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Effective therapies to treat coronavirus disease 2019 (COVID-19) are urgently needed. While many investigational, approved, and repurposed drugs have been suggested as potential treatments, preclinical data from animal models can guide the search for effective treatments by ruling out those that lack efficacy in vivo. Remdesivir (GS-5734) is a nucleotide analogue prodrug with broad antiviral activity 1 , 2 that is currently being investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration 3 , 4 . In animal models, remdesivir was effective against infection with Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) 2 , 5 , 6 . In vitro, remdesivir inhibited replication of SARS-CoV-2 7 , 8 . Here we investigate the efficacy of remdesivir in a rhesus macaque model of SARS-CoV-2 infection 9 . Unlike vehicle-treated animals, macaques treated with remdesivir did not show signs of respiratory disease; they also showed reduced pulmonary infiltrates on radiographs and reduced virus titres in bronchoalveolar lavages twelve hours after the first dose. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, remdesivir-treated animals had lower lung viral loads and reduced lung damage. Thus, treatment with remdesivir initiated early during infection had a clinical benefit in rhesus macaques infected with SARS-CoV-2. Although the rhesus macaque model does not represent the severe disease observed in some patients with COVID-19, our data support the early initiation of remdesivir treatment in patients with COVID-19 to prevent progression to pneumonia. The nucleotide analogue prodrug remdesivir reduces viral load and lung disease in a rhesus macaque model of SARS-CoV-2 infection.

Heavy metals, common environmental pollutants with widespread distribution hazards and several health problems linked to them are distinguished from other toxic compounds by their bioaccumulation in living organisms. They pollute the food chain and threaten the health of animals. Biologically, heavy metals exhibit both beneficial and harmful effects. Certain essential heavy metals such as Co, Mn, Se, Zn, and Mg play crucial roles in vital physiological processes in trace amounts, while others like As, Pb, Hg, Cd, and Cu are widely recognized for their toxic properties. Regardless of their physiological functions, an excess intake of all heavy metals beyond the tolerance limit can lead to toxicity. Animals face exposure to heavy metals through contaminated feed and water, primarily as a result of anthropogenic environmental pollution. After ingestion heavy metals persist in the body for an extended duration and the nature of exposure dictates whether they induce acute or chronic, clinical or subclinical, or subtle toxicities. The toxic effects of metals lead to disruption of cellular homeostasis through the generation of free radicals that develop oxidative stress. In cases of acute heavy metal poisoning, characteristic clinical symptoms may arise, potentially culminating in the death of animals with corresponding necropsy findings. Chronic toxicities manifest as a decline in overall body condition scoring and a decrease in the production potential of animals. Elevated heavy metal levels in consumable animal products raise public health concerns. Timely diagnosis, targeted antidotes, and management strategies can significantly mitigate heavy metal impact on livestock health, productivity, and reproductive performance.

The image contrast of postmortem magnetic resonance imaging (MRI) may differ from that of antemortem MRI because of circulator arrest, changes in postmortem tissue, and low-body-temperature scanning conditions. In fact, we have found that the signal intensity of white matter (WM) on T1-weighted spin-echo (T1WSE) images of the postmortem brain was lower than that of gray matter (GM), which resulted in image contrast reversal between GM and WM relative to the living brain. However, the reason for this phenomenon is unclear. Therefore, the aim of this study is to clarify the reason why image contrast reversal occurs between GM and WM of the postmortem brain. Twenty-three corpses were included in the study (mean age, 60.6 years; range: 19–60 years; mean rectal temperature at scan, 6.9℃; range: 4–11℃). On a 1.5 T MRI system, postmortem T1W-SE MRI of the brain was conducted in the 23 corpses prior to medico-legal autopsy. Next, T1 and T2 of the GM and WM at the level of the basal ganglia were determined in the same participants using inversion recovery and multiple SE sequences, respectively. The proton density (PD) was also calculated from the T1 and T2 images (in the same slice). T1W-SE image contrast between the GM and WM of all postmortem brains was inverted relative to the living brain. T1 (579 ms in GM and 307 ms in WM) and PD (64 in GM and 44 in WM) of the postmortem brain decreased compared with the living brain. While T1 of WM/GM remained below 1 even postmortem, the PD of WM/GM decreased. T2 (110 ms in GM and 98 ms in WM) of the postmortem brain did not differ from the living brain. The decrease in PD of WM/GM in the postmortem brain may be the major driver of contrast reversal between the GM and WM relative to the living brain. •WM/GM is preserved in postmortem brain T1W-SE images.•Postmortem brain T1 and PD are decreased.•Rates of postmortem water reduction differ between WM and GM.•Lower PD of postmortem brain WM drives contrast inversion between the GM and WM.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is considered a zoonotic pathogen mainly transmitted human to human. Few reports indicate that pets may be exposed to the virus. The present report describes a cat suffering from severe respiratory distress and thrombocytopenia living with a family with several members affected by COVID-19. Clinical signs of the cat prompted humanitarian euthanasia and a detailed postmortem investigation to assess whether a COVID-19–like disease was causing the condition. Necropsy results showed the animal suffered from feline hypertrophic cardiomyopathy and severe pulmonary edema and thrombosis. SARS-CoV-2 RNA was only detected in nasal swab, nasal turbinates, and mesenteric lymph node, but no evidence of histopathological lesions compatible with a viral infection were detected. The cat seroconverted against SARS-CoV-2, further evidencing a productive infection in this animal. We conclude that the animal had a subclinical SARS-CoV-2 infection concomitant to an unrelated cardiomyopathy that led to euthanasia.

Complete vaccine-mediated immune control of highly pathogenic Mycobacterium tuberculosis is possible if immune effector responses can intercept the infection at its earliest stages. Despite widespread use of the bacille Calmette–Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent ( Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)—which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4 + and CD8 + memory T cell responses—can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at ∼1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.

Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. Updated total numbers of deaths in children aged 0–27 days and 1–59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1–59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916–1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610–0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252–0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977–1·176), diarrhoea (9·9%; 0·751 million, 0·538–1·031), and malaria (7·4%; 0·564 million, 0·432–0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339–0·547], 0·363 million [0·283–0·419], and 0·359 million [0·215–0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010–15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. The Bill & Melinda Gates Foundation.

Veterinary Necropsy of Dogs and Cats is a practical, case-based guide to lesion interpretation which includes guidance for performing a necropsy and tissue sampling. It takes a body systems approach to cover the cardiovascular system, respiratory system, digestion system, etc., chapter by chapter, each including a clinical history and illustrated pathological findings.Each chapter contains several cases and a self-assessment review, with model answers at core level. Throughout are tips on sample collection, lesion recognition and interpretation, common artefacts and pitfalls, and advice from experienced practitioners on building confidence and competence with general procedures, as well as suggested approaches for dealing with more complicated or difficult cases.Veterinary Necropsy of Dogs and Cats is a useful resource for undergraduates, qualified vets and trainee pathologists, as it provides self-assessment review at different levels, and maps the cases to RCVS Day One competencies. The approach is very practical and accessible, with advice and commentary from the authors, based on their experience.

Extracellular vesicles (EVs) are under evaluation as therapeutics or as vehicles for drug delivery. Preclinical studies of EVs often use mice or other animal models to assess efficacy and disposition. However, as most EVs under evaluation are derived from human cells, they may elicit immune responses which may contribute to toxicities or enhanced EV clearance. Furthermore, EVs from different cell sources or EVs comprising various cargo may differ with respect to immunogenicity or toxicity. To assess EV-induced immune response and toxicity, we dosed C57BL/6 mice with EVs intravenously and intraperitoneally for 3 weeks. EVs were harvested from wild type or engineered HEK293T cells which were modified to produce EVs loaded with miR-199a-3p and chimeric proteins. Blood was collected to assess hematology, blood chemistry, and immune markers. Spleen cells were immunophenotyped, and tissues were harvested for gross necropsy and histopathological examination. No signs of toxicity were observed, and minimal evidence of changes in immune markers were noted in mice dosed with engineered, but not with wild type EVs. This study provides a framework for assessment of immunogenicity and toxicity that will be required as EVs from varying cell sources are tested within numerous animal models and eventually in humans.

Museum specimens play an increasingly important role in predicting the outcomes and revealing the consequences of anthropogenically driven disruption of the biosphere. As ecological communities respond to ongoing environmental change, host–parasite interactions are also altered. This shifting landscape of host–parasite associations creates opportunities for colonization of different hosts and emergence of new pathogens, with implications for wildlife conservation and management, public health, and other societal concerns. Integrated archives that document and preserve mammal specimens along with their communities of associated parasites and ancillary data provide a powerful resource for investigating, anticipating, and mitigating the epidemiological, ecological, and evolutionary impacts of environmental perturbation. Mammalogists who collect and archive mammal specimens have a unique opportunity to expand the scope and impact of their field work by collecting the parasites that are associated with their study organisms. We encourage mammalogists to embrace an integrated and holistic sampling paradigm and advocate for this to become standard practice for museum-based collecting. To this end, we provide a detailed, field-tested protocol to give mammalogists the tools to collect and preserve host and parasite materials that are of high quality and suitable for a range of potential downstream analyses (e.g., genetic, morphological). Finally, we also encourage increased global cooperation across taxonomic disciplines to build an integrated series of baselines and snapshots of the changing biosphere.

Parkinson’s disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson’s disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson’s disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson’s disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson’s disease.