meta‐ethnography. Use of the guidance should raise reporting quality. Better reporting could make assessments of confidence in the findings more robust and increase use of meta‐ethnography outputs to improve practice, policy, and service user outcomes in health and other fields. This is the first tailored reporting guideline for meta‐ethnography. This article is being simultaneously published in the following journals: Journal of Advanced Nursing, Psycho‐oncology, Review of Education, and BMC Medical Research Methodology.
by Sandra F. Lam, Venktesh S. Shirure, Yunli E. Chu, Alan G. Soetikno, Steven C. GeorgeMicrofluidic devices have been successfully used to recreate in vitro biological microenvironments, including disease states. However, one constant issue for replicating microenvironments is that atmospheric oxygen concentration (21% O2) does not mimic physiological values (often around 5% O2). We have created a microfluidic device that can control both the spatial and temporal variations in oxygen tensions that are characteristic of in vivo biology. Additionally, since the microcirculation is responsive to hypoxia, we used a 3D sprouting angiogenesis assay to confirm the biological relevance of the microfluidic platform. Our device consists of three parallel connected tissue chambers and an oxygen scavenger channel placed adjacent to these tissue chambers. Experimentally measured oxygen maps were constructed using phosphorescent lifetime imaging microscopy and compared with values from a computational model. The central chamber was loaded with endothelial and fibroblast cells to form a 3D vascular network. Four to six days later, fibroblasts were loaded into the side chambers, and a day later the oxygen scavenger (sodium sulfite) was flowed through the adjacent channel to induce a spatial and temporal oxygen gradient. Our results demonstrate that both constant chronic and intermittent hypoxia can bias vessel growth, with constant chronic hypoxia showing higher degrees of biased angiogenesis. Our simple design provides consistent control of spatial and temporal oxygen gradients in the tissue microenvironment and can be used to investigate important oxygen-dependent biological processes in conditions such as cancer and ischemic heart disease.
by Bryan M. H. Keng, Fei Gao, Ru San Tan, See Hooi Ewe, Louis L. Y. Teo, Bei Qi Xie, George B. B. Goh, Woon-Puay Koh, Angela S. KohAgeing-related alterations in cardiovascular structure and function are commonly associated with chronic inflammation. A potential blood-based biomarker indicative of a chronic inflammatory state is N-Terminal Pro C-Type Natriuretic Peptide (NTproCNP). We aim to investigate associations between NTproCNP and ageing-related impairments in cardiovascular function. Community-based participants underwent same-day assessment of cardiovascular function and circulating profiles of plasma NTproCNP. Associations between cardiovascular and biomarker profiles were studied in adjusted models including standard covariates. We studied 93 participants (mean age 73 ± 5.3 years, 36 women), of whom 55 (59%) had impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s)
Unlike other forms of evaluation, social return on investment (SROI) methodology offers a way of placing values on personal, social and community outcomes, not just economic outcomes. Developed in 2000, there have been calls for greater academic involvement in development of SROI, which to date has been more typically implemented in-house or by consultants. This protocol describes a systematic review of SROI analysis conducted on health and social care programmes which represent a significant sector of social enterprise internationally. The aims of the systematic review are to (1) identify the extent to which academics have adopted SROI methodology, (2) how academics have interpreted, used and developed SROI methodology and (3) to assess the quality of studies published under peer review.
The systematic review will include peer-reviewed studies since 2000 published in English. Search terms will be ‘social return on investment’ or ‘SROI’. Health and social care interventions will be identified in the initial screening given the proliferation of possible key words in these areas. Databases to be searched include Web of Science, Scopus, Medline, Social Care Online and National Institute for Health and Care Excellence. Two reviewers will independently conduct initial screening based on titles and abstracts against the inclusion criteria. Data extracted will include date of intervention, country, study design, aim of intervention/programme, participants and setting, health and social care measures used, and SROI ratio. The quality of studies will be assessed by two reviewers using a SROI quality framework designed for the purpose of this study.
The systematic review will review existing published academic literature; as such, ethics approval is not required for this study. A paper of the systematic review will be submitted to a peer-reviewed journal.
To evaluate the preliminary effectiveness of the BRief Evaluation of Asthma TH erapy intervention, a 7‐min primary care provider‐delivered shared decision‐making protocol that uses motivational interviewing to address erroneous asthma disease and medication beliefs.
A multi‐centre masked two‐arm group‐randomized clinical trial.
This 2‐year pilot study is funded (September 2016) by the National Institute of Nursing Research. Eight providers will be randomized to one of two arms: the active intervention (N = 4) or a dose‐matched attention control (N = 4). Providers will deliver the intervention to which they were randomized to 10 Black adult patients with uncontrolled asthma (N = 80). Patients will be followed three months postintervention to test the preliminary intervention effects on asthma control (primary outcome) and on medication adherence, lung function, and asthma‐related quality of life (secondary outcomes).
This study will evaluate the preliminary impact of a novel shared decision‐making intervention delivered in a real world setting to address erroneous disease and medication beliefs as a means of improving asthma control in Black adults. Results will inform a future, large‐scale randomized trial with sufficient power to test the intervention's effectiveness.
Shared decision‐making is an evidence‐based intervention with proven effectiveness when implemented in the context of labour‐ and time‐intensive research protocols. Medication adherence is linked with the marked disparities evident in poor and minority adults with asthma. Addressing this requires a novel multifactorial approach as we have proposed. To ensure sustainability, shared decision‐making interventions must be adapted to and integrated into real‐world settings.
Trial registration: Registered at clincialtrials.gov as NCT03036267 and NCT03300752.
by Amy Johnston, Shu-Ching Hsieh, Marc Carrier, Shannon E. Kelly, Zemin Bai, Becky Skidmore, George A. WellsBackground
Venous thromboembolism (VTE) is a major global cause of morbidity and mortality. Low molecular weight heparin (LMWH) and fondaparinux (FDP) are frequently used to treat and prevent VTE and have a variety of safety and practical advantages over other anticoagulants, including use in outpatient settings. These medications are commonly listed on drug formularies, which act as a gateway for health plan prescription coverage by outlining the circumstances under which patients will be covered for specific drugs and drug products. Because patient access to medications is impacted by the nature of their listing on formularies, they must be rigorously reviewed and modernized as new evidence emerges.Methods
As part of a broader drug class review team, we completed a systematic review of clinical practice guidelines to determine whether the recommendations they reported aligned with the indications listed for the coverage of LMWH and FDP in an outpatient drug formulary. Guideline quality was assessed using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. Recommendation matrices were used to systematically compare, categorize, and summarize included recommendations.Results
Twenty-seven guidelines were included from which 168 eligible recommendations were identified. Generally, AGREE II domains were adequately addressed; however, domain five (applicability) was poorly addressed. Most recommendations were based on moderate- to low-quality/limited evidence and reported on the use of LMWHs generally; few reported on specific agents.Conclusions
Our findings contributed to the recommendation that the formulary listing for LMWH and FDP be streamlined to include coverage for specific outpatient indications. The paucity of available evidence on the comparative efficacy of specific LMWH agents against each other and FDP limited agent-specific listing recommendations, highlighting the need for high-quality comparative studies on this topic.
The objectives were to characterise the haematological profile of screen-detected chronic kidney disease (CKD) participants and to correlate the complete blood count measures with the commonly advocated kidney function estimators.
The current cross-sectional study used data, collected between February 2015 and November 2016, of 1564 adults of mixed-ancestry, who participated in the Cape Town Vascular and Metabolic Health study. Kidney function was estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. CKD was defined as estimated glomerular filtration rate (eGFR) 2, and anaemia as haemoglobin level
Based on the MDRD and CKD-EPI equations, the crude prevalence of CKD was 6% and 3%. Irrespective of the equation used, median red blood cell (RBC) indices were consistently lower in those with CKD compared with those without CKD (all p
Though it remains unclear whether common kidney function estimators provide accurate estimates of CKD in Africans, the correlation of their estimates with deteriorating RBC profile, suggests that advocated estimators, to some extent approximate kidney function in African populations.