How context can impact clinical trials : a multi-country qualitative case study comparison of diagnostic biomarker test interventions

Background Context matters for the successful implementation of medical interventions, but its role remains surprisingly understudied. Against the backdrop of antimicrobial resistance, a global health priority, we investigated the introduction of a rapid diagnostic biomarker test (C-reactive protein, or CRP) to guide antibiotic prescriptions in outpatient settings and asked, “Which factors account for cross-country variations in the effectiveness of CRP biomarker test interventions?” Methods We conducted a cross-case comparison of CRP point-of-care test trials across Yangon (Myanmar), Chiang Rai (Thailand), and Hanoi (Vietnam). Cross-sectional qualitative data were originally collected as part of each clinical trial to broaden their evidence base and help explain their respective results. We synthesised these data and developed a large qualitative data set comprising 130 interview and focus group participants (healthcare workers and patients) and nearly one million words worth of transcripts and interview notes. Inductive thematic analysis was used to identify contextual factors and compare them across the three case studies. As clinical trial outcomes, we considered patients’ and healthcare workers’ adherence to the biomarker test results, and patient exclusion to gauge the potential “impact” of CRP point-of-care testing on the population level. Results We identified three principal domains of contextual influences on intervention effectiveness. First, perceived risks from infectious diseases influenced the adherence of the clinical users (nurses, doctors). Second, the health system context related to all three intervention outcomes (via the health policy and antibiotic policy environment, and via health system structures and the ensuing utilisation patterns). Third, the demand-side context influenced the patient adherence to CRP point-of-care tests and exclusion from the intervention through variations in local healthcare-seeking behaviours, popular conceptions of illness and medicine, and the resulting utilisation of the health system. Conclusions Our study underscored the importance of contextual variation for the interpretation of clinical trial findings. Further research should investigate the range and magnitude of contextual effects on trial outcomes through meta-analyses of large sets of clinical trials. For this to be possible, clinical trials should collect qualitative and quantitative contextual information for instance on their disease, health system, and demand-side environment. Trial registration: ClinicalTrials.gov Identifiers NCT02758821 and NCT01918579

Centre-specific bacterial pathogen typing affects infection-control decision making

Whole-genome sequencing is becoming the de facto standard for bacterial outbreak surveillance and infection prevention. This is accompanied by a variety of bioinformatic tools and needs bioinformatics expertise for implementation. However, little is known about the concordance of reported outbreaks when using different bioinformatic workflows. In this multi-centre proficiency testing among 13 major Dutch healthcare-affiliated centres, bacterial whole-genome outbreak analysis was assessed. Centres who participated obtained two randomized bacterial datasets of Illumina sequences, a Klebsiella pneumoniae and a Vancomycin-resistant Enterococcus faecium, and were asked to apply their bioinformatic workflows. Centres reported back on antimicrobial resistance, multi-locus sequence typing (MLST), and outbreak clusters. The reported clusters were analysed using a method to compare landscapes of phylogenetic trees and calculating Kendall–Colijn distances. Furthermore, fasta files were analysed by state-of-the-art single nucleotide polymorphism (SNP) analysis to mitigate the differences introduced by each centre and determine standardized SNP cut-offs. Thirteen centres participated in this study. The reported outbreak clusters revealed discrepancies between centres, even when almost identical bioinformatic workflows were used. Due to stringent filtering, some centres failed to detect extended-spectrum beta-lactamase genes and MLST loci. Applying a standardized method to determine outbreak clusters on the reported de novo assemblies, did not result in uniformity of outbreak-cluster composition among centres

Transport Jc in Bulk Superconductors: A Practical Approach?

The characterisation of the critical current density of bulk high temperature superconductors is typically performed using magnetometry, which involves numerous assumptions including, significantly, that Jc within the sample is uniform. Unfortunately, magnetometry is particularly challenging to apply where a local measurement of Jc across a feature, such as a grain boundary, is desired. Although transport measurements appear to be an attractive alternative to magnetization, it is extremely challenging to reduce the cross-sectional area of a bulk sample sufficiently to achieve a sufficiently low critical current that can be generated by a practical current source. In the work described here, we present a technique that enables transport measurements to be performed on sections of bulk superconductors. Metallographic techniques and resin reinforcement were used to create an I-shaped sample of bulk superconductor from a section of Gd-Ba-Cu-O containing 15 wt % Ag2O. The resulting superconducting track had a cross-sectional area of 0.44 mm2. The sample was found to support a critical current of 110 A using a field criterion in the narrowed track region of 1 μV cm-1. We conclude, therefore, that it is possible to measure critical current densities in excess of 2.5 x 108 A m-2 in sections of a bulk superconductor.This work was supported by the Engineering and Physical Sciences Research Council, via a Doctoral Training Award (grant number is EP/L504920/1) and funding from grant number EP/K02910X/1. This work was also supported by the Boeing Company. All data are provided in full in the results section of this paper.This is the author accepted manuscript. The final version is available from IEEE via http://dx.doi.org/10.1109/TASC.2016.253764

Multi-drug resistant Vibrio cholerae O1 variant El Tor isolated in northern Vietnam between 2007 and 2010

Since 2007, there has been a re-emergence of cholera outbreaks in northern Vietnam. To understand the molecular epidemiological relatedness and determine the antibiotic susceptibility profiles of responsible V. cholerae O1 outbreak strains, a representative collection of 100 V. cholerae O1 strains was characterized. V. cholerae O1 strains isolated from diarrhoeal patients in northern Vietnam between 2007 and 2010 were investigated for antibiotic susceptibility and characterized by using phenotypic and genotypic tests, including PFGE analysis. Ten clinical V. cholerae O1 isolates from Bangladesh and Zimbabwe were included for comparison. The results revealed that all isolates were resistant to co-trimoxazole and nalidixic acid, 29 % were resistant to tetracycline and 1 % were resistant to azithromycin. All strains were susceptible to ampicillin–sulbactam, doxycycline, chloramphenicol and ciprofloxacin and 95 % were susceptible to azithromycin. MIC values did show reduced susceptibility to fluoroquinolones and 63 % of the strains were intermediately resistant to tetracycline. The isolates expressed phenotypic traits of both serogroup O1 Ogawa and El Tor and harboured an rstR El Tor and ctxB classical biotype. Among the outbreak isolates, only a single PFGE pattern was observed throughout the study period. This study shows that multi-drug resistant V. cholerae altered El Tor producing classical CT strains are now predominant in northern Vietnam

Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial

Background Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is diffi cult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. Method We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1–65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecifi ed in the protocol and the statistical analysis plan. All analyses were done on the intention-totreat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. Findings Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0·49, 95% CI 0·40–0·61; p<0·0001). Highly signifi cant diff erences were seen in both children and adults, with substantial heterogeneity of the intervention eff ect across the 10 sites (I²=84%, 95% CI 66–96). 140 patients in the C-reactive protein group and 137 patients in the routine care group missed the urine test on day 3, 4, or 5. Antibiotic activity in urine on day 3, 4, or 5 was found in 267 (30%) of 877 patients in the C-reactive protein group versus 314 (36%) of 882 patients in the routine treatment group (OR 0·78, 95% CI 0·63–0·95; p=0·015). Time to resolution of symptoms was similar in both groups. Adverse events were rare, with no deaths and a total of 14 hospital admissions (six in the C-reactive protein group and eight in the control group). Interpretation C-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients’ recovery in primary health care in Vietnam. Health-care providers might have become familiar with the clinical picture of low C-reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed eff ect, rather than overestimation. Qualitative analysis is needed to address diff erences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries

Laboratory Capacity Building in Asia for Infectious Disease Research: Experiences from the South East Asia Infectious Disease Clinical Research Network (SEAICRN)

Heiman Wertheim and colleagues discuss a network that aims to improve infectious disease management through integrated, collaborative clinical research in South East Asia

Seroprevalence of SARS-CoV-2 antibodies among healthcare workers in Dutch hospitals after the 2020 first wave:a multicentre cross-sectional study with prospective follow-up

BACKGROUND: We aimed to estimate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence and describe its determinants and associated symptoms among unvaccinated healthcare workers (HCWs) after the first wave of the pandemic.METHODS: HCWs from 13 Dutch hospitals were screened for antibodies against the spike protein of SARS-CoV-2 in June-July 2020 and after three months. Participants completed a retrospective questionnaire on determinants for occupational and community exposure to SARS-CoV-2 and symptoms suggestive of COVID-19 experienced since January 2020. The seroprevalence was calculated per baseline characteristic and symptom at baseline and after follow-up. Adjusted odds ratios (aOR) for seropositivity were determined using logistic regression.RESULTS: Among 2328 HCWs, 323 (13.9%) were seropositive at enrolment, 49 of whom (15%) reported no previous symptoms suggestive of COVID-19. During follow-up, only 1% of the tested participants seroconverted. Seroprevalence was higher in younger HCWs compared to the mid-age category (aOR 1.53, 95% CI 1.07-2.18). Nurses (aOR 2.21, 95% CI 1.34-3.64) and administrative staff (aOR 1.87, 95% CI 1.02-3.43) had a higher seroprevalence than physicians. The highest seroprevalence was observed in HCWs in the emergency department (ED) (aOR 1.79, 95% CI 1.10-2.91), the lowest in HCWs in the intensive, high, or medium care units (aOR 0.47, 95% CI 0.31-0.71). Chronic respiratory disease, smoking, and having a dog were independently associated with a lower seroprevalence, while HCWs with diabetes mellitus had a higher seroprevalence. In a multivariable model containing all self-reported symptoms since January 2020, altered smell and taste, fever, general malaise/fatigue, and muscle aches were positively associated with developing antibodies, while sore throat and chills were negatively associated.CONCLUSIONS: The SARS-CoV-2 seroprevalence in unvaccinated HCWs of 13 Dutch hospitals was 14% in June-July 2020 and remained stable after three months. A higher seroprevalence was observed in the ED and among nurses, administrative and young staff, and those with diabetes mellitus, while a lower seroprevalence was found in HCWs in intensive, high, or medium care, and those with self-reported lung disease, smokers, and dog owners. A history of altered smell or taste, fever, muscle aches and fatigue were independently associated with the presence of SARS-CoV-2 antibodies in unvaccinated HCWs.</p

Streptococcus suis, an Important Cause of Adult Bacterial Meningitis in Northern Vietnam

Streptococcus suis can cause severe systemic infection in adults exposed to infected pigs or after consumption of undercooked pig products. S. suis is often misdiagnosed, due to lack of awareness and improper testing. Here we report the first fifty cases diagnosed with S. suis infection in northern Viet Nam.In 2007, diagnostics for S. suis were set up at a national hospital in Hanoi. That year there were 43 S. suis positive cerebrospinal fluid samples, of which S. suis could be cultured in 32 cases and 11 cases were only positive by PCR. Seven patients were blood culture positive for S. suis but CSF culture and PCR negative; making a total of 50 patients with laboratory confirmed S. suis infection in 2007. The number of S. suis cases peaked during the warmer months.S. suis was commonly diagnosed as a cause of bacterial meningitis in adults in northern Viet Nam. In countries where there is intense and widespread exposure of humans to pigs, S. suis can be an important human pathogen

Las políticas de reequilibro territorial e innovación institucional en Madrid, 2015-2019

Lograr un mejor reparto de los recursos materiales es una tarea inseparable de una transformación institucional dirigida a un mejor reparto del poder y de la capacidad de decisión. Es preciso reconfigurar las instituciones para redefinir la relación entre estas y la ciudadanía. El espacio de cooperación entre las instituciones públicas y la sociedad civil organizada es un terreno privilegiado para lograr esa reconfiguración institucional. El Fondo de Reequilibrio Territorial se concibe como un primer paso en ese complejo camino y se relaciona con el proceso de descentralización y con el concepto de cooperación público-social. Debe entenderse en relación con otros desarrollos institucionales, como el Consejo Coordinador de los Distritos o los Foros Locales. Una tarea de estas características no puede realizarse desde un solo espacio institucional y en un solo mandato, pero en todo caso debe hacerse contando con la firme voluntad y dirección política del equipo de gobierno que quiera desempeñarla. El gobierno es una herramienta formidable para emprender un proceso de reequilibrio territorial, pero aun cuando no hay en el mismo voluntad política en este sentido existen posibilidades para estimular o condicionar la voluntad del equipo de gobierno: articular un amplio pacto entre los actores políticos, sociales, económicos, académicos, etc. que ponga la cuestión en el centro de la agenda política y eleve hasta lo impagable el coste político de seguir dando la espalda a una cuestión crucial para el futuro de la democracia.Lograr un mejor reparto de los recursos materiales es una tarea inseparable de una transformación institucional dirigida a un mejor reparto del poder y de la capacidad de decisión. Es preciso reconfigurar las instituciones para redefinir la relación entre estas y la ciudadanía. El espacio de cooperación entre las instituciones públicas y la sociedad civil organizada es un terreno privilegiado para lograr esa reconfiguración institucional.El Fondo de Reequilibrio Territorial se concibe como un primer paso en ese complejo camino y se relaciona con el proceso de descentralización y con el concepto de cooperación público-social. Debe entenderse en relación con otros desarrollos institucionales, como el Consejo Coordinador de los Distritos o los Foros Locales. Una tarea de estas características no puede realizarse desde un solo espacio institucional y en un solo mandato, pero en todo caso debe hacerse contando con la firme voluntad y dirección política del equipo de gobierno que quiera desempeñarla. El gobierno es una herramienta formidable para emprender un proceso de reequilibrio territorial, pero aun cuando no hay en el mismo voluntad política en este sentido existen posibilidades para estimular o condicionar la voluntad del equipo de gobierno: articular un amplio pacto entre los actores políticos, sociales, económicos, académicos, etc. que ponga la cuestión en el centro de la agenda política y eleve hasta lo impagable el coste político de seguir dando la espalda a una cuestión crucial para el futuro de la democracia

Brushland tinamou

p. 271-314 [11] p. of plates : ill., maps ; 27 cm.Includes bibliographical references (p. 314)