NETosis in Parasitic Infections: A Puzzle That Remains Unsolved.

Neutrophils are the key players in the innate immune system, being weaponized with numerous strategies to eliminate pathogens. The production of extracellular traps is one of the effector mechanisms operated by neutrophils in a process called NETosis. Neutrophil extracellular traps (NETs) are complex webs of extracellular DNA studded with histones and cytoplasmic granular proteins. Since their first description in 2004, NETs have been widely investigated in different infectious processes. Bacteria, viruses, and fungi have been shown to induce the generation of NETs. Knowledge is only beginning to emerge about the participation of DNA webs in the host's battle against parasitic infections. Referring to helminthic infections, we ought to look beyond the scope of confining the roles of NETs solely to parasitic ensnarement or immobilization. Hence, this review provides detailed insights into the less-explored activities of NETs against invading helminths. In addition, most of the studies that have addressed the implications of NETs in protozoan infections have chiefly focused on their protective side, either through trapping or killing. Challenging this belief, we propose several limitations regarding protozoan-NETs interaction. One of many is the duality in the functional responses of NETs, in which both the positive and pathological aspects seem to be closely intertwined.

The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused by Plasmodium falciparum and Trypanosoma brucei.

The triamine spermidine is a key metabolite of the polyamine pathway. It plays a crucial role in many infectious diseases caused by viral or parasitic infections. Spermidine and its metabolizing enzymes, i.e., spermidine/spermine-N1-acetyltransferase, spermine oxidase, acetyl polyamine oxidase, and deoxyhypusine synthase, fulfill common functions during infection in parasitic protozoa and viruses which are obligate, intracellular parasites. The competition for this important polyamine between the infected host cell and the pathogen determines the severity of infection in disabling human parasites and pathogenic viruses. Here, we review the impact of spermidine and its metabolites in disease development of the most important, pathogenic human viruses such as SARS-CoV-2, HIV, Ebola, and in the human parasites Plasmodium and Trypanosomes. Moreover, state-of-the-art translational approaches to manipulate spermidine metabolism in the host and the pathogen are discussed to accelerate drug development against these threatful, infectious human diseases.

Eastern Mediterranean Health Journal [2023; Vol.29, Issue 2]

Eastern Mediterranean Health Journal is the official health journal published by the Eastern Mediterranean Regional Office of the World Health Organization. It is a forum for the presentation and promotion of new policies and initiatives in health services; and for the exchange of ideas concepts epidemiological data research findings and other information with special reference to the Eastern Mediterranean Region. It addresses all members of the health profession medical and other health educational institutes interested NGOs WHO Collaborating Centres and individuals within and outside the Region

المجلة الصحية لشرق المتوسط هى المجلة الرسمية التى تصدرعن المكتب الاقليمى لشرق المتوسط بمنظمة الصحة العالمية. وهى منبر لتقديم السياسات والمبادرات الجديدة فى الصحة العامة والخدمات الصحية والترويج لها، و لتبادل الاراء و المفاهيم والمعطيات الوبائية ونتائج الابحاث وغير ذلك من المعلومات، و خاصة ما يتعلق منها باقليم شرق المتوسط. وهى موجهة الى كل اعضاء المهن الصحية، والكليات الطبية وسائر المعاهد التعليمية، و كذا المنظمات غير الحكومية المعنية، والمراكز المتعاونة مع منظمة الصحة العالمية والافراد المهتمين بالصحة فى الاقليم و خارجه

La Revue de Santé de la Méditerranée Orientale est une revue de santé officielle publiée par le Bureau régional de l’Organisation mondiale de la Santé pour la Méditerranée orientale. Elle offre une tribune pour la présentation et la promotion de nouvelles politiques et initiatives dans le domaine de la santé publique et des services de santé ainsi qu’à l’échange d’idées de concepts de données épidémiologiques de résultats de recherches et d’autres informations se rapportant plus particulièrement à la Région de la Méditerranée orientale. Elle s’adresse à tous les professionnels de la santé aux membres des instituts médicaux et autres instituts de formation médico-sanitaire aux ONG Centres collaborateurs de l’OMS et personnes concernés au sein et hors de la Région

Maternal Characteristics and Pregnancy Outcomes During The Pandemic Covid-19 in Indonesian Tertiary Referral Hospital (preprint)

Aim: Analyse differences in intervention and pregnancy outcomes characteristics in obstetric patients with a diagnosis of COVID-19 and non-COVID-19 at one of the Indonesia tertiary referral hospital in East Java. Design: This was cross sectional study. Methods: This study was performed 694 obstetric patients, the data for these patients were obtained from the hospital medical records Sampling was used simple random. This study used Mann-Whitney test to analyse the differences between the variables. Results: There was a significant difference in the Length Of Stay (LOS), LOS of COVID-19 patients tends to be longer than that of non-COVID-19 patients. More than half of the patients gave birth by caesarean delivery, 83 for COVID-19 and 283 for Non COVID-19. Some of the most common complications among COVID-19 patients were maternal infectious and parasitic diseases (1.3% vs 0.0%), abnormalities of forces of labour (12.3% vs 9.6%), complication of puerperium (0.6 % vs 0.0%). 40.9% COVID-19 patient suffered Acute Respiratory Distress Syndrome (ARDS). COVID-19 infection had no significant effect on pregnancy outcomes. Conclusion: Several interventions need to be re-evaluated, such as cesarean delivery in COVID-19 and non-COVID-19 patients. The health-care delivery system must also be re-evaluated, and the tiered referral system must be strengthened.

The mRNA Vaccine Technology Era and the Future Control of Parasitic Infections.

Despite intensive long-term efforts, with very few exceptions, the development of effective vaccines against parasitic infections has presented considerable challenges, given the complexity of parasite life cycles, the interplay between parasites and their hosts, and their capacity to escape the host immune system and to regulate host immune responses. For many parasitic diseases, conventional vaccine platforms have generally proven ill suited, considering the complex manufacturing processes involved and the costs they incur, the inability to posttranslationally modify cloned target antigens, and the absence of long-lasting protective immunity induced by these antigens. An effective antiparasite vaccine platform is required to assess the effectiveness of novel vaccine candidates at high throughput. By exploiting the approach that has recently been used successfully to produce highly protective COVID mRNA vaccines, we anticipate a new wave of research to advance the use of mRNA vaccines to prevent parasitic infections in the near future. This article considers the characteristics that are required to develop a potent antiparasite vaccine and provides a conceptual foundation to promote the development of parasite mRNA-based vaccines. We review the recent advances and challenges encountered in developing antiparasite vaccines and evaluate the potential of developing mRNA vaccines against parasites, including those causing diseases such as malaria and schistosomiasis, against which vaccines are currently suboptimal or not yet available.

Coinfection with Strongyloides and SARS-CoV-2: protocol for a systematic review (preprint)

Rationale for the review: COVID-19 treatment can worsen parasitic disease in patients with coinfection. Consequently, there is a need to investigate the infection with SARS CoV 2 and Strongyloides. We aim to systematically review clinical and laboratory features of COVID 19 and Strongyloides coinfection, to investigate possible interventions and outcomes in this pathology. Also, we aim to identify difficulties in managing the parasitic disease manifestations in this context and to emphasize research gaps requiring further attention. Methods: We will search two electronic databases (LitCOVID, and WHO COVID 19) and will include studies on SARS CoV 2 and Strongyloides coinfection. We will adapt the WHO UMC system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID 19 patients determined acute strongyloidiasis manifestations. Expected results: We will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.

Costs and benefits of maternal nest choice: tradeoffs between brood survival and thermal stress for small carpenter bees (preprint)

Nest site selection is a crucial decision for bees because where mothers construct their nests influences the developmental environment of their offspring. Small carpenter bees ( Ceratina calcarata ) nest in sun or shade, suggesting that maternal decisions about nest sites are influenced by thermal conditions that influence juvenile growth and survival. We investigated the costs and benefits to mothers and their offspring of warmer or cooler nest sites using a field experiment in which mothers and newly founded nests were placed in sunny or shady habitats. Maternal costs and benefits in sunny and shady treatments were quantified by comparing brood provisioning behaviour, nest size, number of brood cells, and offspring survival rates. Juvenile costs and benefits were quantified as body size, high temperature tolerance (CT max ), metabolic rate, and pupal duration. The major maternal benefit of nesting in sun was significantly lower rates of total nest failure (caused by predation, parasitism or abandonment), which led to sun mothers producing 3.2 brood on average, while shade mothers produced only 2.9. However, sun nesting entailed costs to brood, which were significantly smaller, less likely to survive to adulthood and had significantly elevated CT max . This suggests that juvenile bees in sun nests bees experienced thermal stress during development, causing them to shunt resources from growth to thermoprotection, at the cost of smaller size and higher mortality. Pupae raised in a thermal-gradient “BeeCR” machine developed significantly faster at warmer average temperatures, which may be an additional benefit of sun nesting. Overall, our results highlight a tradeoff between maternal benefits and offspring costs when mothers choose nest sites, in which maternal fitness is enhanced by nesting in sun, despite significant physiological costs to offspring, due to the necessity for thermoprotective responses. Thinking through pandemic research The first lockdowns of the COVID-19 pandemic began as we prepared to enter the second field season of this study in 2020. Student research halted overnight. Lab access and travel were restricted. With limited access to field sites and no access to lab equipment, we brainstormed alternative approaches that would repeat, if not replicate, our main experiments of 2019 and fulfill degree requirements for JL de Haan’s MSc in a satisfying way. Our 2019 results had provided convincing evidence developmental temperature has long-term impacts on C. calcarata physiology, so we thought about which physiological measurements would be feasible outside the lab. Authors MH Richards and GJ Tattersall suggested collecting more measurements of CT max the Peltier plate device required running water, but a portable water pump and a bucket allowed the apparatus to be set up anywhere. No calibration of instruments was required, and the only maintenance was to change the water in the bucket after a few hours of use. Thus, a student’s home basement became a laboratory. To investigate how temperatures affect developmental rate, we needed to raise bees in controlled environments, but incubators were not available. Author A Skandalis suggested repurposing a gradient PCR unit as a portable insect incubator (“The BeeCR”). The idea was tested successfully at home in 20202, so a larger study was done by J Maretzki in 2021 when undergraduate lab access was permitted again. Two outcomes of our pandemic pivot produced long-term benefits for our research. The BeeCR is a flexible, inexpensive, easy-to-use incubator perfectly suited for raising small insects at multiple simultaneous sets of variable temperatures. And the ease with which “field” sites could be established in our backyards demonstrates how amenable small carpenter bees are to field manipulations, suggesting this is a model species for addressing a variety of ecological and physiological questions.

How does academia respond to the burden of infectious and parasitic disease?

BACKGROUND: Academic research is one of the main avenues through which humans can fight the threat of infectious diseases. However, there have been concerns regarding whether the academic system has provided sufficient efforts to fight infectious diseases we potentially face. Answering these questions could contribute to evidence-based recommendations for setting research priorities and third-mission policies. METHODS: With a focus on one of the most common categories of communicable diseases, infectious and parasitic diseases (IPDs), we searched Web of Science for articles and reviews relevant to IPDs published during the period 2000-2019 and retrieved WHO data on disease burden in corresponding years. The academic response patterns were explored by IPD subcategory and by human development level (an index established by the United Nations). We conduct the analysis in particular to gain insight into the dynamic relationship between disease burden and research effort on IPDs, scientific efforts contributed by countries with different development levels, and the variation trends in international joint efforts. RESULTS: The greatest burden of IPDs is clustered in the developing regions of Africa, but has received academic response from both developed and developing countries. Highly developed countries dominate the ranks of academic research in this area, yet there is also a clear increase in research efforts from the countries most affected, despite their low human development scale. In fact, the overall analysis reveals an improved capability for addressing local problems from African regions. In terms of international collaboration, highly developed countries such as the United States and United Kingdom have commonly collaborated with needy regions, whereas prolific but developing nations, like China, have not. CONCLUSIONS: From a global perspective, academia has positively responded to health needs caused by IPDs. Although the relevant research output contribution is primarily from the highly developed countries, concentrated and specialized efforts from the undeveloped regions to ease their local burden can be clearly observed. Our findings also indicate a tendency to focus more on local health needs for both developed and undeveloped regions. The insights revealed in this study should benefit a more informed and systemic plan of research priorities.

Transfer of parasitology research to patents worldwide.

Mankind has known about different parasitic diseases since ancient times. There is no doubt that parasites are the infectious agents that have caused the most deaths throughout history. But even today, parasitic diseases affect more than one billion people worldwide. In this paper, the relationship between articles published in the area of parasitology and international patents in this field from 1996 to 2019 was analyzed. For this purpose, Scopus has been used. This is a database developed by Elsevier, which, in addition to having numerous indexed journals and books, has developed SciVal, an analysis tool with which the publications that have been cited in the patents of the 5 largest patent offices in the world have been analyzed. The analysis has allowed us to study 2814 publications, to know their time trend, their Authors, Affiliations, and Countries, as well as the journals in which they have been published. Also, the topics and topic clusters related to parasitology that appear in publications cited in international patents have been known. Thus, the existence of six Topic Clusters that group 94% of all publications has been discovered. Of all of them, the Topic Cluster referring to malaria stands out above all others, with 968 articles (34% of the total), probably due to the fact that malaria continues to be, to this day, one of the great challenges for both industry and basic research throughout the world.

Covalent Reversible Inhibitors of Cysteine Proteases Containing the Nitrile Warhead: Recent Advancement in the Field of Viral and Parasitic Diseases.

In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue.

How to choose the best control strategy? Mathematical models as a tool for pre-intervention evaluation on a macroparasitic disease.

During the last century, emerging diseases have increased in number, posing a severe threat for human health. Zoonoses, in particular, represent the 60% of emerging diseases, and are a big challenge for public health due to the complexity of their dynamics. Mathematical models, by allowing an a priori analysis of dynamic systems and the simulation of different scenarios at once, may represent an efficient tool for the determination of factors and phenomena involved in zoonotic infection cycles, but are often underexploited in public health. In this context, we developed a deterministic mathematical model to compare the efficacy of different intervention strategies aimed at reducing environmental contamination by macroparasites, using raccoons (Procyon lotor) and their zoonotic parasite Bayilsascaris procyonis as a model system. The three intervention strategies simulated are raccoon depopulation, anthelmintic treatment of raccoons and faeces removal. Our results show that all these strategies are able to eliminate the parasite egg population from the environment, but they are effective only above specific threshold coverages. Host removal and anthelmintic treatment showed the fastest results in eliminating the egg population, but anthelmintic treatment requires a higher effort to reach an effective result compared to host removal. Our simulations show that mathematical models can help to shed light on the dynamics of communicable infectious diseases, and give specific guidelines to contain B. procyonis environmental contamination in native, as well as in new, areas of parasite emergence. In particular, the present study highlights that identifying in advance the appropriate treatment coverage is fundamental to achieve the desired results, allowing for the implementation of cost- and time-effective intervention strategies.

The Current Directions of Searching for Antiparasitic Drugs.

Parasitic diseases are still a huge problem for mankind. They are becoming the main cause of chronic diseases in the world. Migration of the population, pollution of the natural environment, and climate changes cause the rapid spread of diseases. Additionally, a growing resistance of parasites to drugs is observed. Many research groups are looking for effective antiparasitic drugs with low side effects. In this work, we present the current trends in the search for antiparasitic drugs. We report known drugs used in other disease entities with proven antiparasitic activity and research on new chemical structures that may be potential drugs in parasitic diseases. The described investigations of antiparasitic compounds can be helpful for further drug development.

Potential of the CRISPR-Cas system for improved parasite diagnosis: CRISPR-Cas mediated diagnosis in parasitic infections: CRISPR-Cas mediated diagnosis in parasitic infections.

CRISPR-Cas technology accelerates development of fast, accurate, and portable diagnostic tools, typified by recent applications in COVID-19 diagnosis. Parasitic helminths cause devastating diseases afflicting 1.5 billion people globally, representing a significant public health and economic burden, especially in developing countries. Currently available diagnostic tests for worm infection are neither sufficiently sensitive nor field-friendly for use in low-endemic or resource-poor settings, leading to underestimation of true prevalence rates. Mass drug administration programs are unsustainable long-term, and diagnostic tools - required to be rapid, specific, sensitive, cost-effective, and user-friendly without specialized equipment and expertise - are urgently needed for rapid mapping of helminthic diseases and monitoring control programs. We describe the key features of the CRISPR-Cas12/13 system and emphasise its potential for the development of effective tools for the diagnosis of parasitic and other neglected tropical diseases (NTDs), a key recommendation of the NTDs 2021-2030 roadmap released by the World Health Organization.

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases.

Human Leukocyte Antigen-G (HLA-G), a polymorphic non-classical HLA (HLA-Ib) with immune-regulatory properties in cancers and infectious diseases, presents both membrane-bound and soluble (sHLA-G) isoforms. Polymorphism has implications in host responses to pathogen infections and in pathogenesis. Differential expression patterns of HLA-G/sHLA-G or its polymorphism seem to be related to different pathological conditions, potentially acting as a disease progression biomarker. Pathogen antigens might be involved in the regulation of both membrane-bound and sHLA-G levels and impact immune responses during co-infections. The upregulation of HLA-G in viral and bacterial infections induce tolerance to infection. Recently, sHLA-G was found useful to identify the prognosis of Coronavirus disease 2019 (COVID-19) among patients and it was observed that the high levels of sHLA-G are associated with worse prognosis. The use of pathogens, such as Plasmodium falciparum, as immune modulators for other infections could be extended for the modulation of membrane-bound HLA-G in COVID-19-infected tissues. Overall, such information might open new avenues concerning the effect of some pathogens such as parasites in decreasing the expression level of HLA-G to restrict pathogenesis in some infections or to influence the immune responses after vaccination among others.

Impact of the COVID-19 Duration on Neglected Parasitic Diseases

The Coronavirus disease-2019 (COVID-19) pandemic, which started in Wuhan, China in December 2019, has affected the whole world and caused approximately four million deaths. Consequently, scientists have done a great deal of research in such a short time about the disease. Meanwhile, parasites, whose evolutionary process is as old as human history, are often underestimated despite their high prevalence and lethality. Recent studies; however, have shown that immunity changes caused by parasitic infections affect the course of viral diseases. For example, because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and Plasmodium use a common CD147 receptor to enter the cell and have similarities in their MHC-presented antigenic determinants, scientists suggest that immunity against parasitic infections protects the body against SARS-CoV-2 infections. This could explain the low COVID-19 incidence in malaria-endemic countries. Additionally, the cytokine storm, which is responsible for mortality in COVID-19 infections, is caused by the activation of the immune system to Th1 way. On the other hand, helminth infections, which activate the immune system to Th2 way, can reduce mortality by preventing the cytokine storm. The relationship between COVID-19 and parasites is not limited to changes in the immune system changes. Studies have shown that the pause in the fight against parasitic infections due to the diversion of all attention toward COVID-19 since the beginning of the pandemic will lead to an increase in incidences of malaria, leishmaniasis, schistosomiasis, and soil-transmitted helminths. For this reason, efforts to mitigate this increase should be resumed as soon as possible by taking additional measures globally.

Specificity of SARS-CoV-2 Antibody Detection Assays against S and N Proteins among Pre-COVID-19 Sera from Patients with Protozoan and Helminth Parasitic Infections.

We aimed to assess the specificity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody detection assays among people with tissue-borne parasitic infections. We tested three SARS-CoV-2 antibody-detection assays (cPass SARS-CoV-2 neutralization antibody detection kit [cPass], Abbott SARS-CoV-2 IgG assay [Abbott Architect], and Standard Q COVID-19 IgM/IgG combo rapid diagnostic test [SD RDT IgM/SD RDT IgG]) among 559 pre-COVID-19 seropositive sera for several parasitic infections. The specificity of assays was 95 to 98% overall. However, lower specificity was observed among sera from patients with protozoan infections of the reticuloendothelial system, such as human African trypanosomiasis (Abbott Architect; 88% [95% CI, 75 to 95]) and visceral leishmaniasis (SD RDT IgG; 80% [95% CI, 30 to 99]), and from patients with recent malaria in areas of Senegal where malaria is holoendemic (ranging from 91% for Abbott Architect and SD RDT IgM to 98 to 99% for cPass and SD RDT IgG). For specimens from patients with evidence of past or present helminth infection overall, test specificity estimates were all ≥96%. Sera collected from patients clinically suspected of parasitic infections that tested negative for these infections yielded a specificity of 98 to 100%. The majority (>85%) of false-positive results were positive by only one assay. The specificity of SARS-CoV-2 serological assays among sera from patients with tissue-borne parasitic infections was below the threshold required for decisions about individual patient care. Specificity is markedly increased by the use of confirmatory testing with a second assay. Finally, the SD RDT IgG proved similarly specific to laboratory-based assays and provides an option in low-resource settings when detection of anti-SARS-CoV-2 IgG is indicated.

Haematological profile of COVID-19 patients from a centre in Singapore.

BACKGROUND: Haematological markers such as absolute lymphopenia have been associated with severe COVID-19 infection. However, in the literature to date, the cohorts described have typically included patients who were moderate to severely unwell with pneumonia and who required intensive care stay. It is uncertain if these markers apply to a population with less severe illness. We sought to describe the haematological profile of patients with mild disease with COVID-19 admitted to a single centre in Singapore. METHODS: We examined 554 consecutive PCR positive SARS-COV-2 patients admitted to a single tertiary healthcare institution from Feb 2020 to April 2020. In all patients a full blood count was obtained within 24 h of presentation. RESULTS: Patients with pneumonia had higher neutrophil percentages (66.5 ± 11.6 vs 55.2 ± 12.6%, p < 0.001), lower absolute lymphocyte count (1.5 ± 1.1 vs 1.9 ± 2.1 x109/L, p < 0.011) and absolute eosinophil count (0.2 ± 0.9 vs 0.7 ± 1.8 × 109/L, p = 0.002). Platelet counts (210 ± 56 vs 230 ± 61, p = 0.020) were slightly lower in the group with pneumonia. We did not demonstrate significant differences in the neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio in patients with or without pneumonia. Sixty-eight patients (12.3%) had peripheral eosinophilia. This was more common in migrant workers living in dormitories. CONCLUSION: Neutrophilia and lymphopenia were found to be markers associated with severe COVID-19 illness. We did not find that combined haematological parameters: neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio, had any association with disease severity in our cohort of patients with mild-moderate disease. Migrant workers living in dormitories had eosinophilia which may reflect concurrent chronic parasitic infection.

Leading Causes of Excess Mortality in Mexico During the COVID-19 Pandemic 2020 – February 2021: A Death Certificates Study in a Lower-Middle-Income Country (preprint)

Background: The death toll after SARS-CoV-2 emergence includes deaths directly or indirectly associated with COVID-19. For Mexico, a 28% excess mortality not directly related to the virus infection has been estimated. We aimed to analyze temporal and percentage changes in the distribution of the leading causes of mortality during the COVID-19 pandemic in Mexico.Methods: We did a retrospective longitudinal study of the leading causes of mortality and their variation with respect to expected deaths in Mexico from 2020 until 27 February 2021 using death certificates information. A Poisson regression model was fitted, to predict the expected, cause specific, mortality during the study period, based on the 2015-2019 registered mortality. Excess deaths were estimated as the weekly difference between expected and observed death. Findings: All-cause excess mortality was 46×5% (CI 95%: 45×2-47×8) over expected mortality. Deaths directly attributed to COVID-19 accounted for 69×6%. Leading causes of excess mortality were: Respiratory infections (59×5%), diabetes (48×0%), ischemic heart diseases (37×8%), hypertensive diseases (30×4%), motor vehicle road injuries (29×6%), and other endocrine, metabolic, hematological, and immunological diseases (28×2%). Causes that decreased with respect to expected mortality were: Other accidents (-29×1%), infectious and parasitic diseases (-23×4%), injuries of undetermined intent (-23×2%), other tumors (-22×5%), and skin diseases (-20×4%).Interpretation: Mortality from COVID-19 became the second cause of death in 2020, after cardiovascular diseases. Respiratory infections, diabetes and cardiovascular increased dramatically with respect to 2019, this could be a consequence of lack of access, but also certification errors.Funding Information: This study did not receive any funds.Declaration of Interests: We declare no competing interests.

Identifying Long-Term Effects of SARS-CoV-2 and Their Association with Social Determinants of Health in a Cohort of Over One Million COVID-19 Survivors (preprint)

Background: Despite an abundance of information on the risk factors of SARS-CoV-2, large scale studies of long-term effects are lacking. In this paper we analyzed a large medical claims database of US based individuals to identify common long-term effects as well as their associations with various social and medical risk factors. Methods: : The medical claims database was obtained from a prominent US based claims data processing company, namely Change Healthcare. In addition to the claims data, the dataset also consisted of various social determinants of health such as race, income, education level and veteran status of the individuals. A self-controlled cohort design (SCCD) observational study was performed to identify ICD-10 codes whose proportion was significantly increased in the outcome period compared to the control period to identify significant long-term effects. A logistic regression-based association analysis was then performed between identified long-term effects and social determinants of health. Results: : Among the over 1.37 million COVID patients in our datasets we found 36 out of 1,724 3-digit ICD-10 codes to be statistically significantly increased in the post-COVID period (p-value <0.05). We also found one combination of ICD-10 codes, corresponding to ‘other anemias’ and ‘hypertension’, that was statistically significantly increased in the post-COVID period (p-value <0.05). Our logistic regression-based association analysis with social determinants of health variables, after adjusting for comorbidities and prior conditions, showed that age and gender were significantly associated with the multiple long-term effects. Race was only associated with ‘other sepsis’, income was only associated with ‘Alopecia areata’, while education level was only associated with ‘Maternal infectious and parasitic diseases’ (p-value <0.05). Conclusion: We identified several long-term effects of SARS-CoV-2 through a self-controlled study on a cohort of over one million patients. Furthermore, we found that while age and gender are commonly associated with the long-term effects, other social determinants of health such as race, income and education levels have rare or no significant associations.