Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Immunochemistry screening for Lynch syndrome in colorectal adenocarcinoma using an initial two antibody panel can replace a four antibody panel.

AIM: The current practice in immunochemistry staining for Lynch syndrome (LS) is to use a four-antibody panel, (MLH1, MSH2, MSH6, PMS2) to screen for the four Mismatch Repair (MMR) gene expressions involved. We hypothesised that testing two antibodies (MSH6 and PMS2), followed by the other two only when there is loss of expression of the first two antibodies, would be equally effective as a four antibody panel in detecting LS. This hypothesis is based on the biochemical binding properties of the MMR proteins. METHODS: We tested this hypothesis on a patient cohort consisting of all cases of colorectal cancer that were stained for MMR gene expression at Auckland City Hospital (Auckland, New Zealand) from the years 2000 to 2010 (inclusive), providing a series of 410 cases for this study. Exclusions were made based on heterogeneous staining pattern and unsatisfactory staining results on MSH6 and PMS2, which left n=400 included in the study. RESULTS: The MMR gene protein stains were regarded as demonstrating loss of expression (LOE) when there was no uptake in the nucleus of the tumour cells, with a positive internal control. The results from our analysis supported our hypothesis. Seventy-four cases showed LOE of MSH6 or PMS2. One of them showed LOE of all four MMR proteins. For the remaining 326 cases, there was no LOE of all four MMR proteins. CONCLUSION: Our study gives further evidence that an initial two-antibody panel consisting of PMS2 and MSH6 would be as effective as a four-antibody panel in detecting DNA MMR gene protein LOE. This study has implications for significant cost cutting and improved efficiency in detection of DNA MMR gene protein LOE in LS.

Southern Ocean deep-water carbon export enhanced by natural iron fertilization.

The addition of iron to high-nutrient, low-chlorophyll regions induces phytoplankton blooms that take up carbon. Carbon export from the surface layer and, in particular, the ability of the ocean and sediments to sequester carbon for many years remains, however, poorly quantified. Here we report data from the CROZEX experiment in the Southern Ocean, which was conducted to test the hypothesis that the observed north-south gradient in phytoplankton concentrations in the vicinity of the Crozet Islands is induced by natural iron fertilization that results in enhanced organic carbon flux to the deep ocean. We report annual particulate carbon fluxes out of the surface layer, at three kilometres below the ocean surface and to the ocean floor. We find that carbon fluxes from a highly productive, naturally iron-fertilized region of the sub-Antarctic Southern Ocean are two to three times larger than the carbon fluxes from an adjacent high-nutrient, low-chlorophyll area not fertilized by iron. Our findings support the hypothesis that increased iron supply to the glacial sub-Antarctic may have directly enhanced carbon export to the deep ocean. The CROZEX sequestration efficiency (the amount of carbon sequestered below the depth of winter mixing for a given iron supply) of 8,600 mol mol(-1) was 18 times greater than that of a phytoplankton bloom induced artificially by adding iron, but 77 times smaller than that of another bloom initiated, like CROZEX, by a natural supply of iron. Large losses of purposefully added iron can explain the lower efficiency of the induced bloom(6). The discrepancy between the blooms naturally supplied with iron may result in part from an underestimate of horizontal iron supply.

Tympanic temperature measurements: are they reliable in the critically ill? A clinical study of measures of agreement.

OBJECTIVE: Accurate measurement of temperature is vital in the intensive care setting. A prospective trial was performed to compare the accuracy of tympanic, urinary, and axillary temperatures with that of pulmonary artery (PA) core temperature measurements. DESIGN: A total of 110 patients were enrolled in a prospective observational cohort study. SETTING: Multidisciplinary intensive care unit of a university teaching hospital. PATIENTS: The cohort was (mean +/- sd) 65 +/- 16 yrs of age, Acute Physiology and Chronic Health Evaluation (APACHE) II score was 25 +/- 9, 58% of the patients were men, and 76% were mechanically ventilated. The accuracy of tympanic (averaged over both ears), axillary (averaged over both sides), and urinary temperatures was referenced (as mean difference, Delta degrees centigrade) to PA temperatures as standard in 6,703 recordings. Lin concordance correlation (pc) and Bland-Altman 95% limits of agreement (degrees centigrade) described the relationship between paired measurements. Regression analysis (linear mixed model) assessed covariate confounding with respect to temperature modes and reliability formulated as an intraclass correlation coefficient. MEASUREMENTS AND MAIN RESULTS: Concordance of PA temperatures with tympanic, urinary, and axillary was 0.77, 0.92, and 0.83, respectively. Compared with PA temperatures, Delta (limits of agreement) were 0.36 degrees C (-0.56 degrees C, 1.28 degrees C), -0.05 degrees C (-0.69 degrees C, 0.59 degrees C), and 0.30 degrees C (-0.42 degrees C, 1.01 degrees C) for tympanic, urinary, and axillary temperatures, respectively. Temperature measurement mode effect, estimated via regression analysis, was consistent with concordance and Delta (PA vs. urinary, p = .98). Patient age (p = .03), sedation score (p = .0001), and dialysis (p = .0001) had modest negative relations with temperature; quadratic relationships were identified with adrenaline and dobutamine. No interactions with particular temperature modes were identified (p > or = .12 for all comparisons) and no relationship was identified with either mean arterial pressure or APACHE II score (p > or = .64). The average temperature mode intraclass correlation coefficient for test-retest reliability was 0.72. CONCLUSION: Agreement of tympanic with pulmonary temperature was inferior to that of urinary temperature, which, on overall assessment, seemed more likely to reflect PA core temperature.

Long-term oceanographic and ecological research in the Western English Channel.

Long-term research in the western English Channel, undertaken by the marine laboratories in Plymouth, is described and details of survey methods, sites, and time series given in this chapter. Major findings are summarized and their limitations outlined. Current research, with recent reestablishment and expansion of many sampling programmes, is presented, and possible future approaches are indicated. These unique long-term data sets provide an environmental baseline for predicting complex ecological responses to local, regional, and global environmental change. Between 1888 and the present, investigations have been carried out into the physical, chemical, and biological components (ranging from plankton and fish to benthic and intertidal assemblages) of the western English Channel ecosystem. The Marine Biological Association of the United Kingdom has performed the main body of these observations. More recent contributions come from the Continuous Plankton Recorder Survey, now the Sir Alister Hardy Foundation for Ocean Science, dating from 1957; the Institute for Marine Environmental Research, from 1974 to 1987; and the Plymouth Marine Laboratory, which was formed by amalgamation of the Institute for Marine Environmental Research and part of the Marine Biological Association, from 1988. Together, these contributions constitute a unique data series-one of the longest and most comprehensive samplings of environmental and marine biological variables in the world. Since the termination of many of these time series in 1987-1988 during a reorganisation of UK marine research, there has been a resurgence of interest in long-term environmental change. Many programmes have been restarted and expanded with support from several agencies. The observations span significant periods of warming (1921-1961; 1985-present) and cooling (1962-1980). During these periods of change, the abundance of key species underwent dramatic shifts. The first period of warming saw changes in zooplankton, pelagic fish, and larval fish, including the collapse of an important herring fishery. During later periods of change, shifts in species abundances have been reflected in other assemblages, such as the intertidal zone and the benthic fauna. Many of these changes appear to be related to climate, manifested as temperature changes, acting directly or indirectly. The hypothesis that climate is a forcing factor is widely supported today and has been reinforced by recent studies that show responses of marine organisms to climatic attributes such as the strength of the North Atlantic Oscillation. The long-term data also yield important insights into the effects of anthropogenic disturbances such as fisheries exploitation and pollution. Comparison of demersal fish hauls over time highlights fisheries effects not only on commercially important species but also on the entire demersal community. The effects of acute ("Torrey Canyon" oil spill) and chronic (tributyltin [TBT] antifoulants) pollution are clearly seen in the intertidal records. Significant advances in diverse scientific disciplines have been generated from research undertaken alongside the long-term data series. Many concepts in marine biological textbooks have originated in part from this work (e.g. the seasonal cycle of plankton, the cycling of nutrients, the pelagic food web trophic interactions, and the influence of hydrography on pelagic communities). Associated projects currently range from studies of marine viruses and bacterial ecology to zooplankton feeding dynamics and validation of ocean colour satellite sensors. Recent advances in technology mean these long-term programmes are more valuable than ever before. New technology collects data on finer temporal and spatial scales and can be used to capture processes that operate on multiple scales and help determine their influence in the marine environment. The MBA has been in the forefront of environmental modelling of shelf seas since the early 1970s. Future directions being pursued include the continued development of coupled physical-ecosystem models using western English Channel time-series data. These models will include both the recent high-resolution data and the long-term time-series information to predict effects of future climate change scenarios. It would be beneficial to provide more spatial and high-resolution temporal context to these data, which are fundamental for capturing processes that operate at multiple scales and understanding how they operate within the marine environment. This is being achieved through employment of technologies such as satellite-derived information and advanced telemetry instruments that provide real-time in situ profile data from the water column.

Copepod hatching success in marine ecosystems with high diatom concentrations.

Diatoms dominate spring bloom phytoplankton assemblages in temperate waters and coastal upwelling regions of the global ocean. Copepods usually dominate the zooplankton in these regions and are the prey of many larval fish species. Recent laboratory studies suggest that diatoms may have a deleterious effect on the success of copepod egg hatching. These findings challenge the classical view of marine food-web energy flow from diatoms to fish by means of copepods. Egg mortality is an important factor in copepod population dynamics, thus, if diatoms have a deleterious in situ effect, paradoxically, high diatom abundance could limit secondary production. Therefore, the current understanding of energy transfer from primary production to fisheries in some of the most productive and economically important marine ecosystems may be seriously flawed. Here we present in situ estimates of copepod egg hatching success from twelve globally distributed areas, where diatoms dominate the phytoplankton assemblage. We did not observe a negative relationship between copepod egg hatching success and either diatom biomass or dominance in the microplankton in any of these regions. The classical model for diatom-dominated system remains valid.