Agricultural chemical exposures and birth defects in the Eastern Cape Province, South Africa A case – control study

BACKGROUND: South Africa is one of the major users of pesticides on the African continent. The Eastern Cape is the second largest province in South Africa. There has been growing concern about the occurrence of certain birth defects which seemed to have increased in the past few years. In this paper we investigate associations between exposure to agricultural chemicals and certain birth defects. Few such studies have been undertaken in the developing world previously. METHODS: Between September 2000 and March 2001 a case – control study was conducted among rural women in the area of the Eastern cape to investigate the association between women's exposure to pesticides and the occurrence of birth defects. Information on birth defects was obtained from the register of the Paediatrics Department at the Cecilia Makiwane Hospital in Mdantsane, one of the largest referral hospitals in the province. The cases were children who were diagnosed with selected birth defects. The controls were children born in the same areas as the cases. Exposure information on the mothers was obtained by interview concerning from their activities in gardens and fields. Data were analysed using conditional logistic regression. RESULTS: A total of 89 case mothers and 178 control mothers was interviewed. Babies with birth defects were seven times more likely to be born to women exposed to chemicals used in gardens and fields compared to no reported exposure (Odds Ratio 7.18, 95% CI 3.99, 13.25); and were almost twice as likely to be born to women who were involved in dipping livestock used to prevent ticks (OR 1.92, 95% CI 1.15, 3.14). They were also 6.5 times more likely to be born to women who were using plastic containers for fetching water (OR 6.5, 95% CI 2.2, 27.9). Some of these containers had previously contained pesticides (OR 1.87, 95% CI 1.06, 3.31). CONCLUSIONS: These findings suggest a link between exposure to pesticides and certain birth defects among the children of rural South African women who work on the land. Education programmes for women alerting them to the dangers to their babies from the use of pesticides and alternative farming methods and elimination of the reuse of pesticide containers are indicated as preventive measures

The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial

Objectives: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. Trial design: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently

Flock House Virus RNA Replicates on Outer Mitochondrial Membranes in Drosophila Cells

The identification and characterization of host cell membranes essential for positive-strand RNA virus replication should provide insight into the mechanisms of viral replication and potentially identify novel targets for broadly effective antiviral agents. The alphanodavirus flock house virus (FHV) is a positive-strand RNA virus with one of the smallest known genomes among animal RNA viruses, and it can replicate in insect, plant, mammalian, and yeast cells. To investigate the localization of FHV RNA replication, we generated polyclonal antisera against protein A, the FHV RNA-dependent RNA polymerase, which is the sole viral protein required for FHV RNA replication. We detected protein A within 4 h after infection of Drosophila DL-1 cells and, by differential and isopycnic gradient centrifugation, found that protein A was tightly membrane associated, similar to integral membrane replicase proteins from other positive-strand RNA viruses. Confocal immunofluorescence microscopy and virus-specific, actinomycin D-resistant bromo-UTP incorporation identified mitochondria as the intracellular site of protein A localization and viral RNA synthesis. Selective membrane permeabilization and immunoelectron microscopy further localized protein A to outer mitochondrial membranes. Electron microscopy revealed 40- to 60-nm membrane-bound spherical structures in the mitochondrial intermembrane space of FHV-infected cells, similar in ultrastructural appearance to tombusvirus- and togavirus-induced membrane structures. We concluded that FHV RNA replication occurs on outer mitochondrial membranes and shares fundamental biochemical and ultrastructural features with RNA replication of positive-strand RNA viruses from other families

The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial

Objectives: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. Trial design: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently. Intervention and comparator: Participants will be randomised 1:1:1:1 to: Group 1: standard of care; Group 2: lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form; Group 3: hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days; Group 4: lopinavir /ritonavir plus hydroxychloroquine. Main outcomes: Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated. Randomisation: The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have individual participant allocation provided through a web-based trial enrolment platform. Blinding (masking): This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required. Numbers to be randomised (sample size): We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required sample size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 2440. Trial Status: ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12620000445976). Prospectively registered April 6, 2020. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol