LC–MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review

There is compelling evidence that a dysregulated immune inflammatory response in neuroinfectious diseases results in modifications in metabolic processes and altered metabolites, directly or indirectly influencing lipid metabolism within the central nervous system (CNS). The challenges in differential diagnosis and the provision of effective treatment in many neuroinfectious diseases are, in part, due to limited understanding of the pathophysiology underlying the disease. Although there are numerous metabolomics studies, there remains a deficit in neurolipidomics research to provide a comprehensive understanding of the connection between altered metabolites and changes in lipid metabolism. The brain is an inherently high-lipid organ; hence, understanding neurolipidomics is the key to future breakthroughs. This review aims to provide an integrative summary of altered cerebrospinal fluid (CSF) metabolites associated with neurolipid metabolism in bacterial and viral CNS infections, with a particular focus on studies that used liquid chromatography-mass spectrometry (LC–MS). Lipid components (phospholipids) and metabolites (carnitine and tryptophan) appear to be the most significant indicators in both bacterial and viral infections. On the basis of our analysis of the literature, we recommend employing neurolipidomics in conjunction with existing neurometabolomics data as a prospective method to enhance our understanding of the cross link between dysregulated metabolites and lipid metabolism in neuroinfectious diseases

Using telehealth to support community health workers in Uganda during COVID-19:a mixed-method study

Background: At the onset of the COVID-19 pandemic, a local consortium in Uganda set up a telehealth approach that aimed to educate 3,500 Community Health Workers (CHW) in rural areas about COVID-19, help them identify, refer and care for potential COVID-19 cases, and support them in continuing their regular community health work. The aim of this study was to assess the functioning of the telehealth approach that was set up to support CHWs during the COVID-19 pandemic. Methods: For this mixed-method study, we combined analysis of routine consultation data from the call-center, 24 interviews with key-informants and two surveys of 150 CHWs. Data were analyzed using constant comparative method of analysis. Results: Between March 2020 and June 2021, a total of 35,553 consultations took place via the call center. While the CHWs made extensive use of the call center, they rarely asked for support for potential Covid-19 cases. According to the CHWs, there were no signs that people in their communities were suffering from severe health problems due to COVID-19. People compared the lack of visible symptoms to diseases such as Ebola and were skeptical about the danger of COVID-19. At the same time, people in rural areas were afraid to report relevant symptoms and get tested for fear of being quarantined and stigmatized. The telehealth approach did prove useful for other purposes, such as supporting CHWs with their regular tasks and coordinating the supply of essential products. The health professionals at the call center supported CHWs in diagnosing, referring and treating patients and adhering to infection prevention and control practices. The CHWs felt more informed and less isolated, saying the support from the call center helped them to provide better care and improved the supply of medicine and other essential health products. Conclusions: The telehealth approach, launched at the start of the COVID-19 pandemic, provided useful support to thousands of CHWs in rural communities in Uganda. The telehealth approach could be quickly set up and scaled up and offers a low cost strategy for providing useful and flexible support to CHWs in rural communities.</p

The church and paediatric HIV care in rural South Africa

Religion has substantial – positive and negative – influence on South Africa’s HIV context. This qualitative study explored possibilities for positive church engagement in paediatric HIV care in a rural district in Limpopo Province, South Africa. Opinions, attitudes and experiences of various stakeholders including religious leaders, healthcare workers and people infected/affected with/by HIV were investigated through participant observation, semi-structured interviews and focus group discussions. During the research the original focus on paediatric HIV care shifted to HIV care in general in reaction to participant responses. Participants identified three main barriers to positive church engagement in HIV care: (a) stigma and disclosure; (b) sexual associations with HIV and (c) religious beliefs and practices. All participant groups appreciated the opportunity and relevance of strengthening church involvement in HIV care. Opportunities for positive church engagement in HIV care that participants identified included: (a) comprehensive and holistic HIV care when churches and clinics collaborate; (b) the wide social reach of churches and (c) the safety and acceptance in churches. Findings indicate that despite barriers great potential exists for increased positive church engagement in HIV care in rural South Africa. Recommendations include increased medical knowledge and dialogue on HIV/AIDS within church settings, and increased collaboration between churches and the medical sector

Bacterial Meningitis in Africa

Bacterial meningitis differs globally, and the incidence and case fatality rates vary by region, country, pathogen, and age group; being a life-threatening disease with a high case fatality rate and long-term complications in low-income countries. Africa has the most significant prevalence of bacterial meningitis illness, and the outbreaks typically vary with the season and the geographic location, with a high incidence in the meningitis belt of the sub-Saharan area from Senegal to Ethiopia. Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are the main etiological agents of bacterial meningitis in adults and children above the age of one. Streptococcus agalactiae (group B Streptococcus), Escherichia coli, and Staphylococcus aureus are neonatal meningitis\u27s most common causal agents. Despite efforts to vaccinate against the most common causes of bacterial neuro-infections, bacterial meningitis remains a significant cause of mortality and morbidity in Africa, with children below 5 years bearing the heaviest disease burden. The factors attributed to this continued high disease burden include poor infrastructure, continued war, instability, and difficulty in diagnosis of bacterial neuro-infections leading to delay in treatment and hence high morbidity. Despite having the highest disease burden, there is a paucity of African data on bacterial meningitis. In this article, we discuss the common etiologies of bacterial neuroinfectious diseases, diagnosis and the interplay between microorganisms and the immune system, and the value of neuroimmune changes in diagnostics and therapeutics

Cerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid

The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study. In this follow-up study, we used targeted ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples. Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities. These results provide experimental evidence to support our conceptual astrocyte-microglia lactate shuttle model formulated from our previous NMR-based metabolomics study - highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease marker

Nutritional status of refugee children living in temporary settlements in Europe and MENA region: a systematic review and meta-analysis

An estimated 41% of all forcibly displaced people are children [1]. Many of these children may live in refugee camps, under poor conditions, for years. The health status of children when arriving in these camps is often not recorded, nor is there a good insight into the impact of camp life on their health. We systematically reviewed the evidence concerning the nutritional status of children living in refugee camps in the European and Middle East and North Africa (MENA) regions. We searched Pubmed, Embase, and Global Index Medicus. The primary outcome was the prevalence of stunting, and the secondary outcome was the prevalence of wasting and being overweight. Out of 1385 studies identified, 12 studies were selected, covering 7009 children from fourteen different refugee camps in the Europe and MENA region. There was great heterogeneity among the included studies, which showed that there was a pooled prevalence of stunting of 16% (95% confidence interval 9.9–23%, I 2 95%, p < 0.01) and of wasting of 4.2% (95% CI 1.82–6.49%, I 2 97%, p < 0.01). Anthropometric measurements were done at random points in time during the children’s camp period. However, no study had a longitudinal design, describing the effect of camp life on the nutritional status. Conclusion: This review showed that there is a relatively high prevalence of stunting and a low prevalence of wasting among refugee children. However, the nutritional status of children when entering the camp and the effect of camp life on their health is not known. This information is critical in order to inform policymakers and to create awareness concerning the health of the most vulnerable group of refugees. What is Known: • Migration is a core determinant of health for children. • There are risk factors at every stage of a refugee child’s journey that lead to compromised health. What is New: • There is a relatively high prevalence of stunting (16%) and a low prevalence of wasting (4.2%) among refugee children living in refugee camps in Europe and the Middle East and North Africa region

Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics

Mycobacterium tuberculosis infection, which claims hundreds of thousands of lives each year, is typically characterized by the formation of tuberculous granulomas — the histopathological hallmark of tuberculosis (TB). Our knowledge of granulomas, which comprise a biologically diverse body of pro- and anti-inflammatory cells from the host immune responses, is based mainly upon examination of lungs, in both human and animal studies, but little on their counterparts from other organs of the TB patient such as the brain. The biological heterogeneity of TB granulomas has led to their diverse, relatively uncoordinated, categorization, which is summarized here. However, there is a pressing need to elucidate more fully the phenotype of the granulomas from infected patients. Newly emerging studies at the protein (proteomics) and metabolite (metabolomics) levels have the potential to achieve this. In this review we summarize the diverse nature of TB granulomas based upon the literature, and amplify these accounts by reporting on the relatively few, emerging proteomics and metabolomics studies on TB granulomas. Metabolites (for example, trimethylamine-oxide) and proteins (such as the peptide PKAp) associated with TB granulomas, and knowledge of their localizations, help us to understand the resultant phenotype. Nevertheless, more multidisciplinary ‘omics studies, especially in human subjects, are required to contribute toward ushering in a new era of understanding of TB granulomas – both at the site of infection, and on a systemic level

Urinary markers of Mycobacterium tuberculosis and dysbiosis in paediatric tuberculous meningitis cases undergoing treatment

Abstract Background The pathogenesis of tuberculous meningitis (TBM) involves infection by Mycobacterium tuberculosis in the meninges and brain. However, recent studies have shown that the immune response and inflammatory processes triggered by TBM can have significant effects on gut microbiota. Disruptions in the gut microbiome have been linked to various systemic consequences, including altered immunity and metabolic dysregulation. Inflammation caused by TBM, antibiotic treatment, and changes in host immunity can all influence the composition of gut microbes. This complex relationship between TBM and the gut microbiome is of great importance in clinical settings. To gain a deeper understanding of the intricate interactions between TBM and the gut microbiome, we report innovative insights into the development of the disease in response to treatment. Ultimately, this could lead to improved outcomes, management strategies and quality of life for individuals affected by TBM. Method We used a targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach to investigate metabolites associated with gut metabolism in paediatric participants by analysing the urine samples collected from a control group (n = 40), and an experimental group (n = 35) with confirmed TBM, which were subdivided into TBM stage 1 (n = 8), stage 2 (n = 11) and stage 3 (n = 16). Findings Our metabolomics investigation showed that, of the 78 initially selected compounds of microbiome origin, eight unique urinary metabolites were identified: 2-methylbutyrlglycine, 3-hydroxypropionic acid, 3-methylcrotonylglycine, 4-hydroxyhippuric acid, 5-hydroxyindoleacetic acid, 5-hydroxyhexanoic acid, isobutyrylglycine, and phenylacetylglutamine as urinary markers of dysbiosis in TBM. Conclusion These results – which are supported by previous urinary studies of tuberculosis – highlight the importance of gut metabolism and of identifying corresponding microbial metabolites as novel points for the foundation of improved management of TBM patients

Urinary metabolic characterization of advanced tuberculous meningitis cases in a South African paediatric population

Tuberculous meningitis (TBM) is a severe form of tuberculosis with high neuro-morbidity and mortality, especially among the paediatric population (aged ≤12 years). Little is known of the associated metabolic changes. This study aimed to identify characteristic metabolic markers that differentiate severe cases of paediatric TBM from controls, through non-invasive urine collection. Urine samples selected for this study were from two paediatric groups. Group 1: controls (n = 44): children without meningitis, no neurological symptoms and from the same geographical region as group 2. Group 2: TBM cases (n = 13): collected from paediatric patients that were admitted to Tygerberg Hospital in South Africa on the suspicion of TBM, mostly severely ill; with a later confirmation of TBM. Untargeted 1H NMR-based metabolomics data of urine were generated, followed by statistical analyses via MetaboAnalyst (v5.0), and the identification of important metabolites. Twenty nine urinary metabolites were identified as characteristic of advanced TBM and categorized in terms of six dysregulated metabolic pathways: 1) upregulated tryptophan catabolism linked to an altered vitamin B metabolism; 2) perturbation of amino acid metabolism; 3) increased energy production–metabolic burst; 4) disrupted gut microbiota metabolism; 5) ketoacidosis; 6) increased nitrogen excretion. We also provide original biological insights into this biosignature of urinary metabolites that can be used to characterize paediatric TBM patients in a South African cohort