Definitions matter: Heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis.

Therapeutic efficacy in COVID-19 is dependent upon disease severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation 'living' guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated, 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of "lack of therapeutic benefit" shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data (IPD) meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19. Achieving this goal will require improved coordination of the main stakeholders developing treatment guidelines and medicine regulatory agencies. Open science, including prompt data sharing, should become the standard to allow IPD meta-analyses

Influence of rearing-water temperature on life stages’ vector attributes, distribution and utilisation of metabolic reserves in Culex quinquefasciatus (Diptera: Culicidae): implications for disease transmission and vector control

Abstract Background This study aims at determining the effects of rearing water temperature on immature development, adult vectorial attributes and teneral accumulation in Culex quinquefasciatus (Cx. quinquefasciatus) mosquitoes. Immature life stages of the species were reared (to adulthood) in water media with temperature regimens of 28, 30, 32 and 34 °C generated and maintained by digital electrical thermostats. Immature and adult vectorial attributes (i.e. duration of development, growth rates, immature and adult survivorship, emergence rates and adult longevity), and rates of accumulation, distribution and utilisation (for pupation and eclosion) of teneral reserve (lipid, glucose, glycogen and protein) by life stages of the species were determined. Result Results revealed significant negative effects of temperature increase on all parameters measured. Among these, only rate of larval growth (range = 0.0589 ± 0.0017 to 0.0930 ± 0.0003 mg/day) increased with temperature rise; others reduced with rise in temperature. Total immature duration (9.75 ± 0.09 to 6.43 ± 0.11 days), immature survivorship (94.01 ± 0.18 to 73.26 ± 3.72%), total emergent adults (72.00 ± 2.14 to 14.50 ± 2.67 adults/100 larvae), percentage of emergence, adult daily survivorship (76.86 ± 1.87 to 63.66 ± 0.18%) and post-emergence longevity (23.91 ± 2.97 to 16.90 ± 1.97 days) reduced with increase in temperature. Accumulation of teneral components increased across larval instars, but decreased with temperature rise and at metamorphosis (pupation and eclosion). Immature composition for lipid, glucose, glycogen and protein ranged, respectively, from 9.79 ± 1.05 to 20.07 ± 0.33, 8.49 ± 0.44 to 14.33 ± 0.44, 28.19 ± 2.34 to 42.87 ± 0.12 and 24.11 ± 0.71 to 35.55 ± 0.15 μg/mosquito. While, adult values for these ranged from 7.53 ± 0.40 to 20.66 ± 0.61, 7.45 ± 0.87 to 13.86 ± 0.83, 22.63 ± 0.85 to 33.64 ± 0.79, and 17.81 ± 1.02 to 31.45 ± 1.40 μg/mosquito, respectively. Glycogen and protein had the highest rates of accumulation, while metabolic reserves utilised for pupation and eclosion varied significantly with temperature change. Conclusion This study revealed significant effects of temperature on the entomological parameters measured. Vectorial fitness indices, such as duration of immature development and survivorship, emergence rates, adult survivorship and longevity, and teneral accumulation and utilisation, tend to reduce with increase in temperature, while larval growth rates increased with temperature rise. The information generated is vital for developing temperature-based models and life-stage control strategies

Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study

OBJECTIVES: Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. DESIGN: A multicentre, international, collaborative cohort study. SETTING: 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. PARTICIPANTS: Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, Wilms' tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. MAIN OUTCOME MEASURE: All-cause mortality at 30 days and 90 days. RESULTS: 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). CONCLUSIONS: The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally