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Preprint ARTICLE | doi:10.20944/preprints202209.0253.v1

Type I interferon receptor subunit 1 deletion attenuates experimental abdominal aortic aneurysm formation

Takahiro Shoji, Jia Guo, Yingbin Ge, Yankui Li, Gang Li, Toru Ikezoe, Wei Wang, Xiaoya Zheng, Sihai Zhao, Naoki Fujimura, Jianhua Huang, Baohui Xu, Ronald L. Dalman

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Abdominal aortic aneurysm; Type I interferon receptor, Leukocytes; Angiogenesis

Online: 19 September 2022 (02:08:07 CEST)

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Preprint CASE REPORT | doi:10.20944/preprints202209.0161.v1

Daratumumab Interferes with Histocompatibility Crossmatch Impacting Immunological Assessment in Solid Organ Transplantation

Chak-Sum Ho, Kyle R. Putnam, Christine R. Peiter, Walter Herczyk, John A. Gerlach, Yee Lu, Erica L. Campagnaro, Kenneth J. Woodside, Matthew F. Cusick

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Antibody-mediated rejection; Crossmatch; Daratumumab; End-stage renal disease; Flow cytometry; HLA; Multiple myeloma; Transplantation

Online: 13 September 2022 (05:48:27 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202209.0137.v1

Machine Learning Classification of Specific Serologic Cytokines May Improve Detection of Recent, Fall Induced, Sub-Concussional Brain Changes in Geriatric Nondemented Subjects

Eduard Drima, Camelia Vrabie

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Chronic geriatric inflammation; machine learning C4.5 classification; brain ventricular volumes; recent fall; subconcussive brain trauma

Online: 9 September 2022 (13:05:28 CEST)

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Preprint REVIEW | doi:10.20944/preprints202209.0115.v1

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Joanne K Tobacman, Sumit Bhattacharyya

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: : N-acetylgalactosamine-4-sulfatase; Arylsulfatase B; chondroitin 4-sulfate; dermatan sulfate; sulfated glycosaminoglycans; mucopolysaccharidosis; cystic fibrosis; malignancy; proteoglycans; Warburg effect

Online: 8 September 2022 (03:07:30 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202209.0079.v1

Hepatitis C Core Protein Induces a Genotype-specific Susceptibility of Hepatocytes to TNF-induced Death in vitro and in vivo

Savvina Moustafa, Katerina Kassela, Maria Bampali, Nikolas Dovrolis, Athanassios Kakkanas, Apostolos Beloukas, Penelope Mavromara, Ioannis Karakasiliotis

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Hepatitis C virus; core protein; TNFα

Online: 6 September 2022 (03:38:14 CEST)

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Preprint CASE REPORT | doi:10.20944/preprints202209.0051.v1

A Case Report: Acute Myocardial Infarction, Coronal Arteritis and Myocarditis after BNT162b2 mRNA Vaccination against Covid-19

Michael Mörz

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: mRNA Vaccine; autopsy

Online: 5 September 2022 (08:14:56 CEST)

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Preprint CASE REPORT | doi:10.20944/preprints202206.0308.v2

A Case Report: Multifocal Necrotizing Encephalitis and Myocarditis after BNT162b2 mRNA Vaccination against Covid-19

Michael Mörz

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: mRNA Vaccine; autopsy

Online: 25 August 2022 (03:54:58 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202208.0378.v1

Frequency and Antibiotic Susceptibility Patterns of Streptococcus Agalactiae Strains Isolated from Women in Yaounde, Cameroon

Cécile Ingrid Djuikoue, Paule Dana Djouela Djoulako, Rodrigue Kamga Wouambo, Rosine Yemetio Foutsa, Dorine Ekeu, Teke Apalata

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Antibiotic resistance; Colonization; Prevalence; GBS; Resistance phenotype

Online: 22 August 2022 (08:04:16 CEST)

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Group B Streptococcus (GBS), a commensal in the body, causes a wide range of infectious diseases. The colonisation levels of GBS and its resistance profile to antibiotics provide important information useful for orienting prevention strategies. There is little data available on the subject with determination of resistance phenotypes in Cameroon. We therefore aimed to determine the prevalence of colonization, antibiotic resistance, including patterns of inducible resistance to clindamycin of GBS in Yaounde. To achieve this goal, a prospective cross-sectional study with an analytical component was carried out from the 28th June to the 29th August 2020 at the BIOSANTE laboratory and the Yaounde Gynaeco-Obstetrics and Paediatrics hospital. Vaginal swabs and urine were collected on 163 women. This samples were analysed using 5% defibrinated sheep blood agar and chocolate plus polyvitex agar. The isolates were identified using the morphology of the colony, Gram staining, haemolysis, catalase test and latex grouping test. Antibiotic susceptibility testing was done by disk diffusion method following the recommendations of the ACFSM 2019. The double disk diffusion method was used to identify isolates with clindamycin inducible resistance. Our data was analysed by the software SPSS version 2.1. The results obtained showed that the global prevalence of colonization by GBS was 37% (57/163), 40.35% in non-pregnant women and 59.65% in pregnant women. Pregnancy (P-value = 0.019) and gestational age (P-value = 0.025) constituted the risk factors of maternal colonization by GBS. In addition, the strains of GBS were resistant to all antibiotics tested. A D test showcased that 64.7% of GBS were resistant in a constitutive manner to clindamycin. We also note the presence of M phenotypes. As a whole, our results demonstrate that the rate of GBS colonization in this study was similar or higher than those in the previous report in Cameroon. All this indicates that attention should be paid to this bacterium in the monitoring of antimicrobial resistance and in the care of pregnant women and newborns.

Preprint ARTICLE | doi:10.20944/preprints202208.0244.v1

Post-injury Buprenorphine Administration Is Associated With Long-Term Region-Specific Glial Alterations in Rats

Jane Ryu, Pantea Jeizan, Saira Ahmed, Sareena Ehsan, Jefin Jose, Sean Regan, Karen Gorse, Corrina Kelliher, Audrey Lafrenaye

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Traumatic brain injury; buprenorphine; Bup-SR-Lab; microglia; astrocyte; myelin, membrane disruption; somatosensory sensitivity

Online: 12 August 2022 (13:52:14 CEST)

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Traumatic brain injury (TBI) is a major leading cause of death and disability. While previous studies regarding focal pathologies following TBI have been done, there is a lack of information concerning the role of analgesics and their influences on injury pathology. Buprenorphine (Bup), an opioid analgesic, is a commonly used analgesic in experimental TBI models. Our previous studies investigated the acute effects of Buprenorphine-sustained release-Lab (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. The current study investigated the longer-term chronic outcomes of Bup-SR-Lab treatment at 4 weeks following TBI utilizing a central fluid percussion injury (cFPI) model in adult male rats. Histological assessments of physiological changes, neuronal damage, cortical and thalamic cytokine expression, microglial and astrocyte morphological changes, and myelin alterations were done, as we had done in our acute study. In the current study the Whisker Nuisance Task (WNT) was also performed pre- and 4w post-injury to assess changes in somatosensory sensitivity following saline or Bup-SR-Lab treatment. Bup-SR-Lab treatment had no impact on overall physiology or neuronal damage at 4w post-injury regardless of region or injury, nor did it have any significant effects on somatosensory sensitivity. However, greater IL-4 cytokine expression with Bup-SR-Lab treatment was observed compared to saline treated animals. Microglia and astrocytes also demonstrated region-specific morphological alterations associated with Bup-SR-Lab treatment, in which cortical microglia and thalamic astrocytes were particularly vulnerable to Bup-mediated changes. There were discernable injury-specific and region-specific differences regarding myelin integrity and changes in specific myelin basic protein (MBP) isoform expression following Bup-SR-Lab treatment. This study indicates that use of Bup-SR-Lab could impact TBI-induced glial alterations in a region-specific manor 4w following diffuse brain injury.

Preprint REVIEW | doi:10.20944/preprints202207.0400.v1

Sergei Jargin

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: asbestos; chrysotile; mesothelioma; lung cancer

Online: 26 July 2022 (09:43:02 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202207.0380.v1

Molecular Mimicry between SARS-CoV-2 and Human Endocrinocytes: A Prerequisite of Post-COVID Endocrine Autoimmunity

Leonid P. Churilov, Muslimbek G. Normatov, Vladimir J. Utekhin

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; COVID-19; autoantibodies; autoimmune endocrinopathies; long-COVID syndrome; molecular mimicry; thyroid gland; adrenals; pituitary; Langerhans’ islets

Online: 26 July 2022 (03:42:01 CEST)

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Preprint REVIEW | doi:10.20944/preprints202204.0078.v2

Big Data in Laboratory Medicine – FAIR Quality for AI?

Tobias Ueli Blatter, Harald Witte, Christos Theodoros Nakas, Alexander Benedikt Leichtle

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: digitalization; clinical chemistry; artificial intelligence; interoperability; FAIRification

Online: 15 July 2022 (05:00:44 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202207.0149.v1

Molecular and Source-Specific Profiling of Hospital Staphylococcus Aureus Reveal Dominance of Skin Infection and Age-Specific Selections in Pediatrics and Geriatrics

Kamaleldin B. Said, Naif Saad Alghasab, Mohed Saleem Elias

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: clinical S.aureus; skin carriage; geriatric-MRSA pneumonia; endogenous-S.aureus

Online: 11 July 2022 (04:33:22 CEST)

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The changing epidemiology of Staphylococcus aureus has created several gaps in its population structure and emergence of strains. Two global shifts in the aftermath of the past methicil-lin-resistant S. aureus (MRSA) pandemic are: a rise in healthcare-associated infections and evolu-tion of cutaneous and soft tissue infections with high morbidities and mortalities. Furthermore, bitter lessons from COVID-19 showed S. aureus necrotizing-pneumonia and skin conditions ag-gravating Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Monkeypox manifestations. Limited data and paucity of high-quality evidence exist for many key clinical questions. Using clinical microbiology, molecular characterization, hospital data on age and in-fection sites, and antibiograms, we have investigated S. aureus infection patterns. We showed that age-specific distribution in both intensive care unit (ICU) and non-ICU revealed highest infection rates (94.7%) in senior-patients >50 years; most were MRSA (81.99%). However, specific distribu-tions of geriatric MRSA and MSSA rates were 46.5% and 4.6% in ICU and 35.48% and 8.065% in non-ICU, respectively. Intriguingly, age groups 0-20 years showed uniquely similar MRSA pat-terns in ICU and non-ICU patients (13.9%, 9.7%, respectively) and MSSA in ICU (11.6%). In age groups 20-50 years, MRSA were 2-fold in non-ICU (35%) than ICU (18.6%). Interestingly, highly significant association was found between infection-site and age-groups (P-value .000). Skin in-fections remained higher in all ages; pediatrics 32.14%, adults 56%, and seniors 25% while res-piratory infections were lower in pediatrics (14.3%) and adult 17%), and highest in seniors (38%). Blood and “other” sites in pediatrics recorded (28.6%; 25%, respectively), slightly lower in adults (18.6%; 8.6%) and seniors (14%); 22.8%), respectively. Further, significant association existed between infection-site and MRSA (Chi-Square Test, P-value .002). The common cutaneous infec-tions across all age-groups and the significant association of MRSA to geriatric-respiratory infec-tions have a high potential for skin-carriage as reservoir for endogenous infection. The similar frequencies of both lineages in youth in all settings imply MSSA-carriage as potential evolutionary origins for MRSA. These findings have important clinical implications for strategic planning in patient management and S. aureus control particularly in age-specific infections and vigilance for potential viral coinfections.

Preprint ARTICLE | doi:10.20944/preprints202206.0359.v1

Biomolecular Fluorescence Complementation Profiling and Artificial Intelligence Structure Prediction of the Kaposi’s Sarcoma-associated Herpesvirus ORF18 and ORF30 Interaction

Yoshiko Maeda, Tadashi Watanabe, Taisuke Izumi, Kazushi Kuriyama, Shinji Ohno, Masahiro Fujimuro

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Kaposi’s sarcoma-associated virus (KSHV); Viral pre-initiation complex (vPIC); Bimolecular fluorescence complementation (BiFC); Artificial intelligence (AI) structure prediction; AlphaFold2

Online: 27 June 2022 (10:15:34 CEST)

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Preprint CASE REPORT | doi:10.20944/preprints202206.0308.v1

A Case Report: Multifocal Necrotizing Encephalitis and Myocarditis after BNT162b2 mRNA Vaccination against Covid-19

Michael Mörz

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: mRNA Vaccine; autopsy

Online: 22 June 2022 (07:53:57 CEST)

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Preprint REVIEW | doi:10.20944/preprints202206.0302.v1

Proteomic Discovery and Validation of Novel Fluid Biomarkers for Improved Patient Selection and Prediction of Clinical Outcomes in Alzheimer’s Disease Patient Cohorts

Shivangi Awasthi, Daniel S. Spellman, Nathan Galen Hatcher

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Neuroproteomics; Alzheimer’s disease biomarker; neurodegeneration

Online: 22 June 2022 (03:44:49 CEST)

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Preprint CASE REPORT | doi:10.20944/preprints202206.0266.v1

Angiogenic Burst After Parp Inhibitor Maintenance Therapy in Relapsed Ovarian Cancer: A Case Report

Lifeng Lin, Rongkui Luo, Wen Gao, Ping Zhang, Yingyong Hou, Rongyu Zang, Tingyan Shi

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: PARP inhibitor; angiogenesis; immune suppression; recurrent ovarian cancer

Online: 20 June 2022 (10:02:09 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202206.0010.v1

The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation and Inflammatory Cytokine Production In Human Lung and Intestinal Epithelial Cells

Christopher B Forsyth, Lijuan Zhang, Abhinav Bhushan, Barbara A. Swanson, João I. Mamede, Maliha Shaikh, Li Zhang, Ali Keshavarzian

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; ARDS; Cytokine Storm; Spike S1 protein; SARS-CoV-2, Long COVID; ACE2; A549 cells; Caco-2 cells

Online: 1 June 2022 (09:49:27 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202205.0216.v2

Comprehensive Biotechnical System for Screening Risk-Based Diagnosis of COVID-19 and Post-COVID Syndrome

Vladimir Savostyanov, Alexander Kobelev, Ivan Kudashov

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Bioimpedance; COVID-19; E-health; Health Care Personnel; Pathophysiology; Post-COVID syndrome; Rheography

Online: 23 May 2022 (05:26:58 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202205.0216.v1

Comprehensive Biotechnical System for Screening Risk-Based Diagnosis of COVID-19 and Post-COVID Syndrome

Vladimir Savostyanov, Alexander Kobelev, Ivan Kudashov

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Bioimpedance; COVID-19; E-health; Health Care Personnel; Pathophysiology; Post-COVID syndrome; Rheography

Online: 17 May 2022 (03:13:32 CEST)

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Preprint REVIEW | doi:10.20944/preprints202205.0189.v1

Machine Learning of Raman Spectroscopy Data for Classifying Cancers: a Review of the Recent Literature

Nathan Blake, Riana Gaifulina, Lewis D. Griffin, Ian M. Bell, Geraint M. H. Thomas

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Raman Spectroscopy; Medical application; Disease screening and diagnosis; Machine learning analyses

Online: 13 May 2022 (10:17:00 CEST)

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Preprint REVIEW | doi:10.20944/preprints202205.0158.v1

Histone Deacetylases as Epigenetic Targets for Treating Parkinson’s Disease

Yan Li, Zhicheng Gu, Shu-xian Lin, Lei Chen, Valentina Dzreyan, Moez Eid, Svetlana Demyanenko, Bin He

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Parkinson’s disease; Epigenetic targets; Histone deacetylases; Inhibitors; PROTACs

Online: 12 May 2022 (05:41:21 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202205.0127.v1

Association Between Systemic Arterial Hypertension with Laboratory Markers, Body Composition, Obstructive Sleep Apnea and Heart Rate Variability in Obese Adults

Clarcson Santos, Laura Lagares, Sarah Santos, Felipe Santos, Mariana Silva, Rodrigo Macedo, Luiz Almeida, Eric Bomfim

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: hypertension; obesity; body composition; intra-abdominal fat; sleep apnea; obstructive

Online: 10 May 2022 (04:45:21 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202205.0082.v1

Emotional Reaction to the First Dose of COVID-19 Vaccine: Post Vaccination Decline in Anxiety and Stress Among Anxious Individuals and Increase Among Individuals with Normal Anxiety Levels Pre Vaccination

Rasmieh Al-Amer, Malakeh Zuhdi Malak, Hala Mohammad Ramadan Burqan, Elena Stănculescu, Sylivia Nalubega, Abdulmajeed A. Alkhamees, Amin Omar Hendawy, Amira Mohammed Ali

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19, vaccine/vaccination; stress; anxiety; hesitancy; preparedness; Jordan/Arab

Online: 6 May 2022 (14:06:14 CEST)

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Although vaccinating the world is adopted by the WHO to limit COVID-19 transmission, people’s worries about vaccines may suppress their desire for vaccination despite vaccine availability. This study aimed to evaluate the levels of stress and anxiety among 250 Jordanians who received their first vaccine dose at a local community health center. The respondents completed the stress and anxiety subscales of the Depression Anxiety and Stress scale 21 (DASS-21) pre- and post-vaccination. The respondents expressed more moderate-severe levels of stress pre than post vaccination (20.8% and 13.2%, respectively). Meanwhile, 37.2% and 45.2% of the respondents expressed moderate-severe anxiety pre and post vaccination, respectively. Wilcoxon signed-rank test revealed that the drop in the level of stress from pre (median (IQR) = 5 (1-8)) to post vaccination (median (IQR) = 3 (1-7)) was statistically significant (z = -3.81, p = 0.001, r = 0.17) while the increase in anxiety was not. Anxiety median significantly dropped among individuals experiencing mild to severe anxiety pre vaccination. Similarly, stress and anxiety significantly increased among individuals expressing normal anxiety pre vaccination (z = -3.57 and -8.24, p values = 0.001, r = 0.16 and 0.37, respectively). Age positively correlated with post vaccination anxiety among respondents with mild pre vaccