South African Children: A Matched Cohort Study of Neurodevelopmental Impairment in Survivors of Invasive Group B Streptococcus Disease Aged 5 to 8 Years.

BACKGROUND: Invasive group B Streptococcus (iGBS) sepsis and meningitis are important causes of child mortality, but studies on neurodevelopmental impairment (NDI) after iGBS are limited. Using Griffiths Mental Development Scales-Extended Revised (GMDS-ER), we described NDI in iGBS survivors and non-iGBS children from South Africa, as part of a 5-country study. METHODS: We identified children aged 5-8 years with a history of iGBS and children with no history of iGBS between October 2019 and January 2021. Children were matched on sex, and birth data (month, year) (matched cohort study). Moderate or Severe NDI was the primary outcome as a composite of GMDS-ER motor, GMDS-ER cognition, hearing, and vision. Secondary outcomes included mild NDI, any emotional-behavioral problems, and GMDS-ER developmental quotients (DQ) calculated by dividing the age equivalent GMDS-ER score by the chronological age. RESULTS: In total, 160 children (iGBS survivors, 43; non-iGBS, 117) were assessed. Among iGBS survivors 13 (30.2%) had meningitis, and 30 (69.8%) had sepsis. Six (13.9%) iGBS survivors, and 5 (4.3%) non-iGBS children had moderate or severe NDI. Children who survived iGBS were 5.56 (95% confidence interval [CI]: 1.07-28.93; P = .041) times more likely to have moderate or severe NDI at 5-8 years than non-iGBS children. Compared to the non-iGBS children, iGBS meningitis survivors had a significantly lower global median DQ (P < .05), as well as a lower median DQ for the language GMDS-ER subscale and performance GMDS-ER subscale (P < .05). CONCLUSIONS: Children surviving iGBS, particularly meningitis, are more likely to have NDI at 5-8 years compared to non-iGBS children. Further research is required to improve detection and care for at-risk newborns

Quantifying long-term health and economic outcomes for survivors of group B Streptococcus invasive disease in infancy: protocol of a multi-country study in Argentina, India, Kenya, Mozambique and South Africa.

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa.  The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Simulated systemic recurrent Mycoplasma infection in rats induces recurrent sickness responses without residual impairment in spatial learning and memory

In spite of their prevalence and importance, recurrent acute infections seldom have been investigated in the laboratory. We set out to measure fever and sickness behaviour in simulated recurrent Mycoplasma infection; Mycoplasma is a common clinical cause of recurrent acute infection. Male Sprague–Dawley rats had radiotransponders implanted to measure abdominal temperature and cage activity. After recovery, rats received three intraperitoneal (I.P.) injections, 10 days apart, of either fibroblast-stimulating lipopeptide-1 (FLS-1), a pyrogenic moiety of Mycoplasma salivarium, at a dose of 500 μg.kg−1 in 1 ml.kg−1 phosphate-buffered saline (PBS), or vehicle (PBS, 1 ml.kg−1). Body mass and food intake were measured daily. For measurement of learning and memory, training in a Morris Water Maze commenced 10 days after the last of the three successive injections and continued daily for 4 days. Spatial memory was assessed on the following day. Hippocampal tissue of rats was collected on the day of the last exposure to the maze. Recurrent FSL-1 administration induced recurrent fevers (~1 °C) for about 9 h, recurrent lethargy (~40–60%) for 1 day, recurrent anorexia (~16–30%) for 1 day, and recurrent reductions in the rate of mass gain (~112%) for 1 day, but did not induce persistent stunting. Recurrent FSL-1 administration did not result in tolerance to fever, lethargy or anorexia. There was no residual histological damage to the hippocampus and no residual detrimental effect in learning or memory in rats. Though we cannot extrapolate our results directly to humans, clinical recurrent acute Mycoplasma infection may not impose a high risk of stunting or impaired spatial learning and memory.National Research Foundation of South Africa, and the South African Medical Research Council

Dissociation between learning and memory impairment and other sickness behaviours during simulated Mycoplasma infection in rats

To investigate potential consequences for learning and memory, we have simulated the effects of Mycoplasma infection, in rats, by administering fibroblast-stimulating lipopepide-1 (FSL-1), a pyrogenic moiety of Mycoplasma salivarium. We measured the effects on body temperature, cage activity, food intake, and on spatial learning and memory in a Morris Water Maze. Male Sprague-Dawley rats had radio transponders implanted to measure abdominal temperature and cage activity. After recovery, rats were assigned randomly to receive intraperitoneal (I.P.) injections of FSL-1 (500 or 1000 µg kg-1 in 1 ml kg-1 phosphate- buffered saline; PBS) or vehicle(PBS, 1 ml kg_1). Body mass and food intake were measured daily. Training in the Maze commenced 18 h after injections and continued daily for four days. Spatial memory was assessed on the fifth day. In other rats, we measured concentrations of brain pro-inflammatory cytokines, interleukin (IL)-1b and IL-6, at 3 and 18 h after injections. FSL-1 administration induced a dosedependent fever (_1 _C) for two days, lethargy (_78%) for four days, anorexia (_65%) for three days and body mass stunting (_6%) for at least four days. Eighteen hours after FSL-1 administration, when concentrations of IL-1b, but not that of IL-6, were elevated in both the hypothalamus and the hippocampus, and when rats were febrile, lethargic and anorexic, learning in the Maze was unaffected. There also was no memory impairment. Our results support emerging evidence that impaired learning and memory is not inevitable during simulated infection

Interleukin-10 modulates the synthesis of inflammatory mediators in the sensory circumventricular organs: implications for the regulation of fever and sickness behaviors

<p>Abstract</p> <p>Background</p> <p>Whereas the role played by interleukin (IL)-10 in modulating fever and sickness behavior has been linked to it targeting the production of pro-inflammatory cytokines in the circulation, liver and spleen, it is not known whether it could directly target the local production of pro-inflammatory cytokines within the sensory circumventricular organs (CVOs) situated within the brain, but outside the blood–brain barrier. Using inactivation of IL-10, we, therefore, investigated whether IL-10 could modulate the synthesis of pro-inflammatory cytokines within the sensory CVOs, in particular the <it>organum vasculosum laminae terminalis</it> (OVLT) and <it>area postrema</it> (AP).</p> <p>Findings</p> <p>Primary OVLT and AP microcultures were established from topographically excised rat pup brain tissue. The microcultures were pretreated with either IL-10 antibodies (AB) (10 μl/350 μl medium) or phosphate-buffered saline (PBS) (10 μl/350 μl medium) before being incubated with lipopolysaccharide (LPS) (100 μg/ml) or PBS in complete medium for 6 h. Supernatants were removed from the microcultures after 6 h of incubation with LPS and used for the determination of IL-6 and tumor necrosis factor (TNF)-α. Pre-treating the OVLT and AP microcultures with IL-10 antibodies significantly enhanced the LPS-induced increase in TNF-α and IL-6 in the supernatant obtained from the microcultures.</p> <p>Conclusions</p> <p>Our results show for the first time that the LPS-induced release of pro-inflammatory cytokines in cells cultured from the AP and OVLT can be modulated in the presence of IL-10 antibodies. Thus, we have identified that the sensory CVOs may have a key role to play in both the initiation and modulation of neuroinflammation.</p

Immune responses against group B Streptococcus monovalent and pentavalent capsular polysaccharide tetanus toxoid conjugate vaccines in Balb/c mice

Summary: Immunization of pregnant women with Group B Streptococcus (GBS) capsular polysaccharide (CPS) conjugate vaccine (CV) could protect young infants against invasive GBS disease. We evaluated the immunogenicity of investigational five GBS monovalent (serotypes Ia, Ib, II, III, and V) CPS-tetanus toxoid (TT)-CV with adjuvant and GBS pentavalent CPS-TT-CV with adjuvant (GBS5-CV-adj) and without adjuvant (GBS5-CV-no-adj), in Balb/c mice. Aluminum phosphate was the adjuvant in the formulations, where included. The homotypic immunoglobulin G (IgG) geometric mean concentration (GMC) and opsonophagocytic activity (OPA) geometric mean titer (GMT) did not differ after the third dose of the GBS5-CV-adj vaccine compared with the monovalent counterparts for all five serotypes. The GBS5-CV-adj induced higher post-vaccination serotype-specific IgG GMCs and OPA GMTs compared to GBS5-CV-no_adj. The GBS5-CV with and without adjuvant should be considered for further development as a potential vaccine for pregnant women to protect their infants against invasive GBS disease