An assessment of false positive rates for malaria rapid diagnostic tests caused by non-Plasmodium infectious agents and immunological factors.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) can produce false positive (FP) results in patients with human African trypanosomiasis and rheumatoid factor (RF), but specificity against other infectious agents and immunological factors is largely unknown. Low diagnostic specificity caused by cross-reactivity may lead to over-estimates of the number of malaria cases and over-use of antimalarial drugs, at the cost of not diagnosing and treating the true underlying condition. METHODS: Data from the WHO Malaria RDT Product Testing Programme was analysed to assess FP rates of 221 RDTs against four infectious agents (Chagas, dengue, Leishmaniasis and Schistosomiasis) and four immunological factors (anti-nuclear antibody, human anti-mouse antibody (HAMA), RF and rapid plasma regain). Only RDTs with a FP rate against clean negative samples less than 10% were included. Paired t-tests were used to compare product-specific FP rates on clean negative samples and samples containing non-Plasmodium infectious agents and immunological factors. RESULTS: Forty (18%) RDTs showed no FP results against any tested infectious agent or immunological factor. In the remaining RDTs significant and clinically relevant increases in FP rates were observed for samples containing HAMA and RF (P<0.001). There were significant correlations between product-matched FP rates for RF and HAMA on all RDT test bands (P<0.001), and FP rates for each infectious agent and immunological factor were also correlated between test bands of combination RDTs (P≤0.002). CONCLUSIONS: False positive results against non-Plasmodium infectious agents and immunological factors does not appear to be a universal property of malaria RDTs. However, since many malaria RDTs have elevated FP rates against HAMA and RF positive samples practitioners may need to consider the possibility of false positive results for malaria in patients with conditions that stimulate HAMA or RF

Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype

Histopathology, clinical chemistry, hematology and gene expression data were collected from the rat liver and blood after treatment with eight known hepatotoxins

Exploration of the beliefs and experiences of Aboriginal people with cancer in Western Australia: a methodology to acknowledge cultural difference and build understanding

<p>Abstract</p> <p>Background</p> <p>Aboriginal Australians experience poorer outcomes, and are 2.5 times more likely to die from cancer than non-Aboriginal people, even after adjustment for stage of diagnosis, cancer treatment and comorbidities. They are also less likely to present early as a result of symptoms and to access treatment. Psycho-social factors affect Aboriginal people's willingness and ability to participate in cancer-related screening and treatment services, but little exploration of this has occurred within Australia to date. The current research adopted a phenomenological qualitative approach to understand and explore the lived experiences of Aboriginal Australians with cancer and their beliefs and understanding around this disease in Western Australia (WA). This paper details considerations in the design and process of conducting the research.</p> <p>Methods/Design</p> <p>The National Health and Medical Research Council (NHMRC) guidelines for ethical conduct of Aboriginal research were followed. Researchers acknowledged the past negative experiences of Aboriginal people with research and were keen to build trust and relationships prior to conducting research with them. Thirty in-depth interviews with Aboriginal people affected by cancer and twenty with health service providers were carried out in urban, rural and remote areas of WA. Interviews were audio-recorded, transcribed verbatim and coded independently by two researchers. NVivo7 software was used to assist data management and analysis. Participants' narratives were divided into broad categories to allow identification of key themes and discussed by the research team.</p> <p>Discussion and conclusion</p> <p>Key issues specific to Aboriginal research include the need for the research process to be relationship-based, respectful, culturally appropriate and inclusive of Aboriginal people. Researchers are accountable to both participants and the wider community for reporting their findings and for research translation so that the research outcomes benefit the Aboriginal community. There are a number of factors that influence whether the desired level of engagement can be achieved in practice. These include the level of resourcing for the project and the researchers' efforts to ensure dissemination and research translation; and the capacity of the Aboriginal community to engage with research given other demands upon their time.</p

Not just bricks and mortar: planning hospital cancer services for Aboriginal people

<p>Abstract</p> <p>Background</p> <p>Aboriginal people in Australia experience higher mortality from cancer compared with non-Aboriginal Australians, despite an overall lower incidence. A notable contributor to this disparity is that many Aboriginal people do not take up or continue with cancer treatment which almost always occurs within major hospitals.</p> <p>Thirty in-depth interviews with urban, rural and remote Aboriginal people affected by cancer were conducted between March 2006 and September 2007. Interviews explored participants' beliefs about cancer and experiences of cancer care and were audio-recorded, transcribed verbatim and coded independently by two researchers. NVivo7 software was used to assist data management and analysis. Information from interviews relevant to hospital services including and building design was extracted.</p> <p>Findings</p> <p>Relationships and respect emerged as crucial considerations of participants although many aspects of the hospital environment were seen as influencing the delivery of care. Five themes describing concerns about the hospital environment emerged: (i) being alone and lost in a big, alien and inflexible system; (ii) failure of open communication, delays and inefficiency in the system; (iii) practicalities: costs, transportation, community and family responsibilities; (iv) the need for Aboriginal support persons; and (v) connection to the community.</p> <p>Conclusions</p> <p>Design considerations and were identified but more important than the building itself was the critical need to build trust in health services. Promotion of cultural safety, support for Aboriginal family structures and respecting the importance of place and community to Aboriginal patients are crucial in improving cancer outcomes.</p

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

One of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling of peripheral T-cells. In contrast to the lymphopenia in most SCID patients, ZAP70-deficient patients have lymphocytosis, despite the selective absence of CD8+ T-cells. The clinical presentation is usually before 2 years of age with typical findings of SCID. Here, we present three new ZAP70-deficient patients who vary in their clinical presentation. One of the ZAP70-deficient patients presented as a classical SCID, the second patient presented as a healthy looking wheezy infant, whereas the third patient came to clinical attention for the eczematous skin lesions simulating atopic dermatitis with eosinophilia and elevated immunoglobulin E (IgE), similar to the Omenn syndrome. This study illustrates that awareness of the clinical heterogeneity of ZAP70 deficiency is of utmost importance for making a fast and accurate diagnosis, which will contribute to the improvement of the adequate treatment of this severe immunodeficiency

Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders

Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.Peer reviewe

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Week 48 resistance analyses of the once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) >= 400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL = 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response