Optimizing drug inventory management with a web-based information system: The TBTC Study 31/ACTG A5349 experience.

INTRODUCTION: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349. MATERIAL AND METHODS: We developed and implemented a technological solution by integrating logistical and regulatory requirements for drug importation with statistical simulations that estimated stock-out times in an online Drug Management Module (DMM). We measured the average shipment-related drug stock-outs and time to drug availability, to assess the efficiency of the DMM compared to the manual approach. RESULTS: An Interrupted Time-Series (ITS) analysis showed a 15.4% [p-value = 0.03; 95% C.I. (-28.8%, -2.0%)] reduction in average shipment-related study drug stock-out after DMM implementation. The DMM streamlined the restocking process at study sites, reducing median transit-time for sites associated with a depot by 2 days [95% C.I. (-3.0, -1.0)]. Under the DMM, study drugs were available for treatment assignment on the day received, compared to one day after receipt under the manual process. DISCUSSION: The DMM provided TBTC's Data and Coordinating Center and site staff with more efficient procedures to manage and consistently maintain study drug inventory at enrolling sites. This DMM framework can improve efficiency in future multicenter clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015.

Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis.

INTRODUCTION: With the growing use of online study management systems and rapid availability of data, timely data review and quality assessments are necessary to ensure proper clinical trial implementation. In this report we describe central monitoring used to ensure protocol compliance and accurate data reporting, implemented during a large phase 3 clinical trial. MATERIAL AND METHODS: The Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) study A5349 (S31) is an international, multi-site, randomized, open-label, controlled, non-inferiority phase 3 clinical trial comparing two 4-month regimens to a standard 6 month regimen for treatment of drug-susceptible tuberculosis (TB) among adolescents and adults with a sample size of 2500 participants. RESULTS: Central monitoring utilized primary study data in a five-tiered approach, including (1) real-time data checks & topic-specific intervention reports, (2) missing forms reports, (3) quality assurance metrics, (4) critical data reports and (5) protocol deviation identification, aimed to detect and resolve quality challenges. Over the course of the study, 240 data checks and reports were programed across the five tiers used. DISCUSSION: This use of primary study data to identify issues rapidly allowed the study sponsor to focus quality assurance and data cleaning activities on prioritized data, related to protocol compliance and accurate reporting of study results. Our approach enabled us to become more efficient and effective as we informed sites about deviations, resolved missing or inconsistent data, provided targeted guidance, and gained a deeper understanding of challenges experienced at clinical trial sites. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015.

Effects of local authority expenditure on childhood obesity.

BACKGROUND: Under the 2013 reforms introduced by the Health and Social Care Act (2012), public health responsibilities in England were transferred from the National Health Service to local authorities (LAs). Ring-fenced grants were introduced to support the new responsibilities. The aim of our study was to test whether the level of expenditure in 2013/14 affected the prevalence of childhood obesity in 2016/17. METHODS: We used National Child Measurement Programme definitions of childhood obesity and datasets. We used LA revenue returns data to derive three measures of per capita expenditure: childhood obesity (<19); physical activity (<19) and the Children's 5-19 Public Health Programme. We ran separate negative binomial models for two age groups of children (4-5 year olds; 10-11 year olds) and conducted sensitivity analyses. RESULTS: With few exceptions, the level of spend in 2013/14 was not significantly associated with the level of childhood obesity in 2016/17. We identified some positive associations between spend on physical activity and the Children's Public Health Programme at baseline (2013/14) and the level of childhood obesity in children aged 4-5 in 2016/17, but the effect was not evident in children aged 10-11. In both age groups, LA levels of childhood obesity in 2016/17 were significantly and positively associated with obesity levels in 2013/14. As these four cohorts comprise entirely different pupils, this underlines the importance of local drivers of childhood obesity. CONCLUSIONS: Higher levels of local expenditure are unlikely to be effective in reducing childhood obesity in the short term.

Local authority commissioning of NHS Health Checks: A regression analysis of the first three years.

In April 2013, the public health function was transferred from the NHS to local government, making local authorities (LAs) responsible for commissioning the NHS Health Check programme. The programme aims to reduce preventable mortality and morbidity in people aged 40-74. The national five-year ambition is to invite all eligible individuals and to achieve an uptake of 75%. This study evaluates the effects of LA expenditure on the programme's invitation rates (the proportion of the eligible population invited to a health check), coverage rates (the proportion of the eligible population who received a health check) and uptake rates (attendance by those who received a formal invitation letter) in the first three years of the reforms. We ran negative binomial panel models and controlled for a range of confounders. Over 2013/14-2015/16, the invitation rate, coverage rate and uptake rate averaged 57% 28% and 49% respectively. Higher per capita spend on the programme was associated with increases in both the invitation rate and coverage rate, but had no effect on the uptake rate. When we controlled for the LA invitation rate, the association between spend and coverage rate was smaller but remained statistically significant. This suggests that alternatives to formal invitation, such as opportunistic approaches in work places or sports centres, may be effective in influencing attendance.

Directors of public health as 'a protected species': qualitative study of the changing role of public health professionals in England following the 2013 reforms.

Background: The Health and Social Care Act 2012 gave councils in England responsibility for improving the health of their populations. Public health teams were transferred from the National Health Service (NHS), accompanied by a ring-fenced public health grant. This study examines the changing role of these teams within local government. Methods: In-depth case study research was conducted within 10 heterogeneous councils. Initial interviews (n = 90) were carried out between October 2015 and March 2016, with follow-up interviews (n = 21) 12 months later. Interviewees included elected members, directors of public health (DsPH) and other local authority officers, plus representatives from NHS commissioners, the voluntary sector and Healthwatch. Results: Councils welcomed the contribution of public health professionals, but this was balanced against competing demands for financial resources and democratic leverage. DsPH-seen by some as a 'protected species'-were relying increasingly on negotiating and networking skills to fulfil their role. Both the development of the existing specialist public health workforce and recruitment to, and development of, the future workforce were uncertain. This poses both threats and opportunities. Conclusions: Currently the need for staff to retain specialist skills and maintain UKPH registration is respected. However, action is needed to address how future public health professionals operating within local government will be recruited and developed.

Organisational challenges in the United Kingdom's post-disaster 'crisis support' work.

Local authorities in the United Kingdom are required to 'lead' multi-agency humanitarian responses to major disasters. Concerns mounted in the late twentieth century that responses to people bereaved in the immediate aftermath of such events at best failed to meet their needs and at worst compounded their distress. Subsequent reviews and reforms reframed some victim needs as 'rights' and established legal, administrative, and practice frameworks to improve matters. Local authority 'crisis support', provided in partnership with other actors, lies at the heart of the UK's contemporary emergency response to the bereaved. Drawing on primary research on the development and the deployment of crisis support in a local authority, and while acknowledging both incident- and context-related difficulties, this paper considers the significance of challenges with their origins in organisational factors. Recent developments within and between responders may exacerbate them. This paper argues, therefore, that further research into such developments is necessary.

Does colloid shape affect detachment of colloids by a moving air-water interface?

Air-water interfaces interact strongly with colloidal particles by capillary forces. The magnitude of the interaction force depends on, among other things, the particle shape. Here, we investigate the effects of particle shape on colloid detachment by a moving air-water interface. We used hydrophilic polystyrene colloids with four different shapes (spheres, barrels, rods, and oblong disks), but otherwise identical surface properties. The nonspherical shapes were created by stretching spherical microspheres on a film of polyvinyl alcohol (PVA). The colloids were then deposited onto the inner surface of a glass channel. An air bubble was introduced into the channel and passed through, thereby generating a receding followed by an advancing air-water interface. The detachment of colloids by the air-water interfaces was visualized with a confocal microscope, quantified by image analysis, and analyzed statistically to determine significant differences. For all colloid shapes, the advancing air-water interface caused pronounced colloid detachment (>63%), whereas the receding interface was ineffective in colloid detachment (<1.5%). Among the different colloid shapes, the barrels were most readily removed (94%) by the advancing interface, followed by the spheres and oblong disks (80%) and the rods (63%). Colloid detachment was significantly affected by colloid shape. The presence of an edge, as it occurs in a barrel-shaped colloid, promoted colloid detachment because the air-water interface is being pinned at the edge of the colloid. This suggests that the magnitude of colloid mobilization and transport in porous media is underestimated for edged particles and overestimated for rodlike particles when a sphere is used as a model colloid.

A biomechanical study of laparoscopic 4S-modified Roeder and Weston knot strength in 3-0 polyglactin 910 and 3-0 polydioxanone.

OBJECTIVE: To (1) evaluate biomechanical strength of 4 different laparoscopic knots using 2 suture types, and (2) evaluate carotid artery ligature bursting pressure of 2 knots using a single suture type. STUDY DESIGN: Biomechanical materials testing. SAMPLE POPULATION: Suture material (3-0 polydioxanone, 3-0 polyglactin 910). METHODS: Four knot types were tested: 4S-modified Roeder (4SMR) Weston plus 3 square throws (W3S); Weston plus 3 granny throws (W3G); and a 4 square throw knot as a control (control); 24 specimens of each knot type were tied with 3-0 polyglactin 910 and 24 of 3 knot types (4SMR, W3S, control) were tied with 3-0 polydioxanone. Suture loop constructs were tested to 3 mm displacement failure and ultimate failure. Carotid artery ligation bursting pressure was tested using 10 samples each of 4SMR and W3S knots with 3-0 polyglactin 910. RESULTS: The W3S, W3G, and controls were similar. The 4SMR was similar to W3S using 3-0 PDS but the 4SMR had lower load to failure and greater elongation than the Weston using 3-0 polyglactin 910. The 4SMR had a higher slippage rate with 3-0 polyglactin 910. All ligatures withstood supraphysiologic pressures. CONCLUSIONS: Surgeons using 3-0 polyglactin 910 should consider using the Weston knot with added throws during laparoscopic procedures.

A low-cost telemetry system suitable for measuring mouse biopotentials.

The ability to generate specific genetic mutations in mice is a powerful tool to study normal and pathophysiological function. In order to determine the effects of a mutation, measurement of physiological variables, such as biopotentials, is often necessary. However, such measurements can be particularly challenging to obtain from an awake, unrestrained mouse. The goal of this study was to design and implement a telemetry system suitable for recording biopotentials from a mouse. A battery-powered system was fabricated from commercially available electronic components mounted on a small circuit board. The frequency response of the system was measured over a range of frequencies and found suitable for recording biopotentials in mice and larger animals. We affixed the circuit board externally to a mouse and connected surface electrodes to measure electrocardiograms (ECG). The size and weight of the board did not disturb normal behavior over 30-60 min. Recorded ECGs had easily identifiable components relevant to physiological parameters and had a similar frequency spectrum compared to recordings obtained from a commercially available measurement system. In conclusion, the telemetry system was low-cost due to the availability of the components, straightforward to implement, and provided biopotential recordings suitable for measuring physiological parameters in an awake mouse.

The Undergraduate Medical Education for the 21st Century (UME-21) project: the Federal Government perspective.

The Undergraduate Medical Education for the 21st Century (UME-21) project was implemented by the Division of Medicine, Bureau of Health Professions, Health Resources and Services Administration (HRSA) to encourage medical schools to collaborate with managed care organizations and others. The purpose of the collaboration was to ensure that medical students are prepared to provide quality patient care and manage that care in an integrated health care system in which the cost of care and use of empirically justified care are important elements. The UME-21 project represents a continuation of HRSA's interest in the managed care arena. The UME-21 project involved the collaboration of eight partner schools and 10 associate partner schools, together with 50 external partners, to develop innovative curricula that integrated UME-21 content from nine special areas as learning objectives. This project demonstrated that concerted efforts by the leadership in medical education can bring about innovative change in medical school curricula. It ís also demonstrated that faculty of the three primary care disciplines of family medicine, general internal medicine, and general pediatrics were able to cooperate to accomplish such change by working together to allocate clerkship time and content. An important lesson learned in this project was that significant innovations in medical school curricula could be accomplished with a broadbased commitment and involvement of both faculties across the three primary care disciplines and top administrative officials of the medical school. It is uncertain, however, if the innovations achieved will produce further changes or if those changes achieved can be sustained without continued funding.

Charged polymers modulate retrovirus transduction via membrane charge neutralization and virus aggregation.

The specific mechanisms of charged polymer modulation of retrovirus transduction were analyzed by characterizing their effects on virus transport and adsorption. From a standard colloidal perspective two mechanisms, charge shielding and virus aggregation, can potentially account for the experimentally observed changes in adsorption behavior and biophysical parameters due to charged polymers. Experimental testing revealed that both mechanisms could be at work depending on the characteristics of the cationic polymer. All cationic polymers enhanced adsorption and transduction via charge shielding; however, only polymers greater than 15 kDa in size were capable of enhancing these processes via the virus aggregation mechanism, explaining the higher efficiency enhancement of the high molecular weight molecules. The role of anionic polymers was also characterized and they were found to inhibit transduction via sequestration of cationic polymers, thereby preventing charge shielding and virus aggregation. Taken together, these findings suggest the basis for a revised physical model of virus transport that incorporates electrostatic interactions through both virus-cell repulsive and attractive interactions, as well as the aggregation state of the virus.

Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes.

Cationic polymers, such as polybrene and protamine sulfate, are typically used to increase the efficiency of retrovirus-mediated gene transfer, however, the mechanism of their enhancement of transduction has remained unclear. As retrovirus transduction is fundamentally limited by the slow diffusion of virus to the target cell surface, we investigated the ability of polybrene to modulate this initial transport step. We compared the ability of both envelope (gp70) and capsid (p30) protein based assays to quantitate virus adsorption and found that p30 based assays were more reliable due to their ability to distinguish virus binding from free gp70 binding. Using the p30 based assay, we established that polybrene concentrations, which yielded 10-fold increases in transduction also, yielded a significant increase in virus adsorption rates on murine fibroblasts. Surprisingly, this enhancement, and adsorption in general, were receptor and envelope independent, as adsorption occurred equivalently on receptor positive and negative Chinese hamster ovary cells, as well as with envelope positive and negative virus particles. These findings suggest that the currently accepted physical model for early steps in retrovirus transduction may need to be reformulated to accommodate an initial adsorption step whose driving force does not include the retrovirus concentration, and the reclassification of currently designated 'receptor' molecules as fusion triggers. The implication of these findings with respect to the development of targeted retrovirus-mediated gene therapy protocols is discussed.