Target product profiles: leprosy diagnostics.

The World Health Organization (WHO) aims to reduce new leprosy cases by 70% by 2030, necessitating advancements in leprosy diagnostics. Here we discuss the development of two WHO's target product profiles for such diagnostics. These profiles define criteria for product use, design, performance, configuration and distribution, with a focus on accessibility and affordability. The first target product profile outlines requirements for tests to confirm diagnosis of leprosy in individuals with clinical signs and symptoms, to guide multidrug treatment initiation. The second target product profile outlines requirements for tests to detect Mycobacterium leprae or M. lepromatosis infection among asymptomatic contacts of leprosy patients, aiding prophylactic interventions and prevention. Statistical modelling was used to assess sensitivity and specificity requirements for these diagnostic tests. The paper highlights challenges in achieving high specificity, given the varying endemicity of M. leprae, and identifying target analytes with robust performance across leprosy phenotypes. We conclude that diagnostics with appropriate product design and performance characteristics are crucial for early detection and preventive intervention, advocating for the transition from leprosy management to prevention.

L'Organisation mondiale de la Santé (OMS) vise à réduire le nombre de nouveaux cas de lèpre de 70% d'ici 2030, ce qui nécessite un meilleur diagnostic de la maladie. Dans le présent document, nous évoquons le développement de deux profils de produit cible établis par l'OMS à cette fin. Ces profils définissent des critères en matière d'utilisation, de conception, de performances, de configuration et de distribution du produit, en accordant une attention particulière à l'accessibilité et à l'abordabilité. Le premier profil de produit cible décrit les exigences pour les tests servant à confirmer le diagnostic de la lèpre chez les individus qui présentent des signes cliniques et des symptômes, afin d'orienter l'instauration d'un traitement à base de plusieurs médicaments. Le second profil de produit cible décrit les exigences pour les tests servant à détecter une infection à Mycobacterium leprae ou M. lepromatosis parmi les contacts asymptomatiques de patients lépreux, ce qui contribue à l'adoption de mesures prophylactiques et à la prévention. Nous avons eu recours à une modélisation statistique pour évaluer les exigences de sensibilité et de spécificité de ces tests diagnostiques. Cet article met en évidence les obstacles à l'atteinte d'un niveau élevé de spécificité en raison de l'endémicité variable de M. leprae, et à l'identification d'analytes cibles offrant de bons résultats chez les phénotypes lépreux. Nous concluons qu'un diagnostic reposant sur des caractéristiques de performance et de conception appropriées est essentiel pour détecter rapidement la maladie et intervenir en amont, et nous plaidons pour une prévention plutôt qu'une gestion de la lèpre.

La Organización Mundial de la Salud (OMS) pretende reducir los nuevos casos de lepra en un 70% para 2030, lo que requiere avances en el diagnóstico de la lepra. Aquí se analiza el desarrollo de dos perfiles de productos objetivo de la OMS para este tipo de diagnósticos. Estos perfiles definen los criterios de uso, diseño, rendimiento, configuración y distribución de los productos, centrándose en su accesibilidad y asequibilidad. El primer perfil de producto objetivo describe los requisitos de las pruebas para confirmar el diagnóstico de la lepra en personas con signos y síntomas clínicos, con el fin de orientar el inicio del tratamiento con múltiples fármacos. El segundo perfil de producto objetivo describe los requisitos de las pruebas para detectar la infección por Mycobacterium leprae o M. lepromatosis entre los contactos asintomáticos de los pacientes con lepra, para facilitar las intervenciones profilácticas y la prevención. Se utilizaron modelos estadísticos para evaluar los requisitos de sensibilidad y especificidad de estas pruebas diagnósticas. El artículo destaca las dificultades para lograr una alta especificidad, dada la diferente endemicidad de M. leprae, y para identificar analitos diana con un rendimiento sólido en todos los fenotipos de lepra. Concluimos que los diagnósticos con un diseño de producto y unas características de rendimiento adecuados son fundamentales para la detección precoz y la intervención preventiva, lo que favorece la transición del manejo de la lepra a la prevención.

Potential Impact of a Diagnostic Test for Detecting Prepatent Guinea Worm Infections in Dogs.

Chad has seen a considerable reduction in cases of Guinea worm disease (or dracunculiasis) in domestic dogs in recent years. Tethering of dogs and application of Abate® larvicide to water sources appear to have contributed to this progress, but with 767 reported dog cases in 2021, accelerating elimination of the disease in Chad may require additional tools. We investigate the potential benefits of a hypothetical diagnostic test that could be capable of detecting prepatent infections in dogs. We adapt an agent-based simulation model for forecasting the impact of interventions on guinea worm disease in dogs to examine the interaction of multiple test factors including test accuracy, when the test can detect infection, dog selection, and dog-owner compliance with tethering recommendations. We find that a diagnostic test could be successful if used in conjunction with existing interventions, and elimination can be achieved within 2 years with 80% or higher test sensitivity, 90% or higher specificity, systematic testing of each dog twice per year, and more than 90% long-term tethering compliance when a dog tests positive or a worm is emerging. Because of the long incubation period of Guinea worm disease (10-14 months) and the fact that no treatment exists, the benefits of the test rely on the testing rollout and response of dog owners. If the test could estimate the timing of worm emergence, long-term tethering could be eliminated and infected dogs could be tethered only when the worms are expected, minimizing the related resources (human and financial) to support the intervention.

What does climbing mean exactly? Assessing spatiotemporal gait characteristics of inclined locomotion in parrots.

At what inclination does climbing begin? In this paper, we investigate the transition from walking to climbing in two species of parrot (Agapornis roseicollis and Nymphicus hollandicus) that are known to incorporate both their tail and their craniocervical system into the gait cycle during vertical climbing. Locomotor behaviors ranging in inclination were observed at angles between 0° and 90° for A. roseicollis, and 45°-85° degrees for N. hollandicus. Use of the tail in both species was observed at 45° inclination, and was joined at higher inclinations (> 65°) by use of the craniocervical system. Additionally, as inclination approached (but remained below) 90°, locomotor speeds were reduced while gaits were characterized by higher duty factors and lower stride frequency. These gait changes are consistent with those thought to increase stability. At 90°, A. roseicollis significantly increased its stride length, resulting in higher overall locomotor speed. Collectively these data demonstrate that the transition between horizontal walking and vertical climbing is gradual, incrementally altering several components of gait as inclinations increase. Such data underscore the need for further investigation into how exactly "climbing" is defined and the specific locomotor characteristics that differentiate this behavior from level walking.

Correction: Onchocerciasis: Target product profiles of in vitro diagnostics to support onchocerciasis elimination mapping and mass drug administration stopping decisions.

[This corrects the article DOI: 10.1371/journal.pntd.0010682.].

Diagnostics to support the control of scabies-Development of two target product profiles.

BACKGROUND: Scabies was added to the WHO NTD portfolio in 2017 and targets for the control of scabies were included in the 2021-2030 WHO NTD roadmap. A major component of scabies control efforts a strategy based on mass drug administration (MDA) with ivermectin. Currently diagnosis of scabies relies on clinical examination with a limited role for diagnostic testing. Under the recommendation of the WHO Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases, a working group was assembled and tasked with agreeing on priority use cases for and developing target product profiles (TPPs) for new diagnostics tools for scabies. METHODOLOGY AND PRINCIPAL FINDINGS: The working group convened three times and established two use cases: establishing if the 10% threshold for mass drug administration had been reached and if the 2% threshold for stopping mass drug administration has been achieved. One subgroup assessed the current diagnostic landscape for scabies and a second subgroup determined the test requirements for both use cases. Draft TPPs were sent out for input from stakeholders and experts. Both TPPs considered the following parameters: product use, design, performance, configuration, cost, access and equity. The group considered the use of the tests as a single step process or as part of a two step process following initial clinical examination. When used a single step test (the ideal scenario) for starting MDA a new diagnostic required a sensitivity of ≥92% and a specificity of ≥98%. When used a single step test (the ideal scenario) for stopping MDA a new diagnostic required a sensitivity of ≥80% and a specificity of ≥99%. CONCLUSIONS: The TPPs developed will provide test developers with guidance to ensure that novel diagnostic tests meet identified public health needs.

Onchocerciasis: Target product profiles of in vitro diagnostics to support onchocerciasis elimination mapping and mass drug administration stopping decisions.

In June 2021, the World Health Organization (WHO), recognizing the need for new diagnostics to support the control and elimination of onchocerciasis, published the target product profiles (TPPs) of new tests that would support the two most immediate needs: (a) mapping onchocerciasis in areas of low prevalence and (b) deciding when to stop mass drug administration programs. In both instances, the test should ideally detect an antigen specific for live, adult O. volvulus female worms. The preferred format is a field-deployable rapid test. For mapping, the test needs to be ≥ 60% sensitive and ≥ 99.8% specific, while to support stopping decisions, the test must be ≥ 89% sensitive and ≥ 99.8% specific. The requirement for extremely high specificity is dictated by the need to detect with sufficient statistical confidence the low seroprevalence threshold set by WHO. Surveys designed to detect a 1-2% prevalence of a given biomarker, as is the case here, cannot tolerate more than 0.2% of false-positives. Otherwise, the background noise would drown out the signal. It is recognized that reaching and demonstrating such a stringent specificity criterion will be challenging, but test developers can expect to be assisted by national governments and implementing partners for adequately powered field validation.

Patterns of single limb forces during terrestrial and arboreal locomotion in rosy-faced lovebirds (Psittaciformes: Agapornis roseicollis).

The biomechanical demands of arboreal locomotion are generally thought to necessitate specialized kinetic and kinematic gait characteristics. While such data have been widely collected across arboreal quadrupeds, no study has yet explored how arboreal substrates influence the locomotor behavior of birds. Parrots - an ancient arboreal lineage that exhibit numerous anatomical specializations towards life in the trees - represent an ideal model group within which to examine this relationship. Here, we quantifiy limb loading patterns within the rosy-faced lovebird (Agapornis roseicollis) across a range of experimental conditions to define the circumstances under which arboreal gaits are triggered, and how, during arboreal walking, gait patterns change across substrates of varying diameter. In so doing, we address longstanding questions as to how the challenges associated with arboreality affect gait parameters. Arboreal locomotion was associated with the adoption of a sidling gait, which was employed exclusively on the small and medium diameter poles but not terrestrially. When sidling, the hindlimbs are decoupled into a distinct leading limb (which imparts exclusively braking forces) and trailing limb (which generates only propulsive forces). Sidling was also associated with relatively low pitching forces, even on the smallest substrate. Indeed, these forces were significantly lower than mediolateral forces experienced during striding on terrestrial and large diameter substrates. We propose that the adoption of sidling gaits is a consequence of avian foot morphology and represents a novel form of arboreal locomotion where inversion/eversion is impossible. Such movement mechanics is likely widespread among avian taxa and may also typify patterns of arboreal locomotion in humans.

Locomotor energetics in the Indonesian blue-tongued skink (Tiliqua gigas) with implications for the cost of belly-dragging in early tetrapods.

During the last decade, biomechanical and kinematic studies have suggested that a belly-dragging gait may have represented a critical locomotor stage during tetrapod evolution. This form of locomotion is hypothesized to facilitate animals to move on land with relatively weaker pectoral muscles. The Indonesian blue-tongued skink (Tiliqua gigas) is known for its belly-dragging locomotion and is thought to employ many of the same spatiotemporal gait characteristics of stem tetrapods. Conversely, the savannah monitor (Varanus exanthematicus) employs a raised quadrupedal gait. Thus, differences in the energetic efficiency of locomotion between these taxa may elucidate the role of energetic optimization in driving gait shifts in early tetrapods. Five Tiliqua and four Varanus were custom-fitted for 3D printed helmets that, combined with a Field Metabolic System, were used to collect open-flow respirometry data including O2 consumption, CO2 production, water vapor pressure, barometric pressure, room temperature, and airflow rates. Energetic data were collected for each species at rest, and when walking at three different speeds. Energetic consumption in each taxon increased at greater speeds. On a per-stride basis, energetic costs appear similar between taxa. However, significant differences were observed interspecifically in terms of net cost of transport. Overall, energy expenditure was ~20% higher in Tiliqua at equivalent speeds, suggesting that belly-dragging does impart a tangible energetic cost during quadrupedal locomotion. This cost, coupled with the other practical constraints of belly-dragging (e.g., restricting top-end speed and reducing maneuverability in complex terrains) may have contributed to the adoption of upright quadrupedal walking throughout tetrapod locomotor evolution.

Are they arboreal? Climbing abilities and mechanics in the red-backed salamander (Plethodon cinereus).

While red-backed salamanders (Plethodon cinereus) are most often observed in terrestrial forested areas, several studies report arboreal substrate use and climbing behavior. However, salamanders do not have any of the anatomical features commonly observed in specialized climbing species (e.g., claws, setae, suction cups). Instead, salamanders cling to surfaces using the shear and adhesive properties of their mucous layer. In this study, we explore the capabilities and spatiotemporal gait patterns of arboreal locomotion in the red-backed salamander as they move across twelve substrate conditions ranging in diameter, orientation, and roughness. On arboreal substrates, red-backed salamanders decreased locomotor speed, stride frequency, phase and stride length, and increased duty factor and stride duration. Such responses have been observed in other non-salamander species and are posited to increase arboreal stability. Furthermore, these findings indicate that amphibian locomotion, or at least the locomotor behavior of the red-backed salamander, is not stereotyped and that some locomotor plasticity is possible in response to the demands of the external environment. However, red-backed salamanders were unable to locomote on any small-diameter or vertically-oriented coarse substrates. This finding provides strong evidence that the climbing abilities of red-backed salamanders are attributable solely to mucous adhesion and that this species is unable to produce the necessary external "gripping" forces to achieve fine-branch arboreal locomotion or scale substrates where adhesion is not possible. The red-backed salamander provides an ideal model for arboreal locomotor performance of anatomically-unspecialized amphibians and offers insight into transitionary stages in the evolution of arborealism in this lineage.

Diagnostics to support elimination of lymphatic filariasis-Development of two target product profiles.

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools.

Assessment of the required performance and the development of corresponding program decision rules for neglected tropical diseases diagnostic tests: Monitoring and evaluation of soil-transmitted helminthiasis control programs as a case study.

Recently, the World Health Organization established the Diagnostic Technical Advisory Group to identify and prioritize diagnostic needs for neglected tropical diseases, and to ultimately describe the minimal and ideal characteristics for new diagnostic tests (the so-called target product profiles (TPPs)). We developed two generic frameworks: one to explore and determine the required sensitivity (probability to correctly detect diseased persons) and specificity (probability to correctly detect persons free of disease), and another one to determine the corresponding samples sizes and the decision rules based on a multi-category lot quality assurance sampling (MC-LQAS) approach that accounts for imperfect tests. We applied both frameworks for monitoring and evaluation of soil-transmitted helminthiasis control programs. Our study indicates that specificity rather than sensitivity will become more important when the program approaches the endgame of elimination and that the requirements for both parameters are inversely correlated, resulting in multiple combinations of sensitivity and specificity that allow for reliable decision making. The MC-LQAS framework highlighted that improving diagnostic performance results in a smaller sample size for the same level of program decision making. In other words, the additional costs per diagnostic tests with improved diagnostic performance may be compensated by lower operational costs in the field. Based on our results we proposed the required minimal and ideal diagnostic sensitivity and specificity for diagnostic tests applied in monitoring and evaluating of soil-transmitted helminthiasis control programs.

Outside the box: will information technology be a viable intervention to improve the quality of cancer care?

The use of health information technology (IT) to resolve the crisis in communication inherent within the fragmented service environment of medical care in the United States is a strategic priority for the Department of Health and Human Services. Yet the deployment of health IT alone is not sufficient to improve quality in health service delivery; what is needed is a human factors approach designed to optimize the balance between health-care users, health-care providers, policies, procedures, and technologies. An evaluation of interface issues between primary and specialist care related to cancer reveals opportunities for human factors improvement along the cancer care continuum. Applications that emphasize cognitive support for prevention recommendations and that encourage patient engagement can help create a coordinated health-care environment conducive to cancer prevention and early detection. An emphasis on reliability, transparency, and accountability can help improve the coordination of activities among multiple service providers during diagnosis and treatment. A switch in emphasis from a transaction-based approach to one emphasizing long-term support for healing relationships should help improve patient outcomes during cancer survivorship and end-of-life care. Across the entire continuum of care, an emphasis on "meaningful use" of health IT-rather than on IT as an endpoint-should help put cancer on a path toward substantive continuous quality improvement. The accompanying research questions will focus on reducing the variance between the social and technical subsystems as IT is used to improve patient outcomes across the interfaces of care.

Micro-scale open-tube capillary separations of functional proteins.

This article describes a novel technique whereby fully functional proteins or multiprotein complexes are efficiently extracted from biological samples to chemically derivatized walls of fused-silica open-tube capillary columns. Proteins are eluted with very high yields into elution volumes that are smaller in volume than the internal volume of the open-tube capillary column itself, thereby achieving 100-fold increases in target protein concentrations from starting samples of less than 1 ml. The open-tube capillary columns are designed for single use; combined with the physical and chemical characteristics of the open-tube capillary column, this provides exceptional purity to the eluted proteins. Affinity-based open-tube capillary columns are demonstrated here to purify, enrich, and maintain functionality for a monomeric and dimeric enzyme, a low-abundance HeLa nuclear complex, and a light-harvesting octadecameric membrane protein complex. The design of the open-tube capillary column allows for facile direction of the processed protein sample to any number of final detection techniques and is capable of generating final protein concentrations required for many structural biology experiments. The open-tube capillary columns are also characterized by exceptional ease of use. Current designs allow for up to 10 open-tube capillary columns to be applied simultaneously with no fundamental impediments to even greater parallel operation.

Pachymetry of donor corneas: effect of ethnicity and gender on central corneal thickness.

PURPOSE: To examine demographic differences associated with the central corneal thickness (CCT) of donor corneas and to investigate whether these differences confirmed previous clinical studies. METHODS: CCT was prospectively measured using noncontact pachymetry among 704 eye bank corneas. The effects of gender, ethnicity, age, cause of death, times until preservation and evaluation, and endothelial cell density and morphometry on CCT were examined. RESULTS: The CCT of black women was significantly thinner (P = 0.05) than that of other corneal donors. The average CCT +/- SD of black women was 530 +/- 35.9 microm, whereas those of white and Hispanic women were 554 +/- 59.1 microm and 556 +/- 51.2 microm, respectively. Average values for black, white, and Hispanic men were 553 +/- 44.7 microm, 551 +/- 53.4 microm, and 543 +/- 50.4 microm, respectively. Age and cause of death did not significantly affect CCT. CONCLUSION: Gender may modify racial differences of CCT. Measurements using donated corneal tissues support pachymetric differences by ethnic origin, although this finding was limited to female donors only.

The postmortem sociomedical interview: uncertainty in confirming infectious disease risks of young tattooed donors.

PURPOSE: To assess the reproducibility of relatives' replies to questions asked at the time of corneal donation and again 2 months later concerning infectious disease risk factors and to identify characteristics associated with inconsistent responses. METHODS: A reinterview study involving individuals who answered questions regarding an eye donor's sociomedical history within 1 day of the decedent's death and who consented to be recontacted 6 to 12 weeks later. The main outcome measures were frequency of answering differently on the same questions of infectious disease risk factors and the donors' and relatives' characteristics that predicted inconsistency. RESULTS: Of 368 individuals who agreed to a reinterview, 263 (71.5%) completed and returned the survey questionnaire. Thirty-eight (14.4%) respondents answered differently on at least one question concerning infectious disease risk factors. The family of donors with a trauma-related death was 2.9 [95% confidence interval (CI), 1.0-8.3] times more likely to give inconsistent responses. Different responses to behavioral questions occurred 22 (95% CI, 1.6-315) times more often by relatives of donors who were both younger than 40 years old and had a tattoo. CONCLUSION: The postmortem sociomedical interview cannot assure complete knowledge of the risk of potentially transmissible disease of all donors. Relatives of young, tattooed donors tend to give inconsistent responses about infectious disease risk factors.