Discordance between clinical and immunological ART eligibility criteria for children in Malawi

Background: Since May 2014, all HIV positive children aged less than five years in Malawi are eligible for ART. For children older than five years they are eligible if they are in WHO stage III/IV, if stage I/II, if their CD4 750. Conclusion: Most children are correctly started on treatment using recent guidelines. 41% more children <5 years will be started on ART

Surgical pathology in sub-Saharan Africa--volunteering in Malawi

The breadth of material found in surgical pathology services in African countries differs from the common spectrum of "the West". We report our experience of a voluntary work in the pathology departments of Blantyre and Lilongwe, Malawi. During a 6-week period, 405 cases (378 histology and 27 cytology cases) were processed. The vast majority showed significant pathological findings (n = 369; 91.1 %): 175 cases (47.4 %) were non-tumoral conditions with predominance of inflammatory lesions, e.g., schistosomiasis (n = 11) and tuberculosis (n = 11). There were 39 (10.6 %) benign tumors or tumor-like lesions. Intraepithelial neoplasia of the cervix uteri dominated among premalignant conditions (n = 15; 4.1 %). The large group of malignancies (n = 140; 37.9 %) comprised 11 pediatric tumors (e.g., rhabdomyosarcoma, small blue round cell tumors) and 129 adult tumors. Among women (n = 76), squamous cell carcinomas (SCCs) of the cervix uteri predominated (n = 25; 32.9 %), followed by breast carcinomas (n = 12; 15.8 %) and esophageal SCC (n = 9; 11.8 %). Males (n = 53) most often showed SCC of the esophagus (n = 9; 17.0 %) and of the urinary bladder (n = 7; 13.2 %). Lymphomas (n = 7) and Kaposi's sarcomas (n = 6) were less frequent. Differences compared to the western world include the character of the conditions in general, the spectrum of inflammatory lesions, and the young age of adult tumor patients (median 45 years; range 18-87 years). Providing pathology service in a low-resource country may be handicapped by lack of personnel, inadequate material resources, or insufficient infrastructure. Rotating volunteers offer a bridge for capacity building of both personnel and the local medical service; in addition, the volunteer's horizons are broadened professionally and personally

The systemic pathology of cerebral malaria in African children

Pediatric cerebral malaria carries a high mortality rate in sub-Saharan Africa. We present our systematic analysis of the descriptive and quantitative histopathology of all organs sampled from a series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and control patients (without coma, or without malaria infection) who were clinically well characterized prior to death. We found brain swelling in all cerebral malaria patients and the majority of controls. The histopathology in patients with sequestration of parasites in the brain demonstrated two patterns: (a) the “classic” appearance (i.e., ring hemorrhages, dense sequestration, and extra-erythrocytic pigment) which was associated with evidence of systemic activation of coagulation and (b) the “sequestration only” appearance associated with shorter duration of illness and higher total burden of parasites in all organs including the spleen. Sequestration of parasites was most intense in the gastrointestinal tract in all parasitemic patients (those with cerebral malarial and those without)

Plasmodium falciparum gene expression measured directly from tissue during human infection

Background: During the latter half of the natural 48-h intraerythrocytic life cycle of human Plasmodium falciparum infection, parasites sequester deep in endothelium of tissues, away from the spleen and inaccessible to peripheral blood. These late-stage parasites may cause tissue damage and likely contribute to clinical disease, and a more complete understanding of their biology is needed. Because these life cycle stages are not easily sampled due to deep tissue sequestration, measuring in vivo gene expression of parasites in the trophozoite and schizont stages has been a challenge. Methods: We developed a custom nCounter® gene expression platform and used this platform to measure malaria parasite gene expression profiles in vitro and in vivo. We also used imputation to generate global transcriptional profiles and assessed differential gene expression between parasites growing in vitro and those recovered from malaria-infected patient tissues collected at autopsy. Results: We demonstrate, for the first time, global transcriptional expression profiles from in vivo malaria parasites sequestered in human tissues. We found that parasite physiology can be correlated with in vitro data from an existing life cycle data set, and that parasites in sequestered tissues show an expected schizont-like transcriptional profile, which is conserved across tissues from the same patient. Imputation based on 60 landmark genes generated global transcriptional profiles that were highly correlated with genome-wide expression patterns from the same samples measured by microarray. Finally, differential expression revealed a limited set of in vivo upregulated transcripts, which may indicate unique parasite genes involved in human clinical infections. Conclusions: Our study highlights the utility of a custom nCounter® P. falciparum probe set, validation of imputation within Plasmodium species, and documentation of in vivo schizont-stage expression patterns from human tissues. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0110-6) contains supplementary material, which is available to authorized users

