The increasing frequency and intensity of dengue outbreaks in endemic and non-endemic countries requires a rational, evidence based response. To this end, we aimed to collate the experiences of a number of affected countries, identify strengths and limitations in dengue surveillance, outbreak preparedness, detection and response and contribute towards the development of a model contingency plan adaptable to country needs. The study was undertaken in five Latin American (Brazil, Colombia, Dominican Republic, Mexico, Peru) and five in Asian countries (Indonesia, Malaysia, Maldives, Sri Lanka, Vietnam). A mixed-methods approach was used which included document analysis, key informant interviews, focus-group discussions, secondary data analysis and consensus building by an international dengue expert meeting organised by the World Health Organization, Special Program for Research and Training in Tropical Diseases (WHO-TDR). Country information on dengue is based on compulsory notification and reporting (“passive surveillance”), with laboratory confirmation (in all participating Latin American countries and some Asian countries) or by using a clinical syndromic definition. Seven countries additionally had sentinel sites with active dengue reporting, some also had virological surveillance. Six had agreed a formal definition of a dengue outbreak separate to seasonal variation in case numbers. Countries collected data on a range of warning signs that may identify outbreaks early, but none had developed a systematic approach to identifying and responding to the early stages of an outbreak. Outbreak response plans varied in quality, particularly regarding the early response. The surge capacity of hospitals with recent dengue outbreaks varied; those that could mobilise additional staff, beds, laboratory support and resources coped best in comparison to those improvising a coping strategy during the outbreak. Hospital outbreak management plans were present in 9/22 participating hospitals in Latin-America and 8/20 participating hospitals in Asia. Considerable variation between countries was observed with regard to surveillance, outbreak detection, and response. Through discussion at the expert meeting, suggestions were made for the development of a more standardised approach in the form of a model contingency plan, with agreed outbreak definitions and country-specific risk assessment schemes to initiate early response activities according to the outbreak phase. This would also allow greater cross-country sharing of ideas.

Preterm newborns are highly susceptible to bacterial infections. This susceptibility is regarded as being due to immaturity of multiple pathways of the immune system. However, it is unclear whether a mechanism that unifies these different, suppressed pathways exists. Here, we argue that the immune vulnerability of the preterm neonate is critically related to arginine depletion. Arginine, a "conditionally essential" amino acid, is depleted in acute catabolic states, including sepsis. Its metabolism is highly compartmentalized and regulated, including by arginase-mediated hydrolysis. Recent data suggest that arginase II-mediated arginine depletion is essential for the innate immune suppression that occurs in newborn models of bacterial challenge, impairing pathways critical for the immune response. Evidence that arginine depletion mediates protection from immune activation during first gut colonization suggests a regulatory role in controlling gut-derived pathogens. Clinical studies show that plasma arginine is depleted during sepsis. In keeping with animal studies, small clinical trials of L-arginine supplementation have shown benefit in reducing necrotizing enterocolitis in premature neonates. We propose a novel, broader hypothesis that arginine depletion during bacterial challenge is a key factor limiting the neonate's ability to mount an adequate immune response, contributing to the increased susceptibility to infections, particularly with respect to gut-derived sepsis.

Background: Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. Methods and findings: Between 4 July 2018 and 18 May 2021, infants born at ≥32⁺⁰ weeks’ gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference −6 bpm, 95% confidence interval (CI) −17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal–infant bonding and higher iron stores. Conclusions: In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32⁺⁰ weeks’ gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213.

Brain injury in the asphyxic newborn infant may be exacerbated by delayed restoration of cardiac output and oxygen delivery. With increasing severity of asphyxia, cerebral autoregulatory responses are compromised. Further brain injury may occur in association with high arterial pressures and cerebral blood flows following the restoration of cardiac output. Initial resuscitation aims to rapidly restore cardiac output and oxygenation whilst mitigating the impact of impaired cerebral autoregulation. Recent animal studies have indicated that the current standard practice of immediate umbilical cord clamping prior to resuscitation may exacerbate injury. Resuscitation prior to umbilical cord clamping confers several haemodynamic advantages. In particular, it retains the low-resistance placental circuit that mitigates the rebound hypertension and cerebrovascular injury. Prolonged cerebral hypoxia–ischaemia is likely to contribute to further perinatal brain injury, while, at the same time, tissue hyperoxia is associated with oxidative stress. Efforts to monitor and target cerebral flow and oxygen kinetics, for example, using near-infrared spectroscopy, are currently being evaluated and may facilitate development of novel resuscitation approaches.