Culture

Astronomers using the Atacama Large Millimeter/submillimeter Array (ALMA) found quasi-periodic flickers in millimeter-waves from the center of the Milky Way, Sagittarius (Sgr) A*. The team interpreted these blinks to be due to the rotation of radio spots circling the supermassive black hole with an orbit radius smaller than that of Mercury. This is an interesting clue to investigate space-time with extreme gravity.

"It has been known that Sgr A* sometimes flares up in millimeter wavelength," tells Yuhei Iwata, the lead author of the paper published in the Astrophysical Journal Letters and a graduate student at Keio University, Japan. "This time, using ALMA, we obtained high-quality data of radio-wave intensity variation of Sgr A* for 10 days, 70 minutes per day. Then we found two trends: quasi-periodic variations with a typical time scale of 30 minutes and hour-long slow variations."

Astronomers presume that a supermassive black hole with a mass of 4 million suns is located at the center of Sgr A*. Flares of Sgr A* have been observed not only in millimeter wavelength, but also in infrared light and X-ray. However, the variations detected with ALMA are much smaller than the ones previously detected, and it is possible that these levels of small variations always occur in Sgr A*.

The black hole itself does not produce any kind of emission. The source of the emission is the scorching gaseous disk around the black hole. The gas around the black hole does not go straight to the gravitational well, but it rotates around the black hole to form an accretion disk.

The team focused on short timescale variations and found that the variation period of 30 minutes is comparable to the orbital period of the innermost edge of the accretion disk with the radius of 0.2 astronomical units (1 astronomical unit corresponds to the distance between the Earth and the Sun: 150 million kilometers). For comparison, Mercury, the solar system's innermost planet, circles around the Sun at a distance of 0.4 astronomical units. Considering the colossal mass at the center of the black hole, its gravity effect is also extreme in the accretion disk.

"This emission could be related with some exotic phenomena occurring at the very vicinity of the supermassive black hole," says Tomoharu Oka, a professor at Keio University.

Their scenario is as follows. Hot spots are sporadically formed in the disk and circle around the black hole, emitting strong millimeter waves. According to Einstein's special relativity theory, the emission is largely amplified when the source is moving toward the observer with a speed comparable to that of light. The rotation speed of the inner edge of the accretion disk is quite large, so this extraordinary effect arises. The astronomers believe that this is the origin of the short-term variation of the millimeter emission from Sgr A*.

The team supposes that the variation might affect the effort to make an image of the supermassive black hole with the Event Horizon Telescope. "In general, the faster the movement is, the more difficult it is to take a photo of the object," says Oka. "Instead, the variation of the emission itself provides compelling insight for the gas motion. We may witness the very moment of gas absorption by the black hole with a long-term monitoring campaign with ALMA." The researchers aim to draw out independent information to understand the mystifying environment around the supermassive black hole.

If we took a journey from Earth's surface to the center, the midway point locates roughly at 1900 km depth in the lower mantle. The lower mantle ranges from 660 to 2900 km depth and occupies 55% of our planet by volume. The chemical composition of the lower mantle is rather simple. It has long been pictured as being made up of 2 major minerals (~95%), namely bridgmanite and ferropericlase. Until recently, this model is directly challenged by a set of discoveries in the lower mantle.

"One of the major lower mantle compositions, ferropericlase (Mg,Fe)O, turns into a pyrite-type structure upon meeting water. This intriguing chemical reaction only occurs at Earth's deep lower mantle which is defined in depths between 1900 and 2900 km" said Qingyang Hu from HPSTAR. "The reaction produces so-called oxygen excessive phases, or simply superoxides. The lower mantle is oxidized in the presence of water." Generally, when all the oxygen atoms in a compound are bonded with metal atoms, they are called oxides. However, if a compound has paired oxygen atoms, like oxygen-oxygen bonding, it becomes a superoxide. Although superoxide is rarely found in nature, it might be common in Earth's deep lower mantle.

"We also found that olivine and its high-pressure phase wadsleyite, the dominating minerals in the upper mantle, decompose to generate superoxides when subducting down into the deep mantle with water." added by Jin Liu from at HPSTAR. Few approaches are available for scientists to probe into the lower mantle mineralogy given its depth. "Our experiments are very challenging. We input appropriate parameters like pressure, temperature, and starting minerals. Then we investigated the outputs including chemical reactions, new mineral assemblages, and their density profiles. Those parameters allow us to better constrain the nature of the lower mantle and its oxidation state." Contrary to the paradigm that the lower mantle is highly reduced, our results indicate that the deep lower mantle is at least locally oxidized wherever water is present.

The team members proceeded with minerals existing on Earth's surface, by squeezing them between two pieces of diamond anvils to generate about 100,000,000 times the atmospheric pressure at sea level, heating them up using infrared laser, before analyzing the samples using a battery of x-ray and electron probes. The experiments have mimicked the extreme pressure-temperatures conditions found in Earth's deep lower mantle.

Previous experiments explored a dry mineral assembly in the absence of water. Those experiments reported that bridgmanite (and/or post-bridgmanite) and ferropericlase are the most abundant and stable minerals throughout the lower mantle. However, when water is introduced, ferropericlase would be partially oxidized to superoxide under the deep lower mantle conditions. The superoxide is verified to stay in harmony with bridgmanite and post-bridgmanite.

This new water-mantle chemistry can be closely linked to the water cycling in the solid Earth. Every year, billions of tons of ocean water falls into the deep Earth at tectonic plate boundaries. While some water returns via underwater volcanoes and hot vents, others goes deep into the Earth's interiors. "Our experiments indicate the deep water is an essential part of mantle chemistry. The water cycling can extend to the deep lower mantle where water has extraordinary oxidation power, producing highly oxidized superoxide and releasing hydrogen." suggested by Dr. Ho-kwang Mao from HPSTAR. "The lower mantle can be oxidized and reduced at the same time."

Lugano, Switzerland, 22 May 2020 - Cancer-related fatigue is a prevalent and potentially persistent issue among breast cancer survivors, which can prevent them from returning to their previous life well after treatment ends and they are declared free of disease. A study, to be presented at the ESMO Breast Cancer Virtual Meeting 2020 (23-24 May), has now shown that existing recommendations and proven strategies for reducing fatigue, which can have physical, emotional as well as cognitive dimensions, may not be sufficiently adhered to by early breast cancer patients. (1)

Explaining the background to the analysis, study author Dr. Antonio Di Meglio of Gustave Roussy in Villejuif, France, stated: "Cancer-related fatigue is an issue that many patients complain about in the clinic, sometimes for years after the completion of treatment. Although there is a lot that we still don't know about the different mechanisms underpinning fatigue, we now have specific, evidence-based recommendations for treating it: the first is to initiate or maintain adequate levels of physical activity and limit sedentary time as much as possible. Data also supports the use of psychosocial interventions such as cognitive behavioural therapy, which can help address maladaptive thoughts like over-dramatising or feelings of helplessness. Our aim with this study was to assess the real-world uptake of these recommendations."

To do this, the research team drew on data from the CANTO cohort study, (2) which assessed long-term toxicities in early breast cancer patients from 26 French cancer centres for at least five years from the time of diagnosis. According to Di Meglio, "CANTO is unique in the field of survivorship research, as it enrolled over 10,000 breast cancer patients nationwide, of which we were able to include more than 7,000 in our analysis. The wealth of clinical, patient-reported and biological data collected makes it an ideal database to answer a lot of questions about cancer-related fatigue." Di Meglio and his colleagues included in their analysis only women who had completed primary treatment and were free of disease, and examined patients' reported utilisation of recommended strategies to treat fatigue over 12 months after a baseline assessment.

Uptake of physical activity recommendations hindered by severe fatigue

"These are patients who were free of disease and whom we would expect to return to their pre-cancer state within six to 12 months after the end of treatment. What we found, however, was that over a third of patients (36%) reported fatigue that we classify as severe at three to six months after treatment," Di Meglio reported. "A majority of study participants (64%) complied with physical activity recommendations in the year that followed, but that still leaves a concerning proportion of women (36%) who were not sufficiently active or completely inactive during this period."

The results additionally showed that patients who reported severe levels of fatigue at baseline were less likely than those with non-severe symptoms to adhere to recommendations of physical activity (60% versus 67%) in the year following the assessment. "The message here is that we need to work harder to encourage patients to stay active, and to make them understand that even if it seems counter-intuitive, it is exercise, not rest, that will help them to overcome fatigue," said Di Meglio.

Supportive care underutilised across the board, with differences observed by fatigue domain

The analysis further brought to light that overall reported utilisation of supportive care was low in this patient population, with only one out of 10 women consulting a psychologist, one out of 12 seeing an acupuncturist and one out of 14 seeking help from a homeopath. "The striking fact here is that patients seem to be using strategies that we have robust evidence for and can refer them to, like psychotherapy, at roughly the same rates as approaches for which we do not have sufficient efficacy data and therefore cannot recommend, like homeopathy," Di Meglio observed. "This suggests that patients may not be sufficiently aware of what the recommendations are, and that we as oncologists need to ensure they are educated about the options at their disposal to reduce fatigue. Better education may also help to diminish the fears and stigma that are still too often associated with psychosocial interventions."

Patients' physical activity uptake and utilisation of supportive care were additionally evaluated for different dimensions of fatigue, revealing differences in women's behaviour depending on whether their fatigue was more physical, cognitive or emotional in nature. "Most notably, we found that patients with severe physical fatigue were less likely to adhere to physical activity recommendations, at 59% compared to 67% of those with non-severe physical fatigue, while high levels of emotional fatigue were more strongly linked to utilisation of psychological consultations, at 17% compared to 8% of non-severe patients in this domain," Di Meglio reported.

He continued: "We also expected women experiencing severe overall fatigue to rely much more heavily on supportive care measures, but in fact they were only 1.3 times more likely to seek out the help of a psychologist, for example, than patients with non-severe fatigue. This may be explained in part by the fact that psychosocial interventions in this context usually come with out-of-pocket costs for patients. That is something our findings may contribute to changing in the future - especially considering that untreated cancer-related fatigue can have long-term social and financial consequences for survivors, some of whom we know never return to their previous life."

Prof. Gabriella Pravettoni, Director of the Psycho-Oncology Division at the European Institute of Oncology (IEO) in Milan, Italy, commented on the findings: "The fact that the strategies patients adopt to manage side-effects are strongly correlated to the type of fatigue they are suffering from is particularly interesting, because patients experiencing significant physical fatigue, for example, may actually benefit substantially from seeing a psychologist. We know that physical activity is proven to reduce cancer-related fatigue, but on its own it does not guarantee the inner healing of the individual."

Pravettoni continued: "By focusing too much on physical activity as the primary remedy for cancer-related fatigue, we are omitting the importance of working on patients' motivation and resilience to help them maintain that activity level and recover fully in the long term. If we leave these women without psychological support, other interventions are almost certain to be less effective as a result. What is truly needed is a 360-degree approach whereby healthcare professionals make therapeutic recommendations in line with patients' unique characteristics and needs. This is all the more important in the context of the current health emergency, which can cause patients to experience strong negative emotions like fear and uncertainty and add to their existing psychological burden from potentially traumatic experiences related to their cancer diagnosis and treatment."

Age, male sex, obesity, and underlying illness have emerged as risk factors for severe covid-19 or death in the UK, according to the largest cohort study to date published by The BMJ today.

The risk of death increases in the over 50s, as does being being male, obese, or having underlying heart, lung, liver and kidney disease.

As the largest prospective observational study reported worldwide to date, it provides a comprehensive picture of the characteristics of patients hospitalised in the UK with covid-19 and their outcomes.

Because the study is ongoing, it has now recruited over 43,000 patients. The findings will help health professionals learn more about how the illness progresses and enable us to compare the UK with other countries, say the researchers.

Studies in China have reported risk factors associated with severe covid-19, but studies describing the features and outcomes of patients with severe covid-19 who have been admitted to hospital in Europe are lacking.

To address this knowledge gap, a team of UK researchers analysed data from 20,133 patients with covid-19 admitted to 208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020.

This represents around a third of all patients admitted to hospital with covid-19 in the UK. The average age of patients in the study was 73 years, and more men (12,068; 60%) were admitted to hospital than women (8,065; 40%).

Besides increasing age, and underlying heart, lung, liver and kidney disease - factors already known to cause poor outcomes - the researchers found that obesity and gender were key factors associated with the need for higher levels of care and higher risk of death in hospital.

At the time of publication, just over a quarter (26%) of all covid-19 patients in hospital had died, 54% were discharged alive, and a third (34%) remained in hospital. Outcomes were poorer for those requiring mechanical ventilation: 37% had died, 17% had been discharged alive, and 46% remained in hospital.

The pattern of disease we describe broadly reflects the pattern reported globally, say the researchers. However, obesity is a major additional risk factor that was not highlighted in data from China. They suspect that reduced lung function or inflammation associated with obesity may play a role.

This is an observational study, so can't establish cause, and the researchers point to some limitations that may have affected their results. Nevertheless, they say this is the largest study of its kind outside of China and clearly shows that severe covid-19 leads to a prolonged hospital stay and a high mortality rate.

"Our study identifies sectors of the population that are at greatest risk of a poor outcome, and shows the importance of forward planning and investment in preparedness studies," they write.

These results have already been shared with the UK Government and World Health Organisation, and are being compared with data from other countries around the world.

At the outset of the covid-19 pandemic, it was natural to focus first on the people with severe disease who might need potentially scarce resources in hospital and intensive care, write US researchers in a linked editorial.

Cohort studies of such patients are important, they say, and this study is a testament to good planning and preparation before, and implementation of data collection during a pandemic.

But they add that if we are going to be managing covid-19 for the next several years, "we need to understand and optimize care before, during, and beyond the hospital."

Lugano, Switzerland, 22 May 2020 - Two novel biomarkers have been found to correlate with improved outcomes with immunotherapy in metastatic breast cancer and may help to identify the patients most likely to benefit from this treatment, according to exploratory studies reported at the ESMO Breast Cancer Virtual Meeting 2020 (1,2). The biomarkers are an increase in the number of programmed death ligand-1 (PDL1/CD274) genes measured by copy number alteration (CNA) and the PD-L1 combined positive score (CPS), which assesses PD-L1 expression on both tumour and immune cells.

"Metastatic breast cancer remains incurable, with many unmet needs and challenges. Triple negative breast cancer has the poorest prognosis among breast cancer subtypes and limited treatment options, mainly involving chemotherapy," said Prof. Sherene Loi, Medical Oncologist and Head of Translational Breast Cancer Genomics and Therapeutics at the Peter MacCallum Cancer Centre, Melbourne, Australia, commenting on the relevance of the new studies. "Immunotherapy has resulted in long durations of disease control and even cures with improved quality of life compared with chemotherapy in other cancers. We are hoping this might also be applicable for some breast cancer patients".

"Previous studies show that not all patients with metastatic breast cancer benefit from immunotherapy. Pre-existing immunity, which can be detected by PD-L1 expression, is required for response to PD-1 or PD-L1 targeting immunotherapy agents. The key question is whether we can identify further patients with metastatic breast cancer that respond to immunotherapy using biomarkers other than just PD-L1 expression."

To explore new potential biomarkers for immunotherapy in advanced breast cancer, researchers assessed the predictive value of copy number alteration (CNA) for the PDL1 gene, which measures whether the gene number has decreased, remained the same (2 copies, one on each chromosome) or increased. (1) They measured CNA values in tumour tissue collected from 126 patients with metastatic breast cancer taking part in the SAFIR-IMMUNO study, the first randomised trial comparing immunotherapy with durvalumab to maintenance chemotherapy in this setting.

"The main predictive markers of immunotherapy efficacy in metastatic breast cancer to date are the absence of hormone receptors and PD-L1 positivity on immune cells," said lead author Prof. Thomas Bachelot, Director of the Breast Cancer Unit, Leon Berard Centre, Lyon, France. But he warned, "Immunohistochemistry analysis of PDL1 expression is not standardised and a more robust predictor of response to immunotherapy is needed."

Results showed that nearly one in four (23.8%) of the patients had copy gain (3 or 4 copies) or amplification (> 4 copies) of the PDL1 gene. Improvement of overall survival with durvalumab was limited to this group, with a median overall survival of 9 months (95% confidence interval [CI] 4-18) in the chemotherapy arm and not reached in the durvalumab arm (hazard ratio 0.17, 95% CI 0.05-0.55).

"This exploratory translational analysis suggested a higher efficacy of durvalumab as maintenance treatment for patients with PDL1 copy gain or amplification," said Bachelot. He suggested: "PDL1 copy number alteration could be an important predictive marker for PD-L1 inhibitor efficacy. If confirmed in larger series, this could have important implications for the development of immunotherapy in patients with metastatic breast cancer, enabling us to better identify patients that are sensitive to PD-L1 inhibitors than current testing for PD-L1 positivity on immune cells."

"At the moment patients with ER-positive breast cancer are not treated with immunotherapy because results of trials were poor. But maybe if we can select the subpopulation that will benefit - the 10% of patients with CNA abnormalities - and show immunotherapy is beneficial for them too, then this would be important," he explained.

Commenting on the potential relevance of the data, Loi said, "The study suggests that PD-L1 amplification may be a predictor for benefit to durvalumab monotherapy, interestingly in all subtypes as well as in triple negative breast cancer." But she cautioned, "It was an unplanned, retrospective analysis so requires further validation in larger studies. There was no analysis presented of whether PD-L1 amplification was associated with overexpression at the protein level, which would be important to understand the underlying biological mechanism of this observation."

Improved health-related quality of life

A second study looked at health-related quality of life (HRQOL) in patients with metastatic triple negative breast cancer randomised to the PD-L1 inhibitor pembrolizumab or chemotherapy in the KEYNOTE-119 trial. (2) Efficacy results for the trial showed no significant difference in overall survival (3) but this analysis described patient reported outcomes for patients by their PD-L1 combined positive score (CPS). CPS is a novel biomarker that assesses PD-L1 expression on both tumour cells and immune cells in contrast to PD-L1 tumour proportion score (TPS), which has been used as a biomarker for immunotherapy in other cancers but fails to take account of immune cell PD-L1 expression. (4)

"The benefit of pembrolizumab versus chemotherapy was observed in nearly all prespecified patient reported outcome endpoints," said lead author Prof. Peter Schmid, Lead of the Centre for Experimental Medicine at Barts Cancer Institute, Queen Mary University of London, UK. "Importantly, time to deterioration score for global health status/QoL scale was longer for patients treated with pembrolizumab compared to those treated with chemotherapy," he reported. The median time to deterioration was 4.3 months for pembrolizumab versus 1.7 months with chemotherapy (hazard ratio 0.70, 95% CI 0.46, 1.05). Scores for symptom scales for fatigue, nausea and vomiting, pain, dyspnoea and loss of appetite all increased with chemotherapy but remained stable or improved slightly with immunotherapy.

"In this CPS-enriched population of patients with metastatic triple negative breast cancer receiving second- and third-line treatments, health-related quality of life was better for patients receiving pembrolizumab than those receiving chemotherapy," said Schmid.

He added: "We are still learning a lot about immunotherapy in metastatic breast cancer. Trials for single agent immunotherapy in the first-line setting have not been positive. But these results clearly show there is a group of patients who do at least as well with single agent immunotherapy as chemotherapy in terms of survival and probably better in terms of quality of life."

Loi commented: "Patients who expressed high levels of PD-L1 protein according to their CPS score had better overall survival with pembrolizumab compared with chemotherapy, and pembrolizumab was far better tolerated than chemotherapy according to HRQOL measures. This underscores the importance of PD-L1 testing in the advanced setting as well as identifying other biomarkers that can help identify those who do best with pembrolizumab monotherapy given its favourable HRQOL impact."

High-entropy alloys (HEAs) are at the frontier of the metal materials community. They are used as alternative materials in the production of high-temperature turbine blades, high-temperature molds and dies, hard coatings on cutting tools or even components of 4th generation nuclear reactors.

By screening proper combinations of HEAs' constituent elements and regulating their proportions, HEAs can exhibit remarkable mechanical properties at high temperatures and display exceptional strength, ductility and fracture toughness at cryogenic temperatures.

Meanwhile, the development of HEAs for 3D printing has also been advancing rapidly, ramping up great potential for the manufacturing of such geometrically complex HEA products with desirable performances.

However, there is a lack of comprehensive understanding on the 3D printing of HEAs. To tackle this issue, researchers from Singapore University of Technology and Design (SUTD), Nanyang Technological University (NTU), Huazhong University of Science and Technology and Hunan University collaborated to publish a thorough review of the recent achievements on 3D printing of HEAs (refer to image). The study was published in Advanced Materials.

The review paper includes the production processes for HEA powders, 3D printing processes for HEA products, and the microstructure, mechanical properties, functionalities and potential applications of the printed products.

"3D printing of HEAs has been undergoing explosive growth in the academia and will gain extensive interest from industry. In our review, laser-based directed energy deposition, selective laser melting and electron beam melting are validated for their applicability to print various high-quality HEA products. It allows for a combination of material selection, design and manufacturing freedoms for lightweight, customizable and non-assembly required products," explained lead author Professor Chua Chee Kai from SUTD.

"The ultrafast cooling rates of certain 3D printing techniques are expected to prevent the formation of undesirable intermetallic compounds in HEA products, thereby enhancing their mechanical properties. The different cooling rates of these printing processes would induce substantial variations in both the microstructures and macroscopic performances of the products," said first author Dr Han Changjun from NTU.

"We believe that this paper serves as a valuable comprehensive review to deepen our understanding of the 3D printing of HEAs by focusing on its unique merits. Hopefully, more researchers would be encouraged to explore this highly interesting field," added corresponding author Associate Professor Zhou Kun from NTU.

Multidisciplinary study of the COVID-19 pandemic and its wide-ranging impact has become an urgent endeavor worldwide. To further and deepen global understanding of the crisis, the Harvard Data Science Review (an open access platform of the Harvard Data Science Initiative) is publishing a special issue examining the novel coronavirus and its impact through the lens of data science.

The issue covers a wide range of topics addressing the societal, epidemiological, political, and educational issues that have rapidly emerged from the SARS-CoV2 pandemic. Articles include:

A Conversation About Covid-19 With Biostatisticians and EpidemiologistsDavid Banks (Duke University), Susan Ellenberg (University of Pennsylvania), Thomas Fleming (University of Washington), M. Elizabeth Halloran (University of Washington), Andrew Lawson (Medical University of South Carolina), and Lance Waller (Emory University)Five leading biostatisticians and epidemiologists debate the probable scope and duration of the pandemic, the kinds of medical responses that we need, and some of the impacts they foresee on the U.S. and on the world. They also discuss the pandemic’s likely effect on higher education.

The Coronavirus Exponential: A Preliminary Investigation into the Public’s UnderstandingAlexander Podkul (Optimus), Scott Tranter (Optimus), Liberty Vittert (Washington University, St. Louis), Alex Alduncin (Optimus)The reasons why we are currently “socially distancing” are based on an understanding of exponential growth and the idea of “flattening the curve.” The authors present and discuss a pair of survey experiments that explore the public’s statistical literacy by examining its ability to calculate and understand exponential growth. These findings may be used to help better ground effective communication strategies aimed at the general public.

Bayesian Adaptive Clinical Trials for Anti-Infective Therapeutics During Epidemic OutbreaksShomesh Chaudhuri (QLS Advisors), Andrew W. Lo (MIT), Danying Xiao (MIT), and Qingyang Xu (MIT)In the midst of the COVID-19 pandemic, how should regulatory agencies adapt their normally lengthy clinical trial and approval process to address the urgency of finding treatments and saving lives? The authors propose a Bayesian adaptive patient-centered framework to optimize the clinical trial development path for anti-infective therapies and vaccines. Their research provides a rational, systematic, transparent, repeatable, and practical framework for regulators, policymakers, and clinical researchers to evaluate the efficacy of anti-infective therapeutics during the course of any epidemic outbreak when the cost of false negatives far outweighs the cost of false positives.

Estimating Probabilities of Success of Vaccine and Other Anti-Infective Therapeutic Development ProgramsAndrew W. Lo (MIT), Kien Wei Siah (MIT), Chi Heem Wong (MIT)The economic value of a drug or medical device development program is typically computed by assessing the program’s cumulative revenues if successful, and companies rely on this data to make business decisions about which programs to pursue and how to fund them.
In this article, the authors provide estimates of clinical trial outcomes for vaccines and other anti-infective therapeutics using 43,414 unique triplets of clinical trial, drug, and disease between January 1, 2000, and January 7, 2020, yielding 2,544 vaccine programs and 6,829 non-vaccine programs targeting infectious diseases—the largest dataset of its kind. As governments around the world begin to formulate a more systematic strategy for dealing with pandemics beyond COVID-19, these estimates can be used by policymakers to identify areas most likely to be undeserved by private-sector engagement and in need of public-sector support.

Tackling Covid-19 through Responsible AI Innovation: Five Steps in the Right DirectionDavid Leslie (The Alan Turing Institute)Innovations in data science and artificial intelligence (AI) have a central role to play in supporting global efforts to combat COVID-19 and address a broad range of biomedical, epidemiological, and socio-economic challenges. However, this wide-reaching scientific capacity also raises ethical challenges.
The authors present a practice-based path to responsible AI design and discovery centered on open, accountable, equitable, and democratically governed processes and products. When taken from the start, these steps will not only enhance the capacity of innovators to tackle Covid-19 responsibly, they will help to set the data science and AI community down a path that is both better prepared to cope with future pandemics and better equipped to support a more humane, rational, and just society of tomorrow.

The special issue will be published on a rolling/continuous basis with new articles appearing weekly through the beginning of July 2020.

Journal

Harvard Data Science Review

DOI

10.1162/99608f92.1b77b932

There are an estimated 2 million older adults who are homebound or unable to leave their homes due to multiple chronic conditions and functional impairment. Home-based primary care provides access to care for these patients and has been shown to save costs for the Medicare program. The federal government's Centers for Medicare and Medicaid Services (CMS) is currently moving from volume-based reimbursement -- where health care providers are paid based on the quantity of care supplied -- to value-based reimbursement -- where providers are rewarded with incentive payments for the quality of care their patients receive. To successfully achieve the shift, it's critical that CMS quality measures include ones focused on medical care provided in the home by physicians.

In a report published in the May 19, 2020, issue of the Annals of Internal Medicine, researchers at Johns Hopkins Medicine and four other U.S. medical institutions examined the performance quality measures used by the CMS Merit-based Incentive Payment System (MIPS) to determine if they appropriately addressed home-based medical care.

In their review of 257 overall quality measures on the CMS 2019 MIPS list, the researchers found that of the 78 potentially appropriate quality measures for home-based care, only 50% (39) included certain codes that enable physicians to report they provided services in a patient's home. These codes indicate that the services are eligible for quality-based incentives.

"This is unfortunate, because strong evidence exists that improving care for frail older adults, particularly those who are homebound, can help improve care and reduce health care costs," says lead author Bruce Leff, M.D., director of the Center for Transformative Geriatric Research and professor of medicine at the Johns Hopkins University School of Medicine. "Currently," he adds, "only 12% of homebound patients receive their medical care at home."

Based on their findings, the researchers recommend that (1) the CMS add home visit codes to all MIPS quality measures relevant to such care; (2) that quality measure developers consider home-based primary care when designing new standards; and (3) that research initiatives foster this development. They also support the establishment of a national learning collaborative and practice-based research network focused on home-based medical care.

The team of researchers from the project "Flora iberica X(2)" have discovered two new native grass on the Iberian Peninsula and in Menorca, respectively. These two species, which are new to science, have been featured in the prestigious American review Systematic Botany. The article of the fruit of the collaboration between the Area of Botany and the University of Seville Herbarium, the Systematic and Evolution Unit for Vascular Plants at the Autonomous University of Barcelona, and researchers from other institutions in the Balearic Islands.

The new species belong to the genus Aira, delicate herbaceous plants, which enjoy their greatest diversity in the Mediterranean Region. One of them, Aira minoricensis is a native species of the siliceous sands of Menorca, where it was collected for the first time in 2014 by the botanist Pere Fraga, curator of the Marimutra Botanical Garden (Blanes) and great expert on the island's flora. The other new species is called Aira hercynica and is widely found in the area of the Iberia Peninsula which approximately coincides with the Iberian Massif (which is also called the Hesperic or Hercynian Massif) and the mountains that surround it. It is, therefore, a common species, which had previously been confused with other species. Its discovery is product of the experience in grass taxonomy of the University of Seville teacher, Carlos Romero Zarco, who, in 2016, identified for the first time the existence of two different species which had previously been considered just one.

The article, coordinated by the teacher Llorenç Sáez (Autonomous University of Barcelona), includes a detailed morphometric study, together with structural, ecological and distribution data, as well as the state of conservation of the population of the species (in accordance with the categories of the International Union for Conservation of Nature), which has shown the clear separation of these two species with regard to those already known in the Mediterranean Region.

"Currently, team continues working on this genus to try to clarify the relationship between these species by means of molecular markers", states the researcher Carlos Romero.

DURHAM, N.C. - A new study by researchers at Duke University and RTI International finds that reusing oilfield water that's been mixed with surface water to irrigate farms in the Cawelo Water District of California's Kern County does not pose major health risks, as some opponents of the practice have feared.

"We did not find any major water quality issues, nor metals and radioactivity accumulation in soil and crops, that might cause health concerns," said Avner Vengosh, professor of water quality and geochemistry at Duke's Nicholas School of the Environment, whose lab led the new study.

Faced with increasing droughts and water shortages, some farmers in the Cawelo district have used diluted oilfield produced water (OPW) for irrigation for their fields for more than 25 years, as permitted under California Water Board policy.

While the oilfield-mixed water contains slightly elevated levels of salts and boron relative to the local groundwater, those levels are still below the standards set by the state for safe drinking water and irrigation in the Cawelo district, Vengosh said.

Boron and salts from the OPW have however, accumulated over time in the irrigated soil. The district's farmers will need to plant boron-tolerant crops and keep mixing the OPW with fresh water to avoid boron toxicity and salinity buildup in their fields, and also to remain within state guidelines. "But all things considered, this is good news," Vengosh said.

The researchers published their peer-reviewed findings May 18 in the journal Science of the Total Environment.

The new study should help allay fears that contaminants in the Cawelo OPW, which is produced as a byproduct of oil and gas extraction at sites adjacent to many farm fields in the district, could impact water and soil quality, harm crop health or pose risks to human health, the researchers said.

"Those concerns assumed that the OPW generated by oil and gas wells in the Cawelo district contains similar mixtures of salts, metals and naturally occurring radioactivity as OPW generated in oil fields in other regions. But our study shows that's not the case," said Andrew Kondash, a research environmental scientist at RTI International, who led the study as part of his 2019 doctoral dissertation at Duke.

"The OPW produced in Kern County is much more diluted and low-saline than common OPW from other parts of the country, so it can be used for irrigation if it is mixed with surface water," Kondash said.

Determining whether it is safe to use OPW for irrigation in other locations would require a similar suite of water and soil testing, Kondash said. "You can't assume that the results in this study could be applied to OPW from other oilfields, where the salinity is typically much higher."

To conduct the new study, the researchers collected and analyzed soil samples, irrigation water samples, OPW samples and groundwater samples from sites across the Cawelo Water District from December 2017 to September 2018 and analyzed them for a wide range of contaminants including, salts, metals and radioactive elements.

The first COVID-19 vaccine to reach phase 1 clinical trial has been found to be safe, well-tolerated, and able to generate an immune response against SARS-CoV-2 in humans, according to new research published in The Lancet. The open-label trial in 108 healthy adults demonstrates promising results after 28 days--the final results will be evaluated in six months [1]. Further trials are needed to tell whether the immune response it elicits effectively protects against SARS-CoV-2 infection.

"These results represent an important milestone. The trial demonstrates that a single dose of the new adenovirus type 5 vectored COVID-19 (Ad5-nCoV) vaccine produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation", says Professor Wei Chen from the Beijing Institute of Biotechnology in Beijing, China, who is responsible for the study. "However, these results should be interpreted cautiously. The challenges in the development of a COVD-19 vaccine are unprecedented, and the ability to trigger these immune responses does not necessarily indicate that the vaccine will protect humans from COVID-19. This result shows a promising vision for the development of COVID-19 vaccines, but we are still a long way from this vaccine being available to all." [2]

The creation of an effective vaccine is seen as the long-term solution to controlling the COVID-19 pandemic. Currently, there are more than 100 candidate COVID-19 vaccines in development worldwide.

The new Ad5 vectored COVID-19 vaccine evaluated in this trial is the first to be tested in humans. It uses a weakened common cold virus (adenovirus, which infects human cells readily but is incapable of causing disease) to deliver genetic material that codes for the SARS-CoV-2 spike protein to the cells. These cells then produce the spike protein, and travel to the lymph nodes where the immune system creates antibodies that will recognize that spike protein and fight off the coronavirus.

The trial assessed the safety and ability to generate an immune response of different dosages of the new Ad5-nCoV vaccine in 108 healthy adults between the ages of 18 and 60 years who did not have SARS-CoV-2 infection. Volunteers were enrolled from one site in Wuhan, China, and assigned to receive either a single intramuscular injection of the new Ad5 vaccine at a low dose (5 × 1010 viral particles/0·5ml, 36 adults), middle dose (1×1011 viral particles/1.0ml, 36 adults), or high dose (1.5 x 1011 viral particles/1.5ml, 36 adults).

The researchers tested the volunteers' blood at regular intervals following vaccination to see whether the vaccine stimulated both arms of the immune system: the body's 'humoral response' (the part of the immune system that produces neutralising antibodies which can fight infection and could offer a level of immunity), and the body's cell-mediated arm (which depends on a group of T cells, rather than antibodies, to fight the virus). The ideal vaccine might generate both antibody and T cell responses to defend against SARS-CoV-2.

The vaccine candidate was well tolerated at all doses with no serious adverse events reported within 28 days of vaccination. Most adverse events were mild or moderate, with 83% (30/36) of those receiving low and middle doses of the vaccine and 75% (27/36) in the high dose group reporting at least one adverse reaction within 7 days of vaccination.

The most common adverse reactions were mild pain at the injection site reported in over half (54%, 58/108) of vaccine recipients, fever (46%, 50/108), fatigue (44%, 47/108), headache (39%, 42/108), and muscle pain (17%, 18/108). One participant given the higher dose vaccine reported severe fever along with severe symptoms of fatigue, shortness of breath, and muscle pain--however these adverse reactions persisted for less than 48 hours.

Within two weeks of vaccination, all dose levels of the vaccine triggered some level of immune response in the form of binding antibodies (that can bind to the coronavirus but do not necessarily attack it - low-dose group 16/36, 44%; medium dose 18/36, 50%; high dose 22/36, 61%), and some participants had detectable neutralising antibodies against SARS-CoV-2 (low-dose group 10/36, 28%; medium dose 11/36, 31%; high dose 15/36, 42%).

After 28 days, most participants had a four-fold increase in binding antibodies (35/36, 97% low-dose group; 34/36 (94%) middle-dose group, and 36/36, 100% in high-dose group), and half (18/36) of participants in the low- and middle-dose groups and three-quarters (27/36) of those in the high-dose group showed neutralising antibodies against SARS-CoV-2.

Importantly, the Ad5-nCoV vaccine also stimulated a rapid T cell response in the majority of volunteers, which was greater in those given the higher and middle doses of vaccine, with levels peaking at 14 days after vaccination (low-dose group (30/36; 83.3%), medium (35/36, 97.2%), and high-dose group (35/36, 97.2%) at 14 days).

Further analyses showed that 28 days after vaccination, the majority of recipients showed either a positive T cell response or had detectable neutralising antibodies against SARS-CoV-2 (low-dose group 28/36, 78%; medium-dose group 33/36, 92%; high-dose group 36/36, 100%).

However, the authors note that both the antibody and T-cell response could be reduced by high pre-existing immunity to adenovirus type 5 (the common cold virus vector/carrier)--in the study, 44%-56% of participants in the trial had high pre-existing immunity to adenovirus type 5, and had a less positive antibody and T-cell response to the vaccine.

"Our study found that pre-existing Ad5 immunity could slow down the rapid immune responses to SARS-CoV-2 and also lower the peaking level of the responses. Moreover, high pre-existing Ad5 immunity may also have a negative impact on the persistence of the vaccine-elicited immune responses", say Professor Feng-Cai Zhu from Jiangsu Provincial Center for Disease Control and Prevention in China who led the study.

The authors note that the main limitations of the trial are its small sample size, relatively short duration, and lack of randomised control group, which limits the ability to pick up rarer adverse reactions to the vaccine or provide robust evidence for its ability to generate an immune reaction. Further research will be needed before this trial vaccine becomes available to all.

A randomised, double-blinded, placebo-controlled phase 2 trial of the Ad5-nCoV vaccine has been initiated in Wuhan to determine whether the results can be replicated, and if there are any adverse events up to 6 months after vaccination, in 500 healthy adults--250 volunteers given a middle dose, 125 given a low dose, and 125 given a placebo as a control. For the first time, this will include participants over 60 years old, an important target population for the vaccine.

RETRACTION: "Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis"

June 4, 2020

Today, three of the authors (Mandeep R. Mehra, MD, MSc, Frank Ruschitzka, MD, Amit N. Patel, MD) of the paper "Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis" have retracted their study.

Please find their retraction below, followed by a statement from The Lancet.

The retraction is published here: https://www.thelancet.com/lancet/article/s0140673620313246

The Lancet Press Office
pressoffice@lancet.com

Retraction from the authors (published here: https://www.thelancet.com/lancet/article/s0140673620313246)

After publication of our Lancet Article [1], several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication. We launched an independent third-party peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.

Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements. As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.

We always aspire to perform our research in accordance with the highest ethical and professional guidelines. We can never forget the responsibility we have as researchers to scrupulously ensure that we rely on data sources that adhere to our high standards. Based on this development, we can no longer vouch for the veracity of the primary data sources. Due to this unfortunate development, the authors request that the paper be retracted.

We all entered this collaboration to contribute in good faith and at a time of great need during the COVID-19 pandemic. We deeply apologise to you, the editors, and the journal readership for any embarrassment or inconvenience that this may have caused.

Mandeep R Mehra, Frank Ruschitzka, Amit N Patel

[1] Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 2020; published online May 22. https://doi.org/10.1016/S0140-6736(20)31180-6

Statement from The Lancet:

Today, three of the authors of the paper, "Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis", have retracted their study. They were unable to complete an independent audit of the data underpinning their analysis. As a result, they have concluded that they "can no longer vouch for the veracity of the primary data sources." The Lancet takes issues of scientific integrity extremely seriously, and there are many outstanding questions about Surgisphere and the data that were allegedly included in this study. Following guidelines from the Committee on Publication Ethics (COPE) and International Committee of Medical Journal Editors (ICMJE), institutional reviews of Surgisphere’s research collaborations are urgently needed.

The retraction notice is published today, June 4, 2020. The article will be updated to reflect this retraction shortly.

For COPE guidelines, please see: https://publicationethics.org/resources/guidelines-new/cooperation-between-research-institutions-and-journals-research-integrity

For ICMJE guidelines, please see: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/scientific-misconduct-expressions-of-concern-and-retraction.html

A large observational study suggests that treatment with the antimalarial drug chloroquine or its analogue hydroxychloroquine (taken with or without the antibiotics azithromycin or clarithromycin) offers no benefit for patients with COVID-19. The study analysed data from nearly 15,000 patients with COVID-19 receiving a combination of any of the four drug regimens and 81,000 controls.

Treatment with these medications among patients with COVID-19, either alone or in combination with macrolide antibiotics, was linked to an increased risk of serious heart rhythm complications in these patients.

Researchers suggest these treatment regimens should not be used to treat COVID-19 outside of clinical trials until results from randomised clinical trials are available to confirm the safety and efficacy of these medications for COVID-19 patients.

Chloroquine is an antimalarial drug and its analogue, hydroxychloroquine, is used to treat autoimmune diseases including lupus and arthritis. Both drugs have a good safety profile as treatments for those specific conditions, and the findings do not imply patients should stop taking these drugs if they are prescribed for approved conditions. They have also been shown to have antiviral effects in laboratory tests and are therefore of interest as potential treatments for COVID-19.

Prof Dr Mandeep R. Mehra, lead author of the study and Executive Director of the Brigham and Women's Hospital Center for Advanced Heart Disease in Boston, USA, said: "This is the first large scale study to find statistically robust evidence that treatment with chloroquine or hydroxychloroquine does not benefit patients with COVID-19. Instead, our findings suggest it may be associated with an increased risk of serious heart problems and increased risk of death. Randomised clinical trials are essential to confirm any harms or benefits associated with these agents. In the meantime, we suggest these drugs should not be used as treatments for COVID-19 outside of clinical trials." [1]

In the study, researchers analysed data from 96,032 patients hospitalised between 20 December 2019 and 14 April 2020 with laboratory confirmed SARS-CoV-2 infection from 671 hospitals. All of the patients included in the study had either been discharged or had died by 21 April 2020.

The team compared outcomes from patients treated with chloroquine alone (1,868), hydroxychloroquine alone (3,016), chloroquine in combination with a macrolide (3,783) or hydroxychloroquine with a macrolide (6,221). Patients from these four groups were compared with the remaining control group of 81,144 patients.

At the end of the study period, around one in 11 patients in the control group had died in hospital (9.3%, 7,530/81,144). All four of the treatments were associated with a higher risk of dying in hospital. Of those treated with chloroquine or hydroxychloroquine alone, around one in six patients had died (16.4%, 307/1,868 chloroquine and 18.0%, 543/3,016 hydroxychloroquine). When the drugs were used in combination with a macrolide, the death rate rose to more than one in five for chloroquine (22.2%, 839/3,783) and almost one in four for hydroxychloroquine (23.8%, 1,479/6,221).

Some of the difference in the rates of mortality is due to underlying differences between patients who received the treatments and those who didn't. After accounting for factors including age, race, body mass index and underlying health conditions including heart disease, lung disease and diabetes, the researchers found the drug regimens were associated with an increased risk of death.

They estimated that the excess risk attributable to the use of the drug regimen rather than other factors such as co-morbidities ranged from 34% to 45%. The authors explain that if the rate of mortality is 9.3% in the control group, after adjustment for the other clinical factors, the rate attributable to the use of the drug regimens would rise to 12.4-13.4% . However, the researchers caution that it is not possible to exclude the possibility that other, unmeasured factors were responsible for the apparent link between treatment with these drugs and the decrease in patient survival because such is the design of observational studies, and randomised trials are urgently needed.

The team also found that serious cardiac arrhythmias, which cause the lower chamber of the heart to beat rapidly and irregularly, were more common in the groups receiving either of the four treatment regimens.

The biggest increase was seen in the group treated with hydroxychloroquine in combination with a macrolide, where 8% of patients developed a heart arrhythmia (502/6,221) compared with 0.3% patients in the control group (226/81144). After accounting for demographic factors and pre-existing conditions, the team calculated that treatment with this combination of drugs is associated with a more than five-fold increase in risk of developing a serious heart arrhythmia while in hospital (as an example, an increase from 0.3% to 1.5% would be attributable to the drug regimen after adjustment for other clinical factors). Similarly, it is not possible to conclusively infer cause and effect between treatment with these medications and the onset of heart arrhythmias. Randomised clinical trials will be required before any conclusion can be reached regarding benefit of harm of these agents in COVID-19 patients.

Prof Dr. Frank Ruschitzka, Director of the Heart Center at University Hospital Zurich who also co-authored the study said: "Several countries have advocated use of chloroquine and hydroxychloroquine, either alone or in combination, as potential treatments for COVID-19. Justification for repurposing these medicines in this way is based on a small number of anecdotal experiences that suggest they may have beneficial effects for people infected with the SARS-CoV-2 virus. However, previous small-scale studies have failed to identify robust evidence of a benefit and larger, randomised controlled trials are not yet completed. However, we now know from our study that the chance that these medications improve outcomes in COVID-19 is quite low." [1]

Writing in a linked Comment article, Professor Christian Funck-Brentano, of the Sorbonne University in Paris, France (who was not involved in the study), said: "This well-conducted observational study adds to preliminary reports suggesting that chloroquine, hydroxychloroquine, alone or with azithromycin is not useful and may be harmful in hospitalized COVID-19 patients."

CHICAGO --- The placentas from 16 women who tested positive for COVID-19 while pregnant showed evidence of injury, according to pathological exams completed directly following birth, reports a new Northwestern Medicine study.

The type of injury seen in the placentas shows abnormal blood flow between the mothers and their babies in utero, pointing to a new complication of COVID-19. The findings, though early, could help inform how pregnant women should be clinically monitored during the pandemic.

The study was published today (May 22) in the journal American Journal of Clinical Pathology. It is the largest study to examine the health of placentas in women who tested positive for COVID-19.

"Most of these babies were delivered full-term after otherwise normal pregnancies, so you wouldn't expect to find anything wrong with the placentas, but this virus appears to be inducing some injury in the placenta," said senior author Dr. Jeffery Goldstein, assistant professor of pathology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine pathologist. "It doesn't appear to be inducing negative outcomes in live-born infants, based on our limited data, but it does validate the idea that women with COVID should be monitored more closely."

This increased monitoring might come in the form of non-stress tests, which examine how well the placenta is delivering oxygen, or growth ultrasounds, which measure if the baby is growing at a healthy rate, said co-author Dr. Emily Miller, assistant professor of obstetrics and gynecology at Feinberg and a Northwestern Medicine obstetrician.

"Not to paint a scary picture, but these findings worry me," Miller said. "I don't want to draw sweeping conclusions from a small study, but this preliminary glimpse into how COVID-19 might cause changes in the placenta carries some pretty significant implications for the health of a pregnancy. We must discuss whether we should change how we monitor pregnant women right now."

Previous research has found that children who were in utero during the 1918-19 flu pandemic, which is often compared to the current COVID-19 pandemic, have lifelong lower incomes and higher rates of cardiovascular disease. Flu doesn't cross the placenta, Goldstein said, so whatever is causing life-long problems in those people is most likely due to immune activity and injury to the placenta.

"Our study, and other studies like it, are trying to get on the ground floor for this exposure so we can think about what research questions we should be asking in these kids and what can or should we do now to mitigate these same types of outcomes," Goldstein said.

Fifteen patients delivered live infants in the third trimester, however one patient had a miscarriage in the second trimester. "That patient was asymptomatic, so we don't know whether the virus caused the miscarriage or it was unrelated," Goldstein said, "We are aware of four other cases of miscarriage with COVID. The other reported patients had symptoms and three of four had severe inflammation in the placenta. I'd like to see more before drawing any conclusions."

The placenta is the first organ to form in fetal development. It acts as the fetus' lungs, gut, kidneys and liver, taking oxygen and nutrients from the mother's blood stream and exchanging waste. The placenta also is responsible for many of the hormonal changes within the mother's body. Examining a woman's placenta allows a pathologist to follow a retroactive roadmap of a woman's pregnancy to learn what happened to the baby in utero or what could happen to both the mother and the infant after birth.

"The placenta acts like a ventilator for the fetus, and if it gets damaged, there can be dire outcomes," Miller said. "In this very limited study, these findings provide some signs that the ventilator might not work as well for as long as we'd like it to if the mother tests positive for SARS-CoV2."

The placentas in these patients had two common abnormalities: insufficient blood flow from the mother to the fetus with abnormal blood vessels called maternal vascular malperfusion (MVM) and blood clots in the placenta, called intervillous thrombi.

In normal cases of MVM, the mother's blood pressure is higher than normal. This condition is typically seen in women with preeclampsia or hypertension. Interestingly, only one of the 15 patients in this study had preeclampsia or hypertension.

"There is an emerging consensus that there are problems with coagulation and blood vessel injury in COVID-19 patients," Goldstein said. "Our finding support that there might be something clot-forming about coronavirus, and it's happening in the placenta."

The 16 women in the study delivered their babies at Northwestern Medicine Prentice Women's Hospital. All tested positive for COVID-19. Four patients came in with flu-like symptoms three to five weeks before delivery and tested positive for the virus. The remaining patients all tested positive when they came in to deliver. Five patients never developed symptoms, others were symptomatic at delivery.

Between 30 and 40 patients deliver at Prentice daily. The team began testing placentas of COVID-19-positive mothers in early April. Fourteen of the live-born infants in the study were born full term and with normal weights and Apgar scores. One live-born infant was premature.

"They were healthy, full-term, beautifully normal babies, but our findings indicate a lot of the blood flow was blocked off and many of the placentas were smaller than they should have been," Miller said. "Placentas get built with an enormous amount of redundancy. Even with only half of it working, babies are often completely fine. Still, while most babies will be fine, there's a risk that some pregnancies could be compromised."

In February, before the pandemic was known to have reached Chicago, Goldstein assembled his research team.

"If you get the flu and you're pregnant, we know nothing about what that looks like in your placenta, so I began thinking how we'd study this flu-like epidemic if it came through Chicago," Goldstein said. "We started setting things up and then lo and behold, the epidemic came here, so we were ready."

Pinnacle Point, a series of archaeological sites that overlook a now submerged section of South Africa's coastline and one of the world's most important localities for the study of modern human origins, was as much of an Eden for animals as it was for early humans. Jamie Hodgkins, PhD, assistant professor of anthropology at University of Colorado Denver, and her team drilled ancient herbivore teeth to find that many local animals stayed put in the ecologically rich ecosystem, which may explain why humans flourished there, too.

Their study was published in a Quaternary Science Reviews special issue: The Palaeo-Agulhas Plain: a lost world and extinct ecosystem this month.

Home to the Earliest Modern Humans

Home to some of the richest evidence for the behavior and culture of the earliest clearly modern humans, the submerged shelf called the Palaeo-Agulhas Plain (PAP) once formed its own ecosystem. Co-author Curtis Marean, PhD, Arizona State University, has worked with teams of scientists for decades to reconstruct the locale back into the Pleistocene, the time period that spanned from 2.6 million to 11,700 years ago.

In this study, the researchers looked specifically at antelope migratory patterns at Pinnacle Point. This series of cave sites that sit on the modern South African coast offers archaeological materials from humans who were living and hunting there back to 170,000 years ago.

"During glacial cycles, the coastal shelf was exposed," said Hodgkins. "There would have been a huge amount of land in front of the cave sites. We thought it was likely that humans and carnivores were hunting animals as they migrated east and west over the exposed shelve."

A Lack of Migratory Pattern

Hodgkins and her team wanted to understand those migratory patterns. They studied the carbon and oxygen isotopes within the tooth enamel of many large herbivores, including Redunca, or reedbuck, a nonmigratory antelope. Tooth enamel can reveal a pattern of migration by tracking changing levels of carbon from the plants an animal eats as its teeth grow.

In general, wetter, cooler environments are home to C3 plants; hotter, drier environments are home to C4 plants. Animals like lush vegetation, which means they tend to follow the rain patterns: in this case east for summer rain (C4 grasses), and west for winter rain (C3 grasses). If animals were migrating between summer and winter rainfall zones, their tooth enamel would register that annual C3 and C4 plant rotation as a sinusoidal curve as their teeth grew.

A) Map of South Africa (SA) showing the distribution of C4 grasses associated with the percentage of summer rain from east to west along the coast, and with the winter rainfall zone in the west (modified from Vogel, 1978); B) A map of SA showing the area of the Greater Cape Floristic Region with the expanded PAP and hypothesized animals migration (i.e. It is hypothesized that animals would have been undertaking long-distance migrations between the east coast in summer rainfall zone and west coast in the winter rainfall zone)

But when Hodgkins and her team used the nonmigratory reedbuck as their control animal, they found that the enamel from its typically migratory pals--like the wildebeest, hartebeest, and springbok--showed no discernible migratory pattern. Most animals seemed happy right where they were.

"They weren't struggling at Pinnacle Point," says Hodgkins. "We now know that powerful river systems supplied the expanded coast, thus animals didn't have to be migratory. It was a great location, resource-wise. During interglacials when the coast moved closer to the caves humans had shellfish and other marine resources, and when the coast expanded in glacial times hunters had access to a rich, terrestrial environment. Hunters wouldn't need to be as mobile with all of these herbivores wandering around."

Thriving in an Ecogeological Haven

Hodgkins' team's findings of this prehistoric Eden echoed another recent discovery. Seventy-four-thousand years ago, one of Earth's largest known eruptions at Mount Toba in Sumatra, Indonesia, created a global winter, causing population crashes. In 2018, researchers from Marean's group found that humans at Pinnacle Point not only survived, but thrived in the haven.

Hodgkins says this is just a first attempt at using isotopic data to test the hypothesis of east and west migration patterns at these sites and further research will be done.

"It is quite possible that animal migration patterns changed as the coastline moved in and out during glacial and interglacial cycles," said Hodgkins.

The paper "Hydroxychloroquine or Chloroquine with or without a Macrolide and Outcome in COVID-19: A Multinational Registry Analysis" referenced in this release has been retracted by The Lancet. Please see the retaction letter below.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31324-6/fulltext

"After publication of our Lancet Article,1 several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication. We launched an independent third-party peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.

Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements. As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.

We always aspire to perform our research in accordance with the highest ethical and professional guidelines. We can never forget the responsibility we have as researchers to scrupulously ensure that we rely on data sources that adhere to our high standards. Based on this development, we can no longer vouch for the veracity of the primary data sources. Due to this unfortunate development, the authors request that the paper be retracted.

We all entered this collaboration to contribute in good faith and at a time of great need during the COVID-19 pandemic. We deeply apologise to you, the editors, and the journal readership for any embarrassment or inconvenience that this may have caused."

Boston, MA -- A research team led by investigators from Brigham and Women's Hospital has evaluated real-world evidence related to outcomes for COVID-19 patients who were treated with hydroxychloroquine or chloroquine analogues (with or without a macrolide). Investigators found no evidence that either drug regimen reduced the death rate among patients. Patients treated with hydroxychloroquine or chloroquine regimens were far more likely to experience abnormal, rapid heart rhythms (known as ventricular arrhythmias) than their counterparts who had not received the drugs. The team's findings are published in The Lancet.

"No matter which way you examine the data, use of these drug regimens did not help," said corresponding author Mandeep R. Mehra, MD, executive director of the Brigham's Center for Advanced Heart Disease. "If anything, patients had a higher likelihood of death. We also saw a quadrupling in the rate of significant ventricular arrhythmias in patients with COVID-19 who had been treated with hydroxychloroquine or chloroquine regimens."

Mehra and colleagues conducted their study using the Surgical Outcomes Collaborative database, an international registry comprised of de-identified data from 671 hospitals across six continents. The analysis included data on more than 96,000 patients hospitalized with COVID-19. This included almost 15,000 patients who had received the anti-malarial drug chloroquine or its analog hydroxyquinone with or without an antibiotic (macrolides such as azithromycin and clarithromycin) early after COVID-19 diagnosis. The study's primary endpoint was death or discharge from the hospital.

Mehra and colleagues found that 10,698 patients died in the hospital (11.1 percent) and 85,334 survived to discharge. The team compared death rates for those taking one of the drug regimens to that of a control group, after accounting for confounding variables, such as age, sex and underlying risk factors. The death rate among the control group was 9.3 percent. Each of the drug regimens of chloroquine or hydroxychloroquine alone, or in combination with a macrolide, was associated with an increased risk of in-hospital death with COVID-19.

In addition, each of the drug regimens was associated with an increase in the risk of ventricular arrhythmia. Among the treatment groups, between 4 and 8 percent of patients experienced a new ventricular arrhythmia, compared to 0.3 percent of patients in the control group.

Chloroquine and hydroxychloroquine have been known to cause cardiovascular toxicity and previous studies have shown that macrolides can increase the risk of sudden cardiac death. A preliminary analysis of patients in Brazil treated with chloroquine and an antibiotic has suggested a high dose of chloroquine may be a safety hazard. Results from randomized, controlled clinical trials are not expected until the summer.

The authors caution that the current study is observational in nature -- this means that it cannot absolutely answer the question of whether the drug regimens were solely responsible for the changes in survival. Randomized clinical trials will be required before any conclusion can be reached regarding harm.

"These findings suggest that these drug regimens should not be used outside of the realm of clinical trials and urgent confirmation from randomized clinical trials is needed," the authors conclude.

The development and maintenance of the Surgical Outcomes Collaborative database was funded by the Surgisphere Corporation. The present analysis was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women's Hospital, Boston. Mehra reports no direct conflicts pertinent to the development of this paper. Other general conflicts include consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus, Roivant and Triple Gene. Dr. Desai is the founder of Surgisphere Corporation, Chicago. The other authors have no pertinent conflicts to report.