A histological method for quantifying Plasmodium falciparum in the brain in fatal paediatric cerebral malaria

Background: The sequestration of Plasmodium falciparum-infected erythrocytes in brain microvasculature through cytoadherence to endothelium, is the hallmark of the definitive diagnosis of cerebral malaria and plays a critical role in malaria pathogenesis. The complex pathophysiology, which leads each patient to the final outcome of cerebral malaria, is multifaceted and thus, metrics to delineate specific patterns within cerebral malaria are needed to further parse patients. Methods: A method was developed for quantification utilizing counts of capillary contents (early-stage parasites, late-stage parasites and fibrin) from histological preparations of brain tissue after death, and compared it to the standard approach, in which the percentage of parasitized vessels in cross-section is determined. Results: Within the initial cohort of 50 patients, two different observers agreed closely on the percentage of vessels parasitized, pigmented parasites and pigment globules (ICC = 0.795-0.970). Correlations between observers for correct diagnostic classification were high (Kendall’s tau-b = 0.8779, Kappa = 0.8413). When these methods were applied prospectively to a second set of 50 autopsy samples, they revealed a heterogeneous distribution of sequestered parasites in the brain with pigmented parasites and pigment globules present in the cerebellum > cortex > brainstem. There was no difference in the distribution of early stages of parasites or in the percentage of vessels parasitized across the same sites. The second cohort of cases was also used to test a previously published classification and regression tree (CART) analysis; the quantitative data alone were able to accurately classify and distinguish cerebral malaria from non-cerebral malaria. Classification errors occurred within a subclassification of cerebral malaria (CM1 vs CM2). A repeat CART analysis for the second cohort generated slightly different classification rules with more accurate subclassification, although misclassification still occurred. Conclusions: The traditional measure of parasite sequestration in falciparum malaria, the percentage of vessels parasitized, is the most reliable and consistent for the general diagnosis of cerebral malaria. Methods that involve quantitative measures of different life cycle stages are useful for distinguishing patterns within the cerebral malaria population; these subclassifications may be important for studies of disease pathogenesis and ancillary treatment

Reducing recurrent care proceedings: initial evidence from new interventions

The English family justice system faces a crisis of recurrence. As many as one in four birth mothers involved in public law care proceedings in English family courts are likely to reappear in a subsequent set of proceedings within seven years. These mothers are involved in up to one-third of total care applications, as they are – by definition – linked to more than one child . Few birth mothers experiencing the removal of a child to care are offered any follow-up support, despite often facing multiple challenges including poverty, addiction, domestic violence and mental health problems. Since 2011, however, a number of new services have been established to begin to address their unmet needs. This article summarises the findings of the first academic-led evaluation of two of these initiatives. Presenting evidence from a mixed-methods evaluative study, it concludes that the new services were able to foster relationships that ‘worked’ in reducing recurrent proceedings. None of the women engaging with the services went on to experience what could be described as a ‘rapid repeat pregnancy’ within the evaluation window. Just as significantly, a number of clients reported some improvement in their psychological functioning, and the practitioners involved reported positively on their experience of delivering and managing innovative services. The article closes with a discussion of the challenges of evaluating personalised, strengths-based interventions and the possibilities of evidencing empowerment in these cases

Temperature and spatial connectivity drive patterns in freshwater macroinvertebrate diversity across the Arctic

Warming in the Arctic is predicted to change freshwater biodiversity through loss of unique taxa and northward range expansion of lower latitude taxa. Detecting such changes requires establishing circumpolar baselines for diversity, and understanding the primary drivers of diversity. We examined benthic macroinvertebrate diversity using a circumpolar dataset of &gt;1,500 Arctic lake and river sites. Rarefied α diversity within catchments was assessed along latitude and temperature gradients. Community composition was assessed through region-scale analysis of β diversity and its components (nestedness and turnover), and analysis of biotic–abiotic relationships. Rarefied α diversity of lakes and rivers declined with increasing latitude, although more strongly across mainland regions than islands. Diversity was strongly related to air temperature, with the lowest diversity in the coldest catchments. Regional dissimilarity was highest when mainland regions were compared with islands, suggesting that connectivity limitations led to the strongest dissimilarity. High contributions of nestedness indicated that island regions contained a subset of the taxa found in mainland regions. High Arctic rivers and lakes were predominately occupied by Chironomidae and Oligochaeta, whereas Ephemeroptera, Plecoptera, and Trichoptera taxa were more abundant at lower latitudes. Community composition was strongly associated with temperature, although geology and precipitation were also important correlates. The strong association with temperature supports the prediction that warming will increase Arctic macroinvertebrate diversity, although low diversity on islands suggests that this increase will be limited by biogeographical constraints. Long-term harmonised monitoring across the circumpolar region is necessary to detect such changes to diversity and inform science-based management.</p

Evidence for spleen dysfunction in malaria-HIV co-infection in a subset of pediatric patients

The spleen has an important role in the clearance of malaria parasites, and the role of HIV co-infection on this process is yet to be described. Using a combination of histological and molecular methods, we systematically evaluated parasite load across multiple organs from HIV-positive and HIV-negative cases of an autopsy study of pediatric comatose children with malaria infection (n = 103) in Blantyre, Malawi. Quantification of parasite load across organs was done using histology. A subset of cases was further characterized for parasite localization and stage of development using immunohistochemistry-based labeling of parasite and host cells (5 HIV-positive, 10 HIV-negative), and quantitative RT-PCR (qRT-PCR) of asexual and sexual-specific genes (4 HIV-positive, 5 HIV-negative). The results were compared with clinical information including HIV status. The HIV positive rate was 21% for the group studied (20 of 95) and HIV-positive patients had a significantly shorter duration of time between onset of illness and death, and were significantly older than HIV-negative patients. We found that spleens of HIV-positive cases had significantly higher parasite loads compared to those of HIV-negative cases in each the three methods we used: (i) standard histology, (ii) immunohistochemistry-based labeling of Plasmodium lactate dehydrogenase (pLDH), and (iii) molecular detection of asexual parasite transcript apical membrane antigen 1 (AMA1). Immunohistochemistry-based labeling of macrophage marker CD163 in a subset of spleens revealed fewer activated macrophages containing engulfed parasites and a greater number of free unphagocytosed parasites in the HIV-positive cases. The mechanism by which HIV infection is associated with more rapid progression to severe cerebral malaria disease is possibly impairment of parasite destruction by splenic macrophages, supported by published in vitro studies showing inefficient phagocytosis of malaria parasites by HIV-infected macrophages

Biomarkers to Distinguish Bacterial From Viral Pediatric Clinical Pneumonia in a Malaria-Endemic Setting.

BACKGROUND: Differential etiologies of pediatric acute febrile respiratory illness pose challenges for all populations globally, but especially in malaria-endemic settings because the pathogens responsible overlap in clinical presentation and frequently occur together. Rapid identification of bacterial pneumonia with high-quality diagnostic tools would enable appropriate, point-of-care antibiotic treatment. Current diagnostics are insufficient, and the discovery and development of new tools is needed. We report a unique biomarker signature identified in blood samples to accomplish this. METHODS: Blood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based, high-dynamic-range, quantitative assay (~1200 proteins). We identified new biomarkers using a training set of samples from patients with established bacterial, viral, or malarial pneumonia. Proteins with significantly variable abundance across etiologies (false discovery rate 90% sensitivity and >80% specificity, regardless of number of pathogen classes. Bacterial pneumonia was strongly associated with neutrophil markers-in particular, degranulation including HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI. CONCLUSIONS: Blood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia