Education, incentive, and engineering-based interventions to promote the use of seat belts.

BACKGROUND: Over 1.3 million people die each year as a result of traffic collisions and hundreds of thousands of others are permanently and seriously injured. Most of these deaths occur in low- and middle-income countries, where mortality rates can be up to 10 times higher than those of some high-income countries. Seat belts are designed to accomplish two key functions - to prevent the occupant from being ejected from the vehicle by the force of impact, and to extend the time that the decelerating force is applied to a person. Seat belts also spread the area of impact both to larger and less vulnerable parts of the body. Since the 1950s, seat belts have been factory-fitted to most vehicles, and today around 90% of high-income countries have adopted seat belt legislation that makes it mandatory for some, if not all, vehicle occupants to wear seat belts. However, the simple passing of laws is not sufficient to ensure seat belt use, and, while the enforcement of seat belt laws does increase seat belt use, other interventions have been developed to encourage voluntary - and hence sustainable - behaviour change. OBJECTIVES: To evaluate the benefits of behavioural-change interventions (educational-based, incentive-based, engineering-based, or a combination, but not enforcement-based) that promote the use of seat belts, and to determine which types of interventions are most effective. SEARCH METHODS: On 9 August 2022, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), OvidSP Embase, OvidSP MEDLINE, 14 other databases, and clinical trials registers. We also screened reference lists and conference proceedings, searched websites of relevant organisations, and contacted road safety experts. The search was performed with no restrictions in terms of language and date of publication. SELECTION CRITERIA: We included randomised controlled trials (RCTs), both individually randomised and cluster-randomised, that evaluated education, engineering, incentive-based interventions (or combinations) that promoted seat belt use. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of RCTs, evaluated the risk of bias, and extracted data. We performed a narrative synthesis based on effect direction due to the heterogeneity observed between RCTs and reported the synthesis in accordance with reporting guidelines for systematic reviews without meta-analysis, as appropriate. We assessed the certainty of the evidence using the GRADE approach. We analysed data on the primary outcome, frequency of wearing a seat belt. None of the included RCTs reported the other primary outcome, crash-related injury rate or the secondary outcome, crash-related mortality rates of interest in this review. MAIN RESULTS: We included 15 completed RCTs (12 individual, parallel-group, and three cluster) that enroled 12,081 participants, published between 1990 and 2022. Four trials were published between 2019 and 2022, and the remaining trials were published 10 or more years ago. We also identified four ongoing RCTs. Thirteen RCTs were conducted in the USA. Trials recruited participants from various sites (worksites, schools, emergency departments, a residential retirement community, and primary care settings) and different age groups (adults, late adolescents, early adolescents, and dyads). Thirteen trials investigated educational interventions, one of which used education in addition to incentives (one of the intervention arms) measured through participant self-reports (12) and observation (one), and two trials investigated engineering-based interventions measured through in-vehicle data monitor systems at various follow-up periods (six weeks to 36 months). We grouped RCTs according to types of education-based interventions: behavioural education-based, health risk appraisal (HRA), and other education-based interventions. The evidence suggests that behavioural education-based (four trials) interventions may promote seat belt use and HRA interventions (one trial) likely promote seat belt use in the short term (six weeks to nine months). Four of the six trials that investigated behavioural education-based interventions found that the intervention compared to no or another intervention may promote seat belt use. These effects were measured through participant self-report and at various time points (six-week to 12-month follow-up) (low-certainty evidence). One of the three trials investigating HRA only or with additional intervention versus no or another intervention showed observed effects likely to promote seat belt use (moderate-certainty evidence). The evidence suggests that engineering-based interventions using vehicle monitoring systems (with in-vehicle alerts and with or without notifications/feedback) may promote the use of seat belts. One trial showed that engineering interventions (in-vehicle alerts and feedback) may promote seat belt use while the other showed unclear effects in two of the three intervention groups (low-certainty evidence). Both trials had small sample sizes and high baseline seat belt use. AUTHORS' CONCLUSIONS: The evidence suggests that behavioural education-based interventions may promote seat belt use and HRA (including incentives) with or without additional interventions likely promote seat belt use. Likewise, for engineering-based interventions using in-vehicle data monitor systems with in-vehicle alerts, with or without notifications/feedback the evidence suggests the interventions may promote the use of seat belts. Well-designed RCTs are needed to further investigate the effectiveness of education and engineering-based interventions. High-quality trials that examine the potential benefits of incentives to promote seat belt use, either alone or in combination with other interventions, as well as trials to investigate other types of interventions (such as technology, media/publicity, enforcement, insurance schemes, employer programmes, etc.) to promote the use of seat belts, are needed. Evidence from low- and middle-income economies is required to improve the generalisability of the data. In addition, research focused on determining which interventions or types of interventions are most effective in different population groups is needed.

Estimating qualification and factors associated with third-line antiretroviral therapy referral in the Western Cape.

BACKGROUND: South Africa's antiretroviral therapy (ART) programme is the largest globally and the universal test-and-treat policy is expected to increase the numbers on ART. This may have implications for treatment failure rates implying a greater future need for third-line regimens. South Africa initiated a third-line programme in 2013. However, there is little evidence quantifying the third-line need in this setting and the programme itself has not been formally evaluated. OBJECTIVES: The study evaluated the third-line ART referral process in the Western Cape. METHOD: Routinely collected data were analysed to derive an estimate of patients meeting criteria for third-line referral and compared with patients who were referred. Factors associated with referral were identified. RESULTS: In the study period, 947 patients met criteria for third-line referral and 167 patients were referred. Comparison revealed a poor overlap of only 42 patients. In multivariate analysis, factors associated with referral included receiving care at a hospital rather than a primary healthcare facility (adjusted odd ratios [aOR] = 2.15, 95% confidence interval [CI] 1.1-4.2), a higher number of viral load [VLs] ≥ 1000 copies/mL whilst on a protease inhibitor (PI) (aOR = 1.2, 95% CI 1.01-1.42) and a greater number of years on a PI (aOR = 1.25, 95% CI 1.07-1.46). Patients with a 6-month gap in dispensing were less likely to be referred (aOR = 0.37, 95% CI 0.17-0.81). CONCLUSION: This study adds to a limited body of knowledge regarding third-line ART programmes. The findings indicate missed opportunities for and inappropriate referral of patients. Factors associated with referral were largely health system related. Clinician awareness and compliance with referral remain unknown and may be contributory.

Perceived enablers and constraints of motivation to conduct undergraduate research in a Faculty of Medicine and Health Sciences: What role does choice play?

BACKGROUND: Enhancing evidence-based practice and improving locally driven research begins with fostering the research skills of undergraduate students in the medical and health sciences. Research as a core component of undergraduate curricula can be facilitated or constrained by various programmatic and institutional factors, including that of choice. Self-Determination Theory (SDT) provides a framework for understanding the influence of choice on student motivation to engage in research. AIM: This study aimed to document the enablers and constraints of undergraduate research at a South African Faculty of Medicine and Health Sciences (FMHS) and to explore how the presence or absence of choice influenced students' engagement with research in this context. METHODS: An exploratory descriptive design was adopted. Undergraduate students who had conducted research and undergraduate programme staff were recruited through purposive sampling. Semi-structured interviews were transcribed and thematically analysed. Findings were interpreted using SDT, focusing on how choice at various levels affects motivation and influences research experiences. RESULTS: Many of the programmatic and institutional enablers and constraints-such as time and supervisory availability-were consistent with those previously identified in the literature, regardless of whether research was compulsory or elective. Choice itself seemed to operate as both an enabler and a constraint, highlighting the complexity of choice as an influence on student motivation. SDT provided insight into how programmatic and institutional factors-and in particular choice-supported or suppressed students' needs for autonomy, competence, and relatedness, thereby influencing their motivation to engage in research. CONCLUSION: While programmatic and institutional factors may enable or constrain undergraduate research, individual-level factors such as the influence of choice on students' motivation play a critical role. The implication for curriculum development is that research engagement might be enhanced if levels of choice are structured into the curriculum such that students' needs for autonomy, competence, and relatedness are met.

Agents of change: The role of healthcare workers in the prevention of nosocomial and occupational tuberculosis.

Healthcare workers (HCWs) play a central role in global tuberculosis (TB) elimination efforts but their contributions are undermined by occupational TB. HCWs have higher rates of latent and active TB than the general population due to persistent occupational TB exposure, particularly in settings where there is a high prevalence of undiagnosed TB in healthcare facilities and TB infection control (TB-IC) programmes are absent or poorly implemented. Occupational health programmes in high TB burden settings are often weak or non-existent and thus data that record the extent of the increased risk of occupational TB globally are scarce. HCWs represent a limited resource in high TB burden settings and occupational TB can lead to workforce attrition. Stigma plays a role in delayed diagnosis, poor treatment outcomes and impaired well-being in HCWs who develop TB. Ensuring the prioritization and implementation of TB-IC interventions and occupational health programmes, which include robust monitoring and evaluation, is critical to reduce nosocomial TB transmission to patients and HCWs. The provision of preventive therapy for HCWs with latent TB infection (LTBI) can also prevent progression to active TB. Unlike other patient groups, HCWs are in a unique position to serve as agents of change to raise awareness, advocate for necessary resource allocation and implement TB-IC interventions, with appropriate support from dedicated TB-IC officers at the facility and national TB programme level. Students and community health workers (CHWs) must be engaged and involved in these efforts. Nosocomial TB transmission is an urgent public health problem and adopting rights-based approaches can be helpful. However, these efforts cannot succeed without increased political will, supportive legal frameworks and financial investments to support HCWs in efforts to decrease TB transmission.

Why healthcare workers are sick of TB.

Dr Thato Mosidi never expected to be diagnosed with tuberculosis (TB), despite widely prevalent exposure and very limited infection control measures. The life-threatening diagnosis of primary extensively drug-resistant TB (XDR-TB) came as an even greater shock. The inconvenient truth is that, rather than being protected, Dr Mosidi and thousands of her healthcare colleagues are at an increased risk of TB and especially drug-resistant TB. In this viewpoint paper we debunk the widely held false belief that healthcare workers are somehow immune to TB disease (TB-proof) and explore some of the key factors contributing to the pervasive stigmatization and subsequent non-disclosure of occupational TB. Our front-line workers are some of the first to suffer the consequences of a progressively more resistant and fatal TB epidemic, and urgent interventions are needed to ensure the safety and continued availability of these precious healthcare resources. These include the rapid development and scale-up of improved diagnostic and treatment options, strengthened infection control measures, and focused interventions to tackle stigma and discrimination in all its forms. We call our colleagues to action to protect themselves and those they care for.

Formation of the black-hole binary M33 X-7 through mass exchange in a tight massive system.

The X-ray source M33 X-7 in the nearby galaxy Messier 33 is among the most massive X-ray binary stellar systems known, hosting a rapidly spinning, 15.65M(⊙) black hole orbiting an underluminous, 70M(⊙) main-sequence companion in a slightly eccentric 3.45-day orbit (M(⊙), solar mass). Although post-main-sequence mass transfer explains the masses and tight orbit, it leaves unexplained the observed X-ray luminosity, the star's underluminosity, the black hole's spin and the orbital eccentricity. A common envelope phase, or rotational mixing, could explain the orbit, but the former would lead to a merger and the latter to an overluminous companion. A merger would also ensue if mass transfer to the black hole were invoked for its spin-up. Here we report simulations of evolutionary tracks which reveal that if M33 X-7 started as a primary body of 85M(⊙)-99M(⊙) and a secondary body of 28M(⊙)-32M(⊙), in a 2.8-3.1-d orbit, its observed properties can be consistently explained. In this model, the main-sequence primary transfers part of its envelope to the secondary and loses the rest in a wind; it ends its life as a ∼16M(⊙) helium star with an iron-nickel core that collapses to a black hole (with or without an accompanying supernova). The release of binding energy, and possibly collapse asymmetries, 'kick' the nascent black hole into an eccentric orbit. Wind accretion explains the X-ray luminosity, and the black-hole spin can be natal.

Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K.

Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys.

Self-assembling PEG-p(CL-co-TMC) copolymers for oral delivery of poorly water-soluble drugs: a case study with risperidone.

Diblock PEG-p(CL-co-TMC) [methoxypoly(ethylene glycol)-poly(caprolactone/trimethylene carbonate)] copolymers form micelles spontaneously and significantly increase the solubility of poorly water-soluble drugs. The aim of this work was to assess these diblock copolymers as oral drug delivery systems in both in vitro and in vivo experiments using risperidone as a model drug. The permeation of risperidone through Caco-2 cell monolayers showed that the apparent permeation coefficient (Papp) was slightly reduced when risperidone was formulated with the copolymer. Based on the higher apparent drug solubility, the copolymer increased drug flux or the total amount of drug which crossed the Caco-2 monolayers. The Papp of the micelle formulation was higher at 37 degrees C than at 4 degrees C. After oral administration to rats, the pharmacokinetic parameters and the pharmacological effect were evaluated. Time courses of receptor occupancy by risperidone after oral administration were similar when risperidone was encapsulated in PEG-p(CL-co-TMC) micelles or solubilized in an aqueous tartaric acid vehicle. The areas under the curve (AUC) were not significantly different although the maximal concentration (Cmax) was twofold lower with the copolymer. The polymeric micelles of PEG-p(CL-co-TMC) seem to be a good candidate for oral drug delivery of poorly soluble drugs.

Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused compounds.

A simple, reliable, and user friendly system was established to cultivate Caco-2 cell monolayer for epithelial transport studies. After an initial growth period of 1 week in a CO(2) incubator, Caco-2 cells were cultivated in an automated continuous perfusion system (Minucells and Minutissue, Germany). Medium was constantly renewed at the apical and basal side of the monolayers, which resulted in a continuous supply of nutrients as well as in a continuous removal of metabolite wastes. The monolayers obtained with the new perfusion culture system were evaluated to estimate the passive transport properties of a series of model compounds. The results produced were compared to those of monolayers obtained with the standard 21-day system. The integrity of cell monolayers was checked by measuring transepithelial electrical resistance (TEER) and by the transport of the paracellular leakage marker sodium fluorescein. The results of confocal microscopy as well as TEER measurements indicated the formation of a monolayer on various support filters. The growth and differentiation of Caco-2 cells were highly dependent upon the individual support filters and extracellular matrix proteins used for Caco-2 attachment. The permeability coefficients of several model compounds across Caco-2 cells obtained with the perfusion system were approximately two-fold higher than those obtained using the traditional 21-day Snapwell-based cultures. A good correlation was found between the transport of passively diffused drugs across Caco-2 monolayers differentiated in the perfusion system and the transport according to the standard method. The rank ordering of high permeable model compounds tested through Caco-2 monolayers, differentiated in a perfusion system, was similar to the standard 21-day culture method.

Pharmacokinetics and tissue distribution of galantamine and galantamine-related radioactivity after single intravenous and oral administration in the rat.

The plasma kinetics and tissue distribution of galantamine hydrobromide [4aS-(4a alpha,6beta,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2-ef] [2benzazepin-6-ol hydrobromide, CAS-1953-04-4], a reversible acetylcholinesterase inhibitor, were studied in male and female non-pregnant and pregnant SPF Wistar rats and in male Fisher x Copenhagen pigmented rats. Most studies were performed using 3H-labelled galantamine hydrobromide, measuring unchanged drug (UD) and non-volatile radioactivity (NVR) in plasma and tissues by high-performance liquid chromatography (HPLC), liquid scintillation counting and quantitative whole-body autoradiography (QWBA). Plasma levels after single intravenous administration of UD (1.25-2.5 mg/kg) declined bi- or triphasically, with an elimination half-life of 3.5 h in male, and 5.1 h in female rats. The plasma clearance (Cl) averaged 1.9 l/kg/h (male rats) and 0.9 l/kg/h (female rats), and the volume of distribution (VdSS) was about 5 l/kg for both male and female rats. Following oral administration (2.5-10 mg/kg), galantamine was rapidly absorbed in both sexes, with an absolute oral bioavailability of 77%. Distribution studies after oral administration of 3H-galantamine showed an almost immediate equilibrium between plasma and tissues, with highest tissue levels of NVR and UD in liver, kidney, salivary glands, adrenal glands and, for the female rat, spleen, and lowest in white fat. To most tissues and especially to brain, the distribution of UD was more pronounced than that of its metabolites. Tissue concentrations of UD and NVR declined at a similar rate as plasma, showing no undue retention. QWBA in the pigmented rat showed the same distribution and elimination pattern of NVR. Only in hair follicles and choroid some retention of NVR was seen, but the calculated half-life was less than one day. In the female pregnant SPF Wistar rat, maternal tissue distribution of NVR was similar to that of the non-pregnant rat. NVR tissue levels in the foetus were similar to those found in maternal blood during the whole experiment, indicating a rapid equilibrium without accumulation.

Pharmacokinetics of galantamine, a cholinesterase inhibitor, in several animal species.

In this publication, single and repeated dose experiments in rats, mice, rabbits and dogs are reported to assess the pharmacokinetics of galantamine (CAS-1953-04-4), a tertiary alkaloid with reversible cholinesterase inhibiting and nicotinic receptor modulatory properties developed for the treatment of Alzheimer's disease in humans. Rats received single i.v. and single and repeated oral administrations of various doses, up to 160 mg/kg/day. In mice, only repeated oral administration of galantamine was investigated, up to 40 mg/kg/day. Galantamine single and repeated oral doses up to 32 mg/kg/day were administered to female pregnant rabbits. Beagle dogs received single i.v. and single and repeated oral administrations of doses up to 8 mg/kg/day. Generally, oral absorption was rapid, with maximal plasma levels reached within 2 h in all species. Absolute oral bioavailability of a gavage dose was high in rat (77%) and dog (78%). In mice and rats, the bioavailability of galantamine administered via the food was lower than of galantamine administered by gavage. Elimination half-life of galantamine was relatively large in rat and dog and smaller in mouse and rabbit. In general, galantamine displayed dose-proportional to somewhat more than dose-proportional kinetics. In rats, plasma levels were lower in females than in males, whereas in mice, females showed higher levels than males. No gender differences were observed in dogs. No relevant differences in exposure to galantamine were found in rats and dogs upon oral administration of galantamine obtained as a natural extract or from chemical synthesis. The exposure to the active metabolite norgalantamine in plasma of the different animal species was low, except in the dog where the steady-state norgalantamine exposure was approximately 75% of galantamine exposure. Galantamine plasma levels after single and repeated administration of 10 mg/kg/day in all species investigated except female rat and rabbit were much higher than mean therapeutic plasma levels of galantamine obtained in humans. The pharmacokinetic profile of galantamine after repeated oral administration in rats was most similar to the profile obtained after repeated administration of 12 mg b.i.d. in man.