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Titus Msoka,1 Josephine Rogath,1 Gary Van Guilder,2 Gibson Kapanda,1 Yvo Smulders,3 Marceline Tutu van Furth,3 John Bartlett,4 Michiel van Agtmael2 1Kilimanjaro Christian Medical Centre, Moshi, Tanzania; 2High Altitude Exercise Physiology, Western Colorado University, Gunnison, CO, USA; 3VU University Medical Centre, Amsterdam, the Netherlands; 4Duke University Medical Centre, Durham, NC, USACorrespondence: Titus MsokaKilimanjaro Christian Medical Centre, P.O.Box 3010, Moshi, TanzaniaEmail ftitus2001@yahoo.co.ukPurpose: Cardiovascular disease (CVD) risk assessment is a suitable way to differentiate between high-risk individuals requiring intervention and risk modification, and those at low risk. However, concerns have been raised when adopting a CVD-risk prediction algorithm for HIV-infected patients in sub-Saharan Africa.Patients and Methods: We compared cardiovascular risk profiles between HIV-infected (with and without antiretroviral therapy (ART)) and HIV-uninfected adults as predicted by the American College of Cardiology/American Heart Association (ASCVD) and the Framingham cardiovascular risk score (FRS) algorithms and assessed the concordance of the algorithms in predicting 10-year CVD risk separately in HIV-infected and uninfected groups in a hospital-based cross-sectional study in Tanzania. A cross-sectional hospital-based study including 40 HIV-infected ART-naive, 64 HIV-infected on ART, and 50 HIV-uninfected adults was conducted. Traditional cardiovascular risk factors were determined by standard investigations. The primary outcome was the absolute 10-year CVD risk score based on the two algorithms.Results: Compared to HIV-uninfected, HIV-infected adults were classified at a higher 10-year CVD risk. ASCVD algorithms predicted a higher proportion of high-risk individuals compared to FRS in both HIV-infected and uninfected groups. The concordance between ASCVD and FRS-lipid algorithms was reasonable for both HIV-infected and uninfected groups though relatively higher in the HIV-uninfected group.Conclusion: HIV-infected individuals have a higher 10-year cardiovascular risk compared to HIV-uninfected persons. The concordance between ASCVD and FRS-lipid algorithms is reasonable in both HIV-uninfected and infected persons in Tanzania. Development of an HIV-specific algorithm is needed to accurately predict CVD risk in this population at high-risk.Keywords: atherosclerotic cardiovascular disease risk score, Framingham risk score, antiretroviral therapy, Kilimanjaro Christian Medical Center, Moshi

The use of archival formalin-fixed paraffin-embedded (FFPE) tissue samples for biochemical analyses is problematic because of the formation of a Schiff base, leading to low protein and metabolite yields during analytical extractions. Here, we overcome this issue using a unified protocol on FFPE tissue for metabolomics and proteomics analyses. Using 20 mg of wet mass tissue, this protocol consistently extracted more than 50 metabolites (across 11 classes of metabolites) and over 900 proteins., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic-pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Samb, De Kroon, Dijkstra, Van Den Brand, Bos, Van Den Dungen, Veldkamp, Wilhelm, De Haan, Bijleveld, Tutu Van Furth, Savelkoul, Swart, Mathot and Van Weissenbruch.)

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's 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barichello, Rocha Catalão, Rohlwink, Kuip, Zaharie, Solomons, van Toorn, Tutu van Furth, Hasbun, Iovino and Namale.)

Though parechovirus (PeV) and enterovirus (EV) are common causes of central nervous system (CNS) infection in childhood, little is known about their long-term neurologic/neurodevelopmental complications. We investigated, longitudinally over a 5-year period, motor neurodevelopment in term-born newborns and infants with RT-qPCR-confirmed PeV- or EV-CNS infection. Motor neurodevelopment was assessed with standardized tests: Alberta Infant Motor Scale (AIMS), Bayley Scales of Infant and Toddler Development version-3 (Bayley-3-NL), and Movement Assessment Battery for Children version-2 (M-ABC-2-NL) at 6, 12, 24, and 60 months post-infection. Results of children with PeV-CNS infection were compared with those of peers with EV-CNS infection and with Dutch norm references. In the multivariate analyses adjustments were made for age at onset, gender, maternal education, and time from CNS infection Sixty of 172 eligible children aged ≤ 3 months were included. Children with PeV-CNS infection had consistently lower, non-significant mean gross motor function (GMF) Z-scores, compared with peers with EV-CNS infection and population norm-referenced GMF. Their GMF improved between 6 and 24 months and decreased at 5 years. Their fine motor function (FMF) scores fell within the population norm reference., Conclusion: These results suggest that the impact of PeV-A3-CNS infection on gross motor neurodevelopment in young children might manifest later in life. They highlight the importance of longitudinal neurodevelopmental assessments of children with PeV-A3-CNS infection up to school age., What Is Known: • Human parechovirus (PeV) is a major cause of central nervous system infection (CNS infection) in newborns and infants. • There is interest in the neurological and neurodevelopmental outcome of newborns and infants with PeV-A3-CNS infection., What Is New: • This prospective study compares the motor neurodevelopment of term-born newborns and infants with PeV-A3-CNS infection with those with EV-CNS infection and with norm references. • The results support the importance of follow-up of newborns and infants with PeV-A3-CNS infection to detect subtle neurodevelopmental delay and start early interventions., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Declaration of interests LS is an honorary consultant at the WHO Collaborating Centre for Community Participation in Palliative Care and Long Term Care. RS is the chair of Patients Know Best, a for-profit company that gives patients and citizens access to and control of their health and social care records. The system can be used to include advanced care plans and advance directives. He is unpaid but has equity in the company. He is also the unpaid chair of the Point of Care Foundation, which works to humanise health and social care, including at the end of life, and of the UK Health Alliance on Climate Change, which brings together many royal colleges, the British Medical Association, The Lancet, and BMJ to mitigate the effects of climate change and emphasise the risks and potential benefits to health. He holds shares in the UnitedHealth Group, a health and wellbeing company operating in the USA, UK, and other countries, that offers end-of-life services. SHA received an honorarium in 2018 by Mundipharma for leading a publication on cancer pain in low-income and middle-income countries. MH is employed as Head of Information Support at Hospice UK. Hospice UK is the national charity for hospice and end-of-life care. It works to ensure all adults and children living with a terminal or life-shortening illness receive the care and support they need, when they need it. CK, like most people, has personal experience of deaths and prolongation of life that influence the way she thinks as a scholar about these issues. She has written about these publicly, in particular the unwanted prolongation of her sister Polly's life contrary to her best interests, and her mother's death, which was greatly supported by an advance decision to refuse treatment and a lasting power of attorney for health and welfare. CK is also on a number of committees, working parties, and charities related to death and dying, including the core group of the British Medical Association group revising the guidance on clinically assisted nutrition and hydration, and the Guideline Development Group on Prolonged Disorders of Consciousness of the Royal College of Physicians. FMK reports consulting fees unrelated to this paper from Merck KGaA/EMD Serono for work on gender equity in leadership, non-financial support from Grunenthal Foundation, and grants from Roche, Vitas Healthcare, Chinoin, Grunenthal, and Novartis, outside the submitted work. JN is the Chair of University College Hospitals NHS Foundation Trust and Whittington Health NHS Trust. MRR is the unpaid chair of Pallium India, a charitable trust in India that works towards integration of palliative care with health care, and the unpaid director of Trivandrum Institute of Palliative Sciences, a WHO Collaborating Centre for Training and Policy on Access to Pain Relief. ES reports personal fees from the Social Science Research Council during the conduct of the study; and personal fees from Saitama Prefectural University (Japan), Kyoto University (Japan), and the University of Tokyo (Japan), outside the submitted work. KES is funded by a National Institute for Health Research Clinician Scientist Fellowship (CS-2015-15-005) and is the Laing Galazka Chair in Palliative Care at King's College London, funded by an endowment from Cicely Saunders International and the Kirby Laing Foundation. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. All other authors declare no competing interests.

Aims: We performed a systematic review and meta-analysis on the effect of HIV infection and antiretroviral therapy (ART) on carotid intima-media thickness (cIMT) to elucidate the role of HIV infection and ART. Also, an analysis on the role of ethnicity and gender on cIMT in HIV-infected populations was performed., Main Methods: We searched the PubMed, Web of Science, the WHO websites and International AIDS Society for published observational studies were conducted by two independent reviewers for studies comparing HIV-infected antiretroviral-experienced patients and/or inexperienced with healthy controls on cIMT. The primary outcome was the standardized mean difference (SMD) of cIMT., Findings: Twenty studies (five cohort, 15 cross-sectional, and two both cohort and cross-sectional studies) were identified comprising 7948 subjects (4656 HIV-infected; 3292 controls). In cohort studies, the standardized mean 1-year change in cIMT between HIV-infected patients and uninfected controls was not significantly different (0.16 mm/yr; 95% CI, -0.16, 0.49; p = 0.326). In 17 cross-sectional studies, the SMD in cIMT was significantly higher in HIV-infected than uninfected persons (0.27 mm; 95% CI, 0.04, 0.49; p = 0.027). HIV-infected patients on ART exhibited significantly higher SMD in cIMT compared to those not on ART (0.75 mm; 95% CI, 0.30, 1.19; p = 0.001). No confounding effect of gender and ethnicity could be established using meta-regression p > 0.05., Significance: HIV infection itself and ART appear to influence the progression of cIMT and hence may be risk factors for cardiovascular events. No firm conclusions could be drawn on the effect of ethnic/race and gender differences on cIMT in HIV-infected populations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Following publication of the original article [1], the authors reported that they have provided the wrong caption.

Background: Effective combined antiretroviral therapy (cART) has improved life expectancy among people living with HIV-1 infection. Treated HIV-1infection increases the prevalence of metabolic syndrome (MS). Despite sub-Saharan Africa having among the highest rates of HIV-1 infection, the effects of MS in HIV-1-infected individuals on cardiovascular risk is poorly explored. The aim of the study was to assess whether MS and/or HIV-1 treatment correlates with large elastic artery stiffness in HIV-1-infected patients treated with first-line cART., Methods: The study sample comprised of 102 subjects free of cardiovascular disease and major risk factors divided into two groups based on HIV-1 infection, treatment, and MS status: HIV-1 + /cART + /MS + (n = 12); HIV-1 + /cART - /MS + (n = 16); HIV-1 - / MS + (n = 10); HIV-1 + /cART + /MS - (n = 42); HIV-1 + /cART - /MS - (n = 32); HIV-1 - / MS - (n = 39). MS was established according the International Diabetes Federation definition. Large artery stiffness was measured using applanation tonometry to assess aortic pulse wave velocity (aPWV) and aortic augmentation index at heart rate of 75 bpm (AIx@HR75). cART included lamivudine/zidovudine and nevirapine or efavirenz., Results: The prevalence of MS in the HIV-1-infected patients was 28%. There were no significant differences in aPWV in the non-MS groups. However, in subjects with MS, aPWV was significantly higher in the HIV-1 cART patients (9.0 ± 1.9 m/s) compared with both controls (7.5 ± 1.8 m/s; P = 0.018) and untreated HIV-1 patients (7.7 ± 1.3 m/s; P = 0.023), and these differences remained after adjustment for blood pressure and sex. Aortic PWV was significantly elevated (P = 0.009) in HIV-1 cART patients with MS compared to their counterparts without MS. Untreated HIV-1 patients with MS also demonstrated increased aPWV compared to their counterparts without MS (P = 0.05). Aortic AIx@HR75 was, on average, ~ 5% higher in HIV-1 cART patients with MS (28.3 ± 62% compared with untreated HIV-1 patients with MS (23.5 ± 9%; P = 0.075). Sub-group multivariate analysis identified MS as an independent predictor of increased aPWV in HIV-1 cART patients., Conclusions: Our study established that presence of MS in HIV-1 patients on treatment was associated with increased aPWV and hence increased arterial stiffness in sub-Saharan African HIV-1 patients on first-line cART.

Background: Following the introduction of a heptavalent pneumococcal conjugate vaccine (PCV7) in the Netherlands in 2006, the incidence of invasive pneumococcal disease (IPD) declined significantly. Since then a shift towards non-vaccine serotype IPD has been noted., Case Description: We present the case of multidrug resistant non-vaccine serotype 19A pneumococcal meningitis in a 5-month-old boy. He was admitted to our Paediatric Intensive Care Unit (PICU) with seizures and septic shock. A barbiturate-induced coma was eventually required to control the seizures; shock was combated with intravenous fluids and inotropes. He received a 6-week course of ceftriaxone and vancomycin. At follow-up, one year after discharge, he had unilateral deafness and minor developmental delay., Conclusion: Worldwide, pneumococcal serotype 19A is now the most common cause of IPD in children, with an increasing incidence of multidrug resistant strains. This trend has not yet been observed in the Netherlands. This case demonstrates that even following the introduction of PCV7 pneumococcal meningitis can still occur. Prompt recognition of the symptoms is still essential.

Infections caused by Mycobacterium haemophilum in immunocompetent patients are unusual. M. haemophilum have been associated with cervicofacial lymphadenitis in children, but inguinal infections have not yet been described. We present a case of an inguinal lymphadenitis caused by M. haemophilum in an immunocompetent girl.

Recently, a prediction rule for developing neurological sequelae after childhood bacterial meningitis was developed on a small derivation set. Before implementing in practice a prediction rule must first be tested in new patients (external validation). Our aim was to study the external validity of this rule and, if necessary, to update the rule. The prediction rule was tested on newly available data (validation set) by assessing the rule's calibration and discrimination. We updated the prediction rule by adding extra predictors and re-estimating the regression coefficients of the original predictors in the combined datasets. The rule showed poor agreement between predicted risks and observed frequencies. The ROC area was 0.65 (95% CI 0.57-0.72), which was statistically significantly lower than in the derivation set (0.87 (0.78-0.96)), p-value<0.01. The updated prediction rule showed adequate performance in the combined data sets; the ROC area was 0.77 (95% CI 0.72-0.82). Further study of the generalizability of this updated rule may stimulate application in clinical practice.

The objectives of this study were to describe health-related quality of life of postmeningitic children and to examine the association between academic and/or behavioral limitations and health-related quality of life. One hundred and eighty-two children (mean age 9.7 years; range 5.3-14.2) were selected randomly from a cohort of 674 school-age children who recovered from non-Haemophilus influenzae type B bacterial meningitis. These children had neither meningitis with 'complex onset', nor prior cognitive or behavioral problems, nor severe disease sequelae. On average 7.4 years after meningitis, they were evaluated using an 'Academic Achievement Test' and their parents filled in the Child Behavior Checklist, the Child Health Questionnaire, and the Health Utilities Index. The long-term incidence of academic and/or behavioral limitations was 32%. Overall health-related quality of life of the postmeningitic children was decreased in comparison with that of a reference population of schoolchildren. The group of postmeningitic children with academic and/or behavioral limitations showed the most marked decrease in quality of life, especially concerning psychosocial health, cognition and family life. The negative effects on quality of life were not significantly influenced by age, gender, causative pathogen, presence of minor neurological impairment, or presence of hearing impairment. In conclusion, health-related quality of life of postmeningitic children is decreased, particularly of those with academic and/or behavioral limitations.