TCP Boston: A Fragmentation-tolerant TCP Protocol for ATM Networks

The popularity of TCP/IP coupled with the premise of high speed communication using Asynchronous Transfer Mode (ATM) technology have prompted the network research community to propose a number of techniques to adapt TCP/IP to ATM network environments. ATM offers Available Bit Rate (ABR) and Unspecified Bit Rate (UBR) services for best-effort traffic, such as conventional file transfer. However, recent studies have shown that TCP/IP, when implemented using ABR or UBR, leads to serious performance degradations, especially when the utilization of network resources (such as switch buffers) is high. Proposed techniques-switch-level enhancements, for example-that attempt to patch up TCP/IP over ATMs have had limited success in alleviating this problem. The major reason for TCP/IP's poor performance over ATMs has been consistently attributed to packet fragmentation, which is the result of ATM's 53-byte cell-oriented switching architecture. In this paper, we present a new transport protocol, TCP Boston, that turns ATM's 53-byte cell-oriented switching architecture into an advantage for TCP/IP. At the core of TCP Boston is the Adaptive Information Dispersal Algorithm (AIDA), an efficient encoding technique that allows for dynamic redundancy control. AIDA makes TCP/IP's performance less sensitive to cell losses, thus ensuring a graceful degradation of TCP/IP's performance when faced with congested resources. In this paper, we introduce AIDA and overview the main features of TCP Boston. We present detailed simulation results that show the superiority of our protocol when compared to other adaptations of TCP/IP over ATMs. In particular, we show that TCP Boston improves TCP/IP's performance over ATMs for both network-centric metrics (e.g., effective throughput) and application-centric metrics (e.g., response time).

Load Profiling for Efficient Route Selection in Multi-Class Networks

High-speed networks, such as ATM networks, are expected to support diverse Quality of Service (QoS) constraints, including real-time QoS guarantees. Real-time QoS is required by many applications such as those that involve voice and video communication. To support such services, routing algorithms that allow applications to reserve the needed bandwidth over a Virtual Circuit (VC) have been proposed. Commonly, these bandwidth-reservation algorithms assign VCs to routes using the least-loaded concept, and thus result in balancing the load over the set of all candidate routes. In this paper, we show that for such reservation-based protocols|which allow for the exclusive use of a preset fraction of a resource's bandwidth for an extended period of time-load balancing is not desirable as it results in resource fragmentation, which adversely affects the likelihood of accepting new reservations. In particular, we show that load-balancing VC routing algorithms are not appropriate when the main objective of the routing protocol is to increase the probability of finding routes that satisfy incoming VC requests, as opposed to equalizing the bandwidth utilization along the various routes. We present an on-line VC routing scheme that is based on the concept of "load profiling", which allows a distribution of "available" bandwidth across a set of candidate routes to match the characteristics of incoming VC QoS requests. We show the effectiveness of our load-profiling approach when compared to traditional load-balancing and load-packing VC routing schemes.

Peanut Allergen Threshold Study (PATS): validation of eliciting doses using a novel single-dose challenge protocol

Background: The eliciting dose (ED) for a peanut allergic reaction in 5% of the peanut allergic population, the ED05, is 1.5 mg of peanut protein. This ED05 was derived from oral food challenges (OFC) that use graded, incremental doses administered at fixed time intervals. Individual patients’ threshold doses were used to generate population dose-distribution curves using probability distributions from which the ED05 was then determined. It is important to clinically validate that this dose is predictive of the allergenic response in a further unselected group of peanut-allergic individuals. Methods/Aims: This is a multi-centre study involving three national level referral and teaching centres. (Cork University Hospital, Ireland, Royal Children’s Hospital Melbourne, Australia and Massachusetts General Hospital, Boston, U.S.A.) The study is now in process and will continue to run until all centres have recruited 125 participates in each respective centre. A total of 375 participants, aged 1–18 years will be recruited during routine Allergy appointments in the centres. The aim is to assess the precision of the predicted ED05 using a single dose (6 mg peanut = 1.5 mg of peanut protein) in the form of a cookie. Validated Food Allergy related Quality of Life Questionnaires-(FAQLQ) will be self-administered prior to OFC and 1 month after challenge to assess the impact of a single dose OFC on FAQL. Serological and cell based in vitro studies will be performed. Conclusion: The validation of the ED05 threshold for allergic reactions in peanut allergic subjects has potential value for public health measures. The single dose OFC, based upon the statistical dose-distribution analysis of past challenge trials, promises an efficient approach to identify the most highly sensitive patients within any given food-allergic population.

The SPHERE Study: Secondary prevention of heart disease in general practice: protocol of a randomised controlled trial of tailored practice and patient care plans with parallel qualitative, economic and policy analyses. [ISRCTN24081411]

Background: The aim of the SPHERE study is to design, implement and evaluate tailored practice and personal care plans to improve the process of care and objective clinical outcomes for patients with established coronary heart disease (CHD) in general practice across two different health systems on the island of Ireland.CHD is a common cause of death and a significant cause of morbidity in Ireland. Secondary prevention has been recommended as a key strategy for reducing levels of CHD mortality and general practice has been highlighted as an ideal setting for secondary prevention initiatives. Current indications suggest that there is considerable room for improvement in the provision of secondary prevention for patients with established heart disease on the island of Ireland. The review literature recommends structured programmes with continued support and follow-up of patients; the provision of training, tailored to practice needs of access to evidence of effectiveness of secondary prevention; structured recall programmes that also take account of individual practice needs; and patient-centred consultations accompanied by attention to disease management guidelines.

Methods: SPHERE is a cluster randomised controlled trial, with practice-level randomisation to intervention and control groups, recruiting 960 patients from 48 practices in three study centres (Belfast, Dublin and Galway). Primary outcomes are blood pressure, total cholesterol, physical and mental health status (SF-12) and hospital re-admissions. The intervention takes place over two years and data is collected at baseline, one-year and two-year follow-up. Data is obtained from medical charts, consultations with practitioners, and patient postal questionnaires. The SPHERE intervention involves the implementation of a structured systematic programme of care for patients with CHD attending general practice. It is a multi-faceted intervention that has been developed to respond to barriers and solutions to optimal secondary prevention identified in preliminary qualitative research with practitioners and patients. General practitioners and practice nurses attend training sessions in facilitating behaviour change and medication prescribing guidelines for secondary prevention of CHD. Patients are invited to attend regular four-monthly consultations over two years, during which targets and goals for secondary prevention are set and reviewed. The analysis will be strengthened by economic, policy and qualitative components.

A randomized controlled trial of tea tree oil (5%) body wash versus standard body wash to prevent colonization with methicillin-resistant Staphylococcus aureus (MRSA) in critically ill adults: research protocol

Background
Over the past ten years MRSA has become endemic in hospitals and is associated with increased healthcare costs. Critically ill patients are most at risk, in part because of the number of invasive therapies that they require in the intensive care unit (ICU). Washing with 5% tea tree oil (TTO) has been shown to be effective in removing MRSA on the skin. However, to date, no trials have evaluated the potential of TTO body wash to prevent MRSA colonization or infection. In addition, detecting MRSA by usual culture methods is slow. A faster method using a PCR assay has been developed in the laboratory, but requires evaluation in a large number of patients.

Methods/Design
This study protocol describes the design of a multicentre, phase II/III prospective open-label randomized controlled clinical trial to evaluate whether a concentration of 5% TTO is effective in preventing MRSA colonization in comparison with a standard body wash (Johnsons Baby Softwash) in the ICU. In addition we will evaluate the cost-effectiveness of TTO body wash and assess the effectiveness of the PCR assay in detecting MRSA in critically ill patients. On admission to intensive care, swabs from the nose and groin will be taken to screen for MRSA as per current practice. Patients will be randomly assigned to be washed with the standard body wash or TTO body wash. On discharge from the unit, swabs will be taken again to identify whether there is a difference in MRSA colonization between the two groups.

Discussion
If TTO body wash is found to be effective, widespread implementation of such a simple colonization prevention tool has the potential to impact on patient outcomes, healthcare resource use and patient confidence both nationally and internationally.

Trial Registration
[ISRCTN65190967]

Multi sulfonamide screening in porcine muscle using a surface plasmon resonance biosensor

A binding protein displaying broad-spectrum cross-reactivity within the sulfonamide group was used in conjunction with a sulfonamide specific sensor chip and a surface plasmon resonance biosensor to develop a rapid broad spectrum screening assay for sulfonamides in porcine muscle. Results for 40 samples were available in just over 5 h after the completion of a simple sample preparation protocol. Twenty sulfonamide compounds were detected. Acetylated metabolites were not recognised by the binding protein. Limit of detection (mean-three times standard deviation value when n = 20) was calculated to be 16.9 ng g(-1) in tissue samples. Intra-assay precision (n = 10) was calculated at 4.3 %CV for a sample spiked at 50 ng g(-1) with sulfamethazine, 3.6 %CV for a sample spiked at 100 ng g(-1) with sulfamethazine, 7.2 %CV for a sample spiked at 50 ng g(-1) with sulfadiazine and 3.1 %CV for a sample spiked at 100 ng g-1 with sulfadiazine. Inter-assay precision (n = 3) was calculated at 9.7 %CV for a sample spiked at 50 ng g-1 with sulfamethazine, 3.8 %CV for a sample spiked at 100 ng g(-1) with sulfamethazine, 3.5 %CV for a sample spiked at 50 ng g(-1) with sulfadiazine and 2.8 %CV for a sample spiked at 100 ng g(-1) with sulfadiazine. (C) 2004 Elsevier B.V. All rights reserved.

Multi-detection of Paralytic, Diarrheic and Amnesic Shellfish Toxins by an Inhibition Immunoassay Using a Microsphere-Flow Cytometry System

The presence of paralytic shellfish poisoning (PSP), diarrheic shellfish poisoning (DSP) and amnesic shellfish poisoning (ASP) toxins in seafood is a severe and growing threat to human health. In order to minimize the risks of human exposure, the maximum content of these toxins in seafood has been limited by legal regulations worldwide. The regulated limits are established in equivalents of the main representatives of the groups: saxitoxin (STX), okadaic acid (OA) and domoic acid (DA), for PSP, DSP and ASP, respectively. In this study a multi-detection method to screen shellfish samples for the presence of these toxins simultaneously was developed. Multiplexing was achieved using a solid-phase microsphere assay coupled to flow-fluorimetry detection, based on the Luminex xMap technology. The multi-detection method consists of three simultaneous competition immunoassays. Free toxins in solution compete with STX, OA or DA immobilized on the surface of three different classes of microspheres for binding to specific monoclonal antibodies. The IC50 obtained in buffer was similar in single- and multi-detection: 5.6 ± 1.1 ng/mL for STX, 1.1 ± 0.03 ng/mL for OA and 1.9 ± 0.1 ng/mL for DA. The sample preparation protocol was optimized for the simultaneous extraction of STX, OA and DA with a mixture of methanol and acetate buffer. The three immunoassays performed well with mussel and scallop matrixes displaying adequate dynamic ranges and recovery rates (around 90 % for STX, 80 % for OA and 100 % for DA). This microsphere-based multi-detection immunoassay provides an easy and rapid screening method capable of detecting simultaneously in the same sample three regulated groups of marine toxins.

A Dynamic Buffer Management Scheme for End-to-End QoS Enhancement of Multi-flow Services in HSDPA

End-user multi-flow services support is a crucial aspect of current and next generation mobile networks. This paper presents a dynamic buffer management strategy for HSDPA end-user multi-flow traffic with aggregated real-time and non-real-time flows. The scheme incorporates dynamic priority switching between the flows for transmission on the HSDPA radio channel. The end-to-end performance of the proposed strategy is investigated with an end-user multi-flow session of simultaneous VoIP and TCP-based downlink traffic using detailed HSDPA system-level simulations. Compared to an equivalent static buffer management scheme, the results show that end-to-end throughput performance gains in the non-real-time flow and better HSDPA channel utilization is attainable without compromising the real-time VoIP flow QoS constraints

First steps: study protocol for a randomized controlled trial of the effectiveness of the Group Family Nurse Partnership (gFNP) program compared to routine care in improving outcomes for high-risk mothers and their children and preventing abuse

Background: Evidence from the USA suggests that the home-based Family Nurse Partnership program (FNP), extending from early pregnancy until infants are 24 months, can reduce the risk of child abuse and neglect throughout childhood. FNP is now widely available in the UK. A new variant, Group Family Nurse Partnership (gFNP) offers similar content but in a group context and for a shorter time, until infants are 12 months old. Each group comprises 8 to 12 women with similar expected delivery dates and their partners. Its implementation has been established but there is no evidence of its effectiveness.

Methods/Design: The study comprises a multi-site randomized controlled trial designed to identify the benefits of gFNP compared to standard care. Participants (not eligible for FNP) must be either aged <20 years at their last menstrual period (LMP) with one or more previous live births, or aged 20 to 24 at LMP with low educational qualifications and no previous live births. 'Low educational qualifications' is defined as not having both Maths and English Language GCSE at grade C or higher or, if they have both, no more than four in total at grade C or higher. Exclusions are: under 20 years and previously received home-based FNP and, in either age group, severe psychotic mental illness or not able to communicate in English. Consenting women are randomly allocated (minimized by site and maternal age group) when between 10 and 16 weeks pregnant to either to the 44 session gFNP program or to standard care after the collection of baseline information. Researchers are blind to group assignment. The primary outcomes at 12 months are child abuse potential based on the revised Adult-Adolescent Parenting Inventory and parent/infant interaction coded using the CARE Index based on a video-taped interaction. Secondary outcomes are maternal depression, parenting stress, health related quality of life, social support, and use of services.

Discussion: This is the first study of the effectiveness of gFNP in the UK. Results should inform decision-making about its delivery alongside universal services, potentially enabling a wider range of families to benefit from the FNP curriculum and approach to supporting parenting.

SWAT-1: The effectiveness of a 'site visit' intervention on recruitment rates in a multi-centre randomised trial

Background: Recruitment rates in multi-centre randomised trials often fall below target recruitment rates, causing problems for study outcomes. The Studies Within A Trial (SWAT) Programme, established by the All-Ireland Hub for Trials Methodology Research in collaboration with the Medical Research Council Network of Hubs in the United Kingdom and others, is developing methods for evaluating aspects of trial methodology through the conduct of research within research. A recently published design for a SWAT-1 provides a protocol for evaluating the effect of a site visit by the principal investigator on recruitment in multi-centre trials.

Methods: Using the SWAT-1 design, the effect of a site visit, with the sole purpose of discussing trial recruitment, on recruitment rates in a large multicentre trial in the Republic of Ireland was evaluated. A controlled before and after intervention comparison was used, where the date of the site visit provides the time point for the intervention, and for the comparison to control sites. Site A received the intervention. Site B and Site C acted as the controls. Z-scores for proportions were calculated to determine within site recruitment differences. Odds ratios and 95% confidence intervals were calculated to determine between site recruitment differences.

Results: Recruitment rates were increased in Site A post-intervention (17% and 14% percentage point increases at 1 and 3 months, respectively). No differences in recruitment occurred in Site B or in Site C. Comparing between site differences, at 3 months post-intervention, a statistically significant difference was detected in favour of higher recruitment in Site A (34% versus 25%; odds ratio 1.57, 95% confidence interval 1.09 to 2.26).

Conclusions: This is the first reported example of a study in the SWAT programme.. It provides evidence that a site visit, combined with a scheduled meeting, increases recruitment in a clinical trial. Using this example, other researchers might be encouraged to consider conducting a similar study, allowing the findings of future SWAT-1s to be compared and combined, so that higher level evidence on the effect of a site visit by the principal investigator can be obtained.

THE SAAF STUDY: evaluation of the Safeguarding Children Assessment and Analysis Framework (SAAF), compared with management as usual, for improving outcomes for children and young people who have experienced, or are at risk of, maltreatment: study protocol for a randomised controlled trial

Background: Serious case reviews and research studies have indicated weaknesses in risk assessments conducted by child protection social workers. Social workers are adept at gathering information but struggle with analysis and assessment of risk. The Department for Education wants to know if the use of a structured decision-making tool can improve child protection assessments of risk.

Methods/design: This multi-site, cluster-randomised trial will assess the effectiveness of the Safeguarding Children Assessment and Analysis Framework (SAAF). This structured decision-making tool aims to improve social workers' assessments of harm, of future risk and parents' capacity to change. The comparison is management as usual.

Inclusion criteria: Children's Services Departments (CSDs) in England willing to make relevant teams available to be randomised, and willing to meet the trial's training and data collection requirements.

Exclusion criteria: CSDs where there were concerns about performance; where a major organisational restructuring was planned or under way; or where other risk assessment tools were in use.

Six CSDs are participating in this study. Social workers in the experimental arm will receive 2 days training in SAAF together with a range of support materials, and access to limited telephone consultation post-training. The primary outcome is child maltreatment. This will be assessed using data collected nationally on two key performance indicators: the first is the number of children in a year who have been subject to a second Child Protection Plan (CPP); the second is the number of re-referrals of children because of related concerns about maltreatment. Secondary outcomes are: i) the quality of assessments judged against a schedule of quality criteria and ii) the relationship between the three assessments required by the structured decision-making tool (level of harm, risk of (re) abuse and prospects for successful intervention).

Discussion: This is the first study to examine the effectiveness of SAAF. It will contribute to a very limited literature on the contribution that structured decision-making tools can make to improving risk assessment and case planning in child protection and on what is involved in their effective implementation.

Effectiveness of a biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use: protocol for a randomised controlled trial (VAPrapid-2):Study protocol for a randomised controlled trial

Background Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. Methods/Design This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at > 104 colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a ‘biomarker-guided recommendation on antibiotics’ in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to ‘routine use of antibiotics’ in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. Discussion This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP.

Protocol for a pilot randomised controlled trial of an intervention to increase the use of traffic light food labelling in UK shoppers (the FLICC trial)

Background: Traffic light labelling of foods—a system that incorporates a colour-coded assessment of the level of total fat, saturated fat, sugar and salt on the front of packaged foods—has been recommended by the UK Government and is currently in use or being phased in by many UK manufacturers and retailers. This paper describes a protocol for a pilot randomised controlled trial of an intervention designed to increase the use of traffic light labelling during real-life food purchase decisions.

Methods/design: The objectives of this two-arm randomised controlled pilot trial are to assess recruitment, retention and data completion rates, to generate potential effect size estimates to inform sample size calculations for the main trial and to assess the feasibility of conducting such a trial. Participants will be recruited by email from a loyalty card database of a UK supermarket chain. Eligible participants will be over 18 and regular shoppers who frequently purchase ready meals or pizzas. The intervention is informed by a review of previous interventions encouraging the use of nutrition labelling and the broader behaviour change literature. It is designed to impact on mechanisms affecting belief and behavioural intention formation as well as those associated with planning and goal setting and the adoption and maintenance of the behaviour of interest, namely traffic light label use during purchases of ready meals and pizzas. Data will be collected using electronic sales data via supermarket loyalty cards and web-based questionnaires and will be used to estimate the effect of the intervention on the nutrition profile of purchased ready meals and pizzas and the behavioural mechanisms associated with label use. Data collection will take place over 48 weeks. A process evaluation including semi-structured interviews and web analytics will be conducted to assess feasibility of a full trial.

Discussion: The design of the pilot trial allows for efficient recruitment and data collection. The intervention could be generalised to a wider population if shown to be feasible in the main trial.

Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial

BACKGROUND: In sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9-10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.

METHODS/DESIGN: TRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children. The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4-6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness.

DISCUSSION: If confirmed by the trial, a cheap and widely available 'bundle' of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalised with severe anaemia every year, if widely implemented.

Improving allied health professionals' research implementation behaviours for children with cerebral palsy: protocol for a before-after study

BACKGROUND: Cerebral palsy is a permanent disorder of posture and movement caused by disturbances in the developing brain. It affects approximately 1 in every 500 children in developed countries and is the most common form of childhood physical disability. People with cerebral palsy may also have problems with speech, vision and hearing, intellectual difficulties and epilepsy. Health and therapy services are frequently required throughout life, and this care should be effective and evidence informed; however, accessing and adopting new research findings into day-to-day clinical practice is often delayed.

METHODS/DESIGN: This 3-year study employs a before and after design to evaluate if a multi-strategy intervention can improve research implementation among allied health professionals (AHPs) who work with children and young people with cerebral palsy and to establish if children's health outcomes can be improved by routine clinical assessment. The intervention comprises (1) knowledge brokering with AHPs, (2) access to an online research evidence library, (3) provision of negotiated evidence-based training and education, and (4) routine use of evidence-based measures with children and young people aged 3-18 years with cerebral palsy. The study is being implemented in four organisations, with a fifth organisation acting as a comparison site, across four Australian states. Effectiveness will be assessed using questionnaires completed by AHPs at baseline, 6, 12 and 24 months, and by monitoring the extent of use of evidence-based measures. Children's health outcomes will be evaluated by longitudinal analyses.

DISCUSSION: Government, policy makers and service providers all seek evidence-based information to support decision-making about how to distribute scarce resources, and families are seeking information to support intervention choices. This study will provide knowledge about what constitutes an efficient, evidence-informed service and which allied health interventions are implemented for children with cerebral palsy.

TRIAL REGISTRATION: Trial is not a controlled healthcare intervention and is not registered.