Acceptance and perceived value of non-invasive malaria diagnostic tests in malaria-endemic countries.

BACKGROUND: The diagnosis of malaria, using microscopy or rapid diagnostic tests (RDTs), requires the collection of capillary blood. This procedure is relatively simple to perform but invasive and poses potential risks to patients and health workers, arising from the manipulation of potentially infectious bodily fluids. Less or non-invasive diagnostic tests, based on urine, saliva or requiring no sampling, have the potential to generate less discomfort for the patient and to offer simpler and less risky testing procedures that could be safely performed by untrained staff or even self-performed. To explore the potential acceptance and perceived value of such non-invasive tests, an online, international survey was conducted to gather feedback from National Malaria Control Programme (NMCP) representatives. METHODS: An online survey comprising nineteen questions, available in English, French or Spanish, was emailed to 300 individuals who work with NMCPs in malaria-endemic countries. Answers were collected between November and December 2017; responses were qualitatively analysed to identify key themes and trends and quantitatively analysed to determine average values stratified by region. RESULTS: Responses were received from 70 individuals, from 33 countries. Approximately half of the respondents (52 %) considered current blood-based tests for malaria to be minimally invasive and non-problematic in their setting. For these participants, non-invasive tests would only be of interest if they brought additional performance improvements, as compared with the performance of microscopy and RDTs. Most respondents were of the view that saliva-based (80 %) and urine-based (66 %) tests would be more readily acceptable among children than blood-based tests. Potential use-case scenarios of interest for both saliva- and urine-based tests were ease-of-testing by community health workers, additional surveillance, self-testing, and outbreak investigation. Many respondents (41 %) thought that if saliva-based tests retailed at <$0.50 per unit they could largely replace conventional RDTs, whereas only 25 % of respondents thought a similarly priced urine-based test would do so. CONCLUSIONS: Although limited to NMCP stakeholders, this survey indicated that current tests for malaria, based on capillary blood, are generally perceived to be minimally invasive and non-problematic. Non-invasive tests, especially if saliva-based, would be welcome if they could match or out-perform the price and performance of current blood-based tests.

Barriers to Access to New Gonorrhea Point-of-Care Diagnostic Tests in Low- and Middle-Income Countries and Potential Solutions: A Qualitative Interview-Based Study.

BACKGROUND: To assess the potential market for 2 hypothetical diagnostic tests, one for Neisseria gonorrhoeae/Chlamydia trachomatis (NG/CT) detection and one for NG antimicrobial resistance (AMR) marker identification. METHODS: This is a qualitative interview-based study. Semistructured interviews with global- and country-level experts were performed. Interviewees were provided with simplified versions of Foundation for Innovative New Diagnostics/World Health Organization-developed target product profiles for each test. Interviewees were asked to comment on use cases, test characteristics, and factors that may influence test adoption. RESULTS: Twenty-one experts were interviewed, including 15 country-level experts (from South Africa, India, Zimbabwe, Ghana, China, Peru, Kenya, and Cambodia). Interviewees welcomed an NG/CT point-of-care test, with near-universal preference for a test that could detect symptomatic and asymptomatic infections. Interviewees also saw value in a test that could be used to screen high-risk populations. Factors that may drive adoption of the NG/CT test identified by interviewees included price, cost-effectiveness, evidence of public health benefit, and World Health Organization guidance. Interviewees felt that AMR test use would likely be limited to patients failing first-line treatment. CONCLUSIONS: Although the potential target population for an NG/CT diagnostic test in low- and middle-income countries is sizeable, there are areas of uncertainty relating to the price of the test and its intended use, warranting further research to determine the most effective positioning. An NG AMR test would likely be used very selectively.

Priority use cases for antibody-detecting assays of recent malaria exposure as tools to achieve and sustain malaria elimination.

Measurement of malaria specific antibody responses represents a practical and informative method for malaria control programs to assess recent exposure to infection. Technical advances in recombinant antigen production, serological screening platforms, and analytical methods have enabled the identification of several target antigens for laboratory based and point-of-contact tests. Questions remain as to how these serological assays can best be integrated into malaria surveillance activities to inform programmatic decision-making. This report synthesizes discussions from a convening at Institut Pasteur in Paris in June 2017 aimed at defining practical and informative use cases for serology applications and highlights five programmatic uses for serological assays including: documenting the absence of transmission; stratification of transmission; measuring the effect of interventions; informing a decentralized immediate response;  and testing and treating P. vivax hypnozoite carriers.

Female Athlete Triad.

The female athlete triad is a condition seen in physically active female athletes, consisting of low energy availability, menstrual dysfunction, and low bone mineral density. The condition should be viewed as a metabolic injury. It can have an impact on female athletes at any age or level. Activities at highest risk are those emphasizing leanness, aesthetics, and endurance. The cornerstone of treatment is improving mismatched energy balance. A multidisciplinary team, including health care providers, dieticians, and mental health professionals, is vital in caring for female athlete triad patients. Increased awareness and education are needed for medical as well as athletic communities.

Musculoskeletal Outcomes from Chronic High-Speed, High-Impulse Resistance Exercise.

While bones and muscles adapt to mechanical loading, it appears that very specific types of stimuli must be applied to achieve osteogenesis. Our study assessed musculoskeletal outcomes to 30 training sessions on an Inertial Exercise Trainer (Newnan, GA). Subjects (n=13) performed workouts with their left leg, while their right served as an untreated control. Workouts entailed three 60-s sets each of knee extension, hip extension and calf press exercises, separated by 90-s rests. Before and after the 30 training sessions, subjects underwent strength tests (knee and ankle extensors of both legs), DEXA scans (hip, knee and ankles of both legs), and blood draws. After 30 training sessions 2×2 ANOVAs showed left leg peak torques rose significantly. 2×2 ANCOVAs, with bone scan area as a covariate, showed significant left leg calcaneal bone mineral content (+29%) and density (+33%) increases after 30 training sessions. A significant decline in C-terminal telopeptides of type I collagen, a blood marker of bone resorption, also occurred after 30 training sessions. The Inertial Exercise Trainer's large volume of training session repetitions elicited high peak force, peak acceleration and impulses that likely provided a mechanical loading stimulus that evoked calcaneal accretion.

International survey to identify diagnostic needs to support malaria elimination: guiding the development of combination highly sensitive rapid diagnostic tests.

BACKGROUND: In malaria elimination settings, the very low levels of transmission now being attained present challenges that demand new strategies to identify and treat low-density infections in both symptomatic and asymptomatic populations. Accordingly, passive case detection activities need to be supplemented by active case detection (ACD) strategies with more sensitive diagnostic tools. Malaria rapid diagnostic tests (RDTs) have provided low- and middle-income countries with unprecedented access to malaria diagnostics. Nevertheless, conventional RDTs miss a potentially important proportion of sub-microscopic infections. Therefore, new combination highly sensitive (HS-)RDTs, able to detect low parasite densities and identify all infected individuals, could support countries implementing ACD strategies for radical cure to accelerate malaria elimination. To address this need, an on-line survey was conducted to gather information from malaria control programme representatives to guide the development of next-generation RDTs. RESULTS: Most of respondents confirmed that ACD was a common activity in their programmes (56/75; 75%). Although microscopy was the preferred method in case management and reactive case detection, RDTs were the primary diagnostic tests used in proactive case detection (31/75; 41%). In terms of preferences for species detection in a new combination HS-RDT, data was not one-directional. Survey respondents slightly preferred the Pf/Pv/Pan combination (42%; 21/50), while Pf/Pan was more popular among end-users. Survey respondents also valued a low-cost (< $1.00 USD), lightweight and portable test, able to detect asymptomatic infections and differentiate species, as well as provide immediate results that could be interpreted with the naked eye. In addition, respondents were open to new tests and even to replace the existing ones for ACD (63%; 47/75). CONCLUSIONS: This survey provided valuable information on the use and current limitations of ACD, on the primary product characteristics for a next-generation combination HS-RDT to support ACD and radical cure, and on the potential adoption of such a test, if available, to support malaria elimination.

Acute Monoarthritis: Diagnosis in Adults.

Acute monoarthritis can be the initial manifestation of many joint disorders. The most common diagnoses in the primary care setting are osteoarthritis, gout, and trauma. It is important to understand the prevalence of specific etiologies and to use the appropriate diagnostic modalities. A delay in diagnosis and treatment, particularly in septic arthritis, can have catastrophic results including sepsis, bacteremia, joint destruction, or death. The history and physical examination can help guide the use of laboratory and imaging studies. The presence of focal bone pain or recent trauma requires radiography of the affected joint to rule out metabolic bone disease, tumor, or fracture. If there is a joint effusion in the absence of trauma or recent surgery, and signs of infection (e.g., fever, erythema, warmth) are present, subsequent arthrocentesis should be performed. Inflammatory synovial fluid containing monosodium urate crystals indicates a high probability of gout. Noninflammatory synovial fluid suggests osteoarthritis or internal derangement. Pitfalls in the diagnosis and early treatment of acute monoarthritis include failure to perform arthrocentesis, administering antibiotics before aspirating the joint when septic arthritis is suspected (or failing to start antibiotics after aspiration), and starting treatment based solely on laboratory data, such as an elevated uric acid level.

Rapid diagnostic tests for malaria.

Maintaining quality, competitiveness and innovation in global health technology is a constant challenge for manufacturers, while affordability, access and equity are challenges for governments and international agencies. In this paper we discuss these issues with reference to rapid diagnostic tests for malaria. Strategies to control and eliminate malaria depend on early and accurate diagnosis. Rapid diagnostic tests for malaria require little training and equipment and can be performed by non-specialists in remote settings. Use of these tests has expanded significantly over the last few years, following recommendations to test all suspected malaria cases before treatment and the implementation of an evaluation programme to assess the performance of the malaria rapid diagnostic tests. Despite these gains, challenges exist that, if not addressed, could jeopardize the progress made to date. We discuss recent developments in rapid diagnostic tests for malaria, highlight some of the challenges and provide suggestions to address them.

Le maintien de la qualité, de la compétitivité et de l'innovation dans les technologies de la santé au niveau mondial représente un défi constant pour les fabricants, tandis que l'accessibilité économique, l'accès et l'équité constituent un défi pour les gouvernements et les organismes internationaux. Nous abordons ces questions dans le présent rapport en ce qui concerne les tests de diagnostic rapide du paludisme. Les stratégies visant à enrayer et à éradiquer le paludisme reposent sur un diagnostic précoce et précis. Les tests de diagnostic rapide du paludisme nécessitent peu de formation et de matériel et peuvent être réalisés par des non-spécialistes dans des endroits isolés. L'utilisation de ces tests s'est considérablement répandue au cours des dernières années suite aux recommandations préconisant d'examiner tous les cas présumés de paludisme avant la mise en route d'un traitement et de mettre en œuvre un programme d'évaluation pour mesurer les performances des tests de diagnostic rapide du paludisme. Il demeure, malgré ces avancées, des défis, qui, s'ils ne sont pas surmontés, risquent de compromettre les progrès accomplis jusqu'à présent. Le présent rapport fait état des améliorations récemment apportées aux tests de diagnostic rapide du paludisme, souligne un certain nombre de défis et propose des solutions pour les surmonter.

Mantener la calidad, competitividad e innovación en la tecnología de salud mundial es un desafío constante para los fabricantes, mientras que la asequibilidad, el acceso y la equidad son desafíos para los gobiernos y las agencias internacionales. En este artículo se debaten estas cuestiones con relación a las pruebas de diagnóstico rápido del paludismo. Las estrategias para controlar y eliminar el paludismo dependen de un diagnóstico temprano y preciso. Las pruebas de diagnóstico rápido del paludismo requieren muy poco entrenamiento y equipo y pueden ser llevadas a cabo por no especialistas en lugares apartados. La utilización de estas pruebas se ha expandido significantemente durante los últimos años, tras las recomendaciones de hacer una prueba en todos los casos de posible paludismo antes del tratamiento y la implementación de un programa de evaluación para examinar el rendimiento de las pruebas de diagnóstico rápido del paludismo. A pesar de estos avances, todavía existen desafíos que, si no se abordan, podrían poner en peligro el progreso hecho hasta la fecha. Se debaten los recientes desarrollos de las pruebas de diagnóstico rápido del paludismo, se destacan algunos de los desafíos y se proporcionan sugerencias para tratarlos.

Longitudinally extensive optic neuritis in neuromyelitis optica spectrum disorder.

BACKGROUND: Neuomyelitis optica, sarcoid, and multiple sclerosis can all cause optic neuritis. Further means of distinguishing the causes of optic neuritis among these etiologies would be valuable for the clinician. METHODS: This is a retrospective, cohort study from a single university based hospital and neuro-ophthalmology clinic. Blinded interpretation of orbit MRIs was performed on patients with acute optic neuritis from multiple sclerosis (n=25), sarcoid (n=5) and neuromyelitis optica spectrum disorder (n=6). RESULTS: A length of >40 mm anterior visual pathway enhancement distinguished neuromyelitis optica spectrum disorder from multiple sclerosis (p=0.0376). No statistically significant differences were found for presence of pain or papillitis, however there was a trend for bilateral involvement and chiasmal involvement in neuromyelitis optica spectrum disorder compared to multiple sclerosis. CONCLUSIONS: In acute optic neuritis, enhancing anterior visual pathway lesion length >40 mm helps differentiate neuromyelitis optica spectrum disorder from multiple sclerosis. This degree of involvement can be considered longitudinally extensive optic neuritis. Further characterization is necessary as this degree of enhancement occurs in other clinical syndromes besides neuromyelitis optica.

Spatial and temporal silencing of the human maternal UBE3A gene.

Angelman syndrome (AS) is characterized by severe cognitive disruption, seizures, difficulty speaking and ataxia. Nearly all cases are attributed to the disruption or absence of the imprinted maternal copy of UBE3A, transcribing an E3-type ubiquitin ligase. Much of what is known about the molecular and biochemical changes in the CNS associated with AS has been obtained through this murine model. This widely used mouse model created by a null mutation of the maternal UBE3A gene recapitulates the major phenotypes characteristic of AS patients. The imprinting of maternal UBE3A was originally believed to be brain region specific; however recent reports using the AS mouse model have revealed a more wide-spread absence of the protein. The present study is the first to determine that the Ube3a protein ablation seen in the AS mouse model is also characteristic of AS patients and the silencing of the paternal UBE3A allele appears to be lifelong.

Adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for Angelman syndrome.

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr(286) and Thr(305/306), resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients.

Radiology update in neuro-ophthalmology.

PURPOSE OF REVIEW: Radiologic imaging is indispensible for the diagnosis and management of many neuro-ophthalmologic conditions. Advances in the radioimaging of neuro-ophthalmologic disorders may evolve from the clinical or the radiological side, meaning there is a constant stream of new information for the clinician. RECENT FINDINGS: Functional MRI, diffusion tensor MRI, magnetization transfer imaging, and magnetic resonance spectroscopy are examples of nonstandard radiographic techniques, which have expanded the knowledge of neuro-ophthalmologic conditions. Studies using conventional MRI have also led to advances in understanding optic neuropathies, the ocular motor system, pseudotumor cerebri, posterior reversible encephalopathy syndrome and migraine. SUMMARY: This article discusses recent radiologic advances relevant to neuro-ophthalmology.

Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression or mutation-induced dysfunction of its protein product, the E3 ubiquitin-protein ligase, UBE3A. In humans and rodents, UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution of native UBE3A/Ube3a(1) protein expression has not been comprehensively examined. To address this, we systematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3a maternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked loss of Ube3a protein in hippocampus, hypothalamus, olfactory bulb, cerebral cortex, striatum, thalamus, midbrain, and cerebellum in AS mice relative to WT littermates. Also, Ube3a expression in heart and liver of AS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization studies showed Ube3a expression to be primarily neuronal in all brain regions and present in GABAergic interneurons as well as principal neurons. These findings suggest that neuronal function throughout the brain is compromised in AS.

Challenges in implementing CD4 testing in resource-limited settings.

The scale-up of HIV antiretroviral therapy in recent years has led to a rapid increase in CD4 and CD4% count capacity to meet the diagnostic needs of staging and monitoring disease progression and treatment efficacy in adults and infants. The speed of implementation of this technology has been unrivalled in recent years and has met challenges with technology selection, laboratory infrastructure development, human resource limitations, cost-effectiveness, instrument maintenance, and ensuring testing access and quality. The lessons learned from dealing with these challenges have helped strengthen existing laboratory systems for other diagnostics. They may also facilitate the implementation of new diagnostics in future.

Maternal transplantation of human umbilical cord blood cells provides prenatal therapy in Sanfilippo type B mouse model.

Numerous data support passage of maternal cells into the fetus during pregnancy in both human and animal models. However, functional benefits of maternal microchimerism in utero are unknown. The current study attempted to take advantage of this route for prenatal delivery of alpha-N-acetylglucosaminidase (Naglu) enzyme into the enzyme-deficient mouse model of Sanfilippo syndrome type B (MPS III B). Enzymatically sufficient mononuclear cells from human umbilical cord blood (MNC hUCB) were intravenously administered into heterozygote females modeling MPS III B on the 5th day of pregnancy during blastocyst implantation. The major findings were 1) administered MNC hUCB cells transmigrated and diffused into the embryos (E12.5); 2) some transmigrated cells expressed CD34 and CD117 antigens; 3) transmigrated cells were found in both the maternal and embryonic parts of placentas; 4) transmigrated cells corrected Naglu enzyme activity in all embryos; 5) administered MNC hUCB cells were extensively distributed in the organs and the blood of heterozygote mothers at one week after transplantation. Results indicate that prenatal delivery of Naglu enzyme by MNC hUCB cell administration into mothers of enzyme-deficient embryos is possible and may present a significant opportunity for new biotechnologies to treat many inherited disorders.