Smartphone-enabled video-observed versus directly observed treatment for tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority trial.

BACKGROUND: Directly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s, but it is inconvenient for patients and service providers. Video-observed therapy (VOT) has been conditionally recommended by WHO as an alternative to DOT. We tested whether levels of treatment observation were improved with VOT. METHODS: We did a multicentre, analyst-blinded, randomised controlled superiority trial in 22 clinics in England (UK). Eligible participants were patients aged at least 16 years with active pulmonary or non-pulmonary tuberculosis who were eligible for DOT according to local guidance. Exclusion criteria included patients who did not have access to charging a smartphone. We randomly assigned participants to either VOT (daily remote observation using a smartphone app) or DOT (observations done three to five times per week in the home, community, or clinic settings). Randomisation was done by the SealedEnvelope service using minimisation. DOT involved treatment observation by a health-care or lay worker, with any remaining daily doses self-administered. VOT was provided by a centralised service in London. Patients were trained to record and send videos of every dose ingested 7 days per week using a smartphone app. Trained treatment observers viewed these videos through a password-protected website. Patients were also encouraged to report adverse drug events on the videos. Smartphones and data plans were provided free of charge by study investigators. DOT or VOT observation records were completed by observers until treatment or study end. The primary outcome was completion of 80% or more scheduled treatment observations over the first 2 months following enrolment. Intention-to-treat (ITT) and restricted (including only patients completing at least 1 week of observation on allocated arm) analyses were done. Superiority was determined by a 15% difference in the proportion of patients with the primary outcome (60% vs 75%). This trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN26184967. FINDINGS: Between Sept 1, 2014, and Oct 1, 2016, we randomly assigned 226 patients; 112 to VOT and 114 to DOT. Overall, 131 (58%) patients had a history of homelessness, imprisonment, drug use, alcohol problems or mental health problems. In the ITT analysis, 78 (70%) of 112 patients on VOT achieved ≥80% scheduled observations successfully completed during the first 2 months compared with 35 (31%) of 114 on DOT (adjusted odds ratio [OR] 5·48, 95% CI 3·10-9·68; p<0·0001). In the restricted analysis, 78 (77%) of 101 patients on VOT achieved the primary outcome compared with 35 (63%) of 56 on DOT (adjusted OR 2·52; 95% CI 1·17-5·54; p=0·017). Stomach pain, nausea, and vomiting were the most common adverse events reported (in 16 [14%] of 112 on VOT and nine [8%] of 114 on DOT). INTERPRETATION: VOT was a more effective approach to observation of tuberculosis treatment than DOT. VOT is likely to be preferable to DOT for many patients across a broad range of settings, providing a more acceptable, effective, and cheaper option for supervision of daily and multiple daily doses than DOT. FUNDING: National Institute for Health Research.

High prevalence of latent tuberculosis and bloodborne virus infection in a homeless population.

INTRODUCTION: Urban homeless populations in the UK have been shown to have high rates of active tuberculosis, but less is known about the prevalence of latent tuberculosis infection (LTBI). This study aimed to estimate the prevalence of LTBI among individuals using homeless hostels in London. METHODS: We performed a cross-sectional survey with outcome follow-up in homeless hostels in London. Our primary outcome was prevalence of LTBI. Recruitment for the study took place between May 2011 and June 2013. To estimate an LTBI prevalence of 10% with 95% CIs between 8% and 13%, we required 500 participants. RESULTS: 491/804 (61.1%) individuals agreed to be screened. The prevalence of LTBI was 16.5% (81/491; 95% CI 13.2 to 19.8). In UK-born individuals, a history of incarceration was associated with increased risk of LTBI (OR 3.49; 95% CI 1.10 to 11.04; P=0.018) after adjusting for age, length of time spent homeless and illicit drug use. Of the three subjects who met English treatment guidelines for LTBI at the time of the study, none engaged with services after referral for treatment. Prevalence of past hepatitis B infection was 10.4% (51/489; 95% CI 7.7 to 13.1), and 59.5% (291/489; 95% CI 55.1 to 63.9) of individuals were non-immune. Prevalence of current hepatitis C infection was 10.4% (51/489; 95% CI 7.8 to 13.1). CONCLUSIONS: This study demonstrates the high prevalence of LTBI in homeless people in London and the associated poor engagement with care. There is a large unmet need for LTBI and hepatitis C infection treatment, and hepatitis B vaccination, in this group.

A cluster-randomized trial of client and provider-directed financial interventions to align incentives with appropriate case management in retail medicine outlets: Results of the TESTsmART Trial in western Kenya.

ACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years, made possible by publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to overconsumption. We test an innovative, scalable strategy to target ACT-subsidies to clients with a confirmatory diagnosis. We supported malaria testing(mRDTs) in 39 medicine outlets in western Kenya, randomized to three study arms; control arm offering subsidized mRDT testing (0.4USD), client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully-subsidized) ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions, resulting in targeting of ACTs to confirmed malaria cases- 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates(RD = 0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients(RD = 0.01,95% CI:-0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. This uncertainty undermines our ability to definitively conclude that client-directed subsidies are not effective for improving testing and appropriate treatment. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain. Trial registration: ClinicalTrials.gov NCT04428307.

A cluster-randomized trial of client and provider directed financial interventions to align incentives with appropriate case management in private medicine retailers: Results of the TESTsmART trial in Lagos, Nigeria.

Malaria remains a major health priority in Nigeria. Among children with fever who seek care, less than a quarter gets tested for malaria, leading to inappropriate use of the recommended treatment for malaria; Artemisinin-based Combination Therapy (ACT). Here we test an innovative strategy to target ACT subsidies to clients seeking care in Nigeria's private retail health sector who have a confirmed malaria diagnosis. We supported point-of-care malaria testing (mRDTs) in 48 Private Medicine Retailers (PMRs) in the city of Lagos, Nigeria and randomized them to two study arms; a control arm offering subsidized mRDT testing for USD $0.66, and an intervention arm where, in addition to access to subsidized testing as in the control arm, clients who received a positive mRDT at the PMR were eligible for a free (fully subsidized) first-line ACT and PMRs received USD $0.2 for every mRDT performed. Our primary outcome was the proportion of ACTs dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients who were tested at the PMR and adherence to diagnostic test results. Overall, 23% of clients chose to test at the PMR. Test results seemed to inform treatment decisions and resulted in enhanced targeting of ACTs to confirmed malaria cases with only 26% of test-negative clients purchasing an ACT compared to 58% of untested clients. However, the intervention did not offer further improvements, compared to the control arm, in testing rates or dispensing of ACTs to test-positive clients. We found that ACT subsidies were not passed on to clients testing positive in the intervention arm. We conclude that mRDTs could reduce ACT overconsumption in Nigeria's private retail health sector, but PMR-oriented incentive structures are difficult to implement and may need to be complemented with interventions targeting clients of PMRs to increase test uptake and adherence. Trials registration: Clinical Trials Registration Number: NCT04428307. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816435/ Correction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476591/.

Colistin susceptibility testing: evaluation of reliability for cystic fibrosis isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

OBJECTIVES: Antibiotic susceptibility methods that are commonly used to test bacterial isolates from patients with cystic fibrosis are of uncertain reliability for the polymyxins. To assess the reliability of four standard testing methods, this pilot study used a challenge set that included polymyxin-resistant isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. METHODS: Twenty-five P. aeruginosa and 12 S. maltophilia isolates were tested for susceptibility to colistin (polymyxin E). Repeatability (concordance of replicates performed concurrently), reproducibility (concordance of replicates performed over time) and comparability (concordance of different methods) of agar dilution, broth microdilution, Etest and disc diffusion were assessed through the use of descriptive statistics and scatterplot analyses. RESULTS: All four methods displayed excellent repeatability (overall concordance rate of 99%). However, analysis of reproducibility revealed substantially lower rates of concordance (74% for agar dilution, 84% for broth microdilution and Etest, and 91% for disc diffusion). In addition, comparability to agar dilution of the three other methods was generally poor, with overall rates of very major error ranging from 12% for broth microdilution to 18% for Etest and disc diffusion. CONCLUSIONS: Compared with agar dilution, other susceptibility testing methods give high rates of apparent false polymyxin susceptibility for cystic fibrosis isolates of P. aeruginosa and S. maltophilia. Prospective study of the correlation between in vitro susceptibility and clinical response is needed to clarify whether these discrepancies reflect oversensitivity of the agar dilution method or insensitivity of the other methods.

Infection control in cystic fibrosis: barriers to implementation and ideas for improvement.

PURPOSE OF REVIEW: This review will focus on recent research documenting baseline adherence to infection control recommendations and barriers to their implementation as experienced by multidisciplinary cystic fibrosis (CF) care providers. In addition, controversies regarding optimal infection control will be discussed. Finally, suggestions to improve infection control in CF will be proposed. RECENT FINDINGS: Compliance with recent guidelines was assessed for clinical microbiology laboratories and for infection control policies at CF care centers in the United States. Unlike earlier reports, the vast majority of laboratories used selective media for Burkholderia cepacia complex and identified all species of nonlactose fermenting Gram-negative bacilli. Fewer used selective media for Staphylococcus aureus or used agar-based susceptibility testing assays for Pseudomonas aeruginosa. Only 103 (65%) of 158 CF care centers provided written infection control policies for review and these were more likely to address inpatient than outpatient settings. Surveys of healthcare professionals showed that access to a copy of the CF infection control guidelines reduced barriers to adherence to selected infection control practices. SUMMARY: These data suggest that access to national infection control guidelines and written local policies are critically important to improving infection control for CF.

Effectiveness of peer educators on the uptake of mobile X-ray tuberculosis screening at homeless hostels: a cluster randomised controlled trial.

TRIAL DESIGN: Cluster randomised controlled trial. OBJECTIVE: To compare current practice for encouraging homeless people to be screened for tuberculosis on a mobile digital X-ray unit in London, UK, with the additional use of volunteer peer educators who have direct experience of tuberculosis, homelessness or both. PARTICIPANTS: 46 hostels took part in the study, with a total of 2342 residents eligible for screening. The study took place between February 2012 and October 2013 at homeless hostels in London, UK. INTERVENTION: At intervention sites, volunteer peer educators agreed to a work plan that involved moving around the hostel in conjunction with the hostel staff, and speaking to residents in order to encourage them to attend the screening. RANDOMISATION: Cluster randomisation (by hostel) was performed using an internet-based service to ensure allocation concealment, with minimisation by hostel size and historical screening uptake. BLINDING: Only the study statistician was blinded to the allocation of intervention or control arms. PRIMARY OUTCOME: The primary outcome was the number of eligible clients at a hostel venue screened for active pulmonary tuberculosis by the mobile X-ray unit. RESULTS: A total of 59 hostels were considered for eligibility and 46 were randomised. Control sites had a total of 1192 residents, with a median uptake of 45% (IQR 33-55). Intervention sites had 1150 eligible residents with a median uptake of 40% (IQR 25-61). Using Poisson regression to account for the clustered study design, hostel size and historical screening levels, there was no evidence that peer educators increased uptake (adjusted risk ratio 0.98; 95% CIs 0.80 to 1.20). The study team noted no adverse events. CONCLUSIONS: This study found no evidence that volunteer peer educators increased client uptake of mobile X-ray unit screening for tuberculosis. Further qualitative work should be undertaken to explore the possible ancillary benefits to peer volunteers. TRIAL REGISTRATION NUMBER: ISRCTN17270334.

A survey of latent tuberculosis infection among laboratory healthcare workers in New York City.

OBJECTIVE: To determine the prevalence of positive tuberculin skin tests (TSTs), incidence of TST conversion, risk factors for positive TSTs, and history of active TB among HCWs in microbiology laboratories in New York City. DESIGN: Two-year survey from May 1999 to June 2001. SETTING: Nineteen microbiology laboratories. RESULTS: During the first year, interviews were conducted with 345 laboratory HCWs (mean, 18 HCWs per site; range, 2 to 51) to assess the prevalence of positive TSTs, but 3 (1%) could not recall their result and were excluded from further analyses. The mean age of the remaining 342 HCWs was 48 years; 68% (n = 233) were female, 54% (n = 183) received bacille Calmette-Guerin (BCG) vaccination, and 71% (n = 244) were foreign born. The prevalence of a positive TST was 57% (n = 196), but only 20% (n = 39) of the HCWs received isoniazid. The incidence of TST conversion in the second year of the study was 1% (1 of 108). Multivariate analysis identified age (odds ratio [OR] per year, 1.05; 95% confidence interval [CI95], 1.02-1.08), foreign birth (OR, 3.80; CI95, 1.98-7.28), BCG immunization (OR, 4.89; CI95, 2.72-8.80), and employment in a mycobacteriology laboratory (OR, 2.14; CI95, 1.25-3.68) as risk factors for a positive TST. Only one HCW had been treated for active TB. CONCLUSIONS: The prevalence of positive TSTs was high among laboratory HCWs, but the TST conversion rate was low. Higher rates of treatment for latent TB infection are desirable.

Costs of implementing and maintaining a tuberculin skin test program in hospitals and health departments.

OBJECTIVE: To determine (1) the annual costs of implementing and maintaining tuberculin skin test (TST) programs at participating study sites, (2) the cost of the TST program per healthcare worker (HCW), and (3) the outcomes of the TST programs, including the proportion of HCWs with a documented TST conversion and the proportion who accepted and completed treatment for latent TB infection, before and after the implementation of staffTRAK-TB software (Centers for Disease Control and Prevention, Atlanta, GA). DESIGN: Cost analysis in which costs for salaries, training, supplies, radiography, and data analysis were collected for two 12-month periods (before and after the implementation of staffTRAK-TB). SETTING: Four hospitals (two university and two city) and two health departments (one small county and one big city). RESULTS: The annual cost of implementing and maintaining a TST program ranged from dollars 66,564 to dollars 332,728 for hospitals and dollars 92,886 to dollars 291,248 for health departments. The cost of the TST program per HCW ranged from dollars 41 to dollars 362 for hospitals and dollars 176 to dollars 264 for health departments. CONCLUSIONS: Costs associated with implementing and maintaining a TST program varied widely among the participating study sites, both before and after the implementation of staffTRAK-TB. Compliance with the TB infection control guidelines of the Centers for Disease Control and Prevention may require a substantial investment in personnel time, effort, and commitment.

Infection control knowledge, attitudes, and practices among cystic fibrosis patients and their families.

BACKGROUND: In 2003, the Cystic Fibrosis (CF) Foundation in the United States published evidence-based infection control guidelines and distributed these to CF care centers. However, it is unclear how well the guidelines have been disseminated to patients and families, how well patients and families understand the principles of infection control, and what barriers they experience implementing the guidelines. METHODS: We assessed infection control knowledge, attitudes, and practices among CF patients and their families at 17 randomly selected CF centers. Anonymous surveys were completed by CF patients (≥16 years old) or their family members (patients <16 years old). To adjust for similarities of patients within each center, generalized estimating equations regression was used. RESULTS: From January 2007 to May 2009, 1,399 respondents completed surveys of whom 38% were patients and 62% were family members (overall mean age of patients = 14 years). Overall, 65% of respondents were aware of the CF infection control guidelines, but only 30% had discussed them more than once with their CF care team. More than one discussion was associated with increased knowledge of infection control, including routes of pathogen transmission; the importance of avoiding close contact with other CF patients; increased confidence in practicing infection control; and increased belief in the health benefits of infection control. CONCLUSIONS: This study revealed that many CF patients and families are aware of the infection control guidelines, but that few had discussed them more than once with their CF teams. These findings underscore the importance of engaging patients and their families in regular discussions about infection control that address questions and concerns including the potential impact of infection control on health and well-being. Further strategies are needed to overcome barriers to implementing these guidelines.

Subjects great and small: Maxwell on Saturn's rings and kinetic theory.

Since 1890, James Clerk Maxwell's reputation has rested upon his theory of electromagnetism. However, during his lifetime he was recognized 'as the leading molecular scientist' of his generation. We will explore the foundation of his significance before 1890 using his work on the stability of Saturn's rings and the development of his kinetic theory of gases, and then briefly discuss the grounds for the change of his reputation.

Survey of infection control policies for patients with cystic fibrosis in the United States.

Written infection control policies used at cystic fibrosis (CF) care sites in the United States were compared with recently published guidelines. Most policies recommended contact precautions for hospitalized patients infected with Burkholderia cepacia complex (73%), multidrug-resistant organisms (63%), and methicillin-resistant Staphylococcus aureus (64%). Socializing among CF patients was discouraged in 80% of inpatient policies and 55% of outpatient policies. Although routine mask use by patients remains an unresolved issue, many policies advocated this practice. Future studies should address barriers to implementation of these evidence-based guidelines and continue to monitor implementation.

Barriers to adherence to cystic fibrosis infection control guidelines.

BACKGROUND: In 2003, the American Cystic Fibrosis (CF) Foundation published revised, evidence-based guidelines for infection control. We sought to assess potential barriers to adherence to these guidelines experienced by health care professionals (HCPs) caring for CF patients. METHODS: From April 2004 to December 2005, a knowledge, attitude, and practice survey was administered to HCPs at randomly selected CF centers in the United States to explore potential barriers to adherence to selected guidelines: (1) obtaining quarterly cultures from CF patients, (2) discouraging socialization among CF patients during hospitalization, (3) educating patients and families about hand hygiene, (4) educating patients and families to clean and disinfect home nebulizers, and (5) cleaning the clinic exam rooms between CF patients. RESULTS: The survey was completed by 528 HCPs from 25 sites (5-50 respondents per site). Only 60% of respondents were aware of the guidelines, but despite awareness, 31-47% were unfamiliar with the specific guidelines. Self-reported adherence was low; only 23-63% of respondents reported practicing the selected guidelines >75% of the time/opportunities. Lack of self-efficacy, that is, confidence in adequately performing the guidelines, was commonly experienced by respondents. Access to a copy of the guidelines was associated with increased agreement with the recommendations and increased self-efficacy. CONCLUSIONS: Strategies to reduce barriers to adherence to CF infection control guidelines are needed. Strategies could include quality improvement initiatives with enhanced education and skills workshops, sharing successful interventions among CF centers, and linking adherence to improved patient outcomes.

Antimicrobial susceptibility and synergy studies of Burkholderia cepacia complex isolated from patients with cystic fibrosis.

Susceptibility (18 antimicrobial agents including high-dose tobramycin) and checkerboard synergy (23 combinations) studies were performed for 2,621 strains of Burkholderia cepacia complex isolated from 1,257 cystic fibrosis patients. Minocycline, meropenem, and ceftazidime were the most active, inhibiting 38%, 26%, and 23% of strains, respectively. Synergy was rarely noted (range, 1% to 15% of strains per antibiotic combination).

Compliance of clinical microbiology laboratories in the United States with current recommendations for processing respiratory tract specimens from patients with cystic fibrosis.

Respiratory tract specimens from patients with cystic fibrosis (CF) require unique processing by clinical microbiology laboratories to ensure detection of all potential pathogens. The present study sought to determine the compliance of microbiology laboratories in the United States with recently published recommendations for CF respiratory specimens. Microbiology laboratory protocols from 150 of 190 (79%) CF care sites were reviewed. Most described the use of selective media for Burkholderia cepacia complex (99%), Staphylococcus aureus (82%), and Haemophilus influenzae (89%) and identified the species of all gram-negative bacilli (87%). Only 52% delineated the use of agar diffusion assays for susceptibility testing of Pseudomonas aeruginosa. Standardizing laboratory practices will improve treatment, infection control, and our understanding of the changing epidemiology of CF microbiology.

In vitro activity of doripenem (S-4661) against multidrug-resistant gram-negative bacilli isolated from patients with cystic fibrosis.

Doripenem 50% inhibitory concentrations (MIC50) and 90% inhibitory concentrations (MIC90) for multidrug-resistant strains of mucoid Pseudomonas aeruginosa (n=200 strains), nonmucoid P. aeruginosa (n=200), and Burkholderia cepacia complex (n=200) isolated from patients with cystic fibrosis were 8 and 32, 8 and 64, and 8 and 32 microg/ml, respectively. Doripenem had somewhat better activity than established antimicrobial agents.

Evaluation of MicroScan Autoscan for identification of Pseudomonas aeruginosa isolates from cystic fibrosis patients.

Accurate identification of gram-negative bacilli from cystic fibrosis (CF) patients is essential. Only 57% (108 of 189) of nonmucoid strains and 40% (24 of 60) of mucoid strains were definitively identified as Pseudomonas aeruginosa with MicroScan Autoscan. Most common misidentifications were Pseudomonas fluorescens-Pseudomonas putida (i.e., the strain was either P. fluorescens or P. putida, but the system did not make the distinction and yielded the result P. fluorescens/putida) and Alcaligenes spp. Extending the incubation to 48 h improved identification, but 15% of isolates remained misidentified. The MicroScan Autoscan system cannot be recommended for the identification of P. aeruginosa isolates from CF patients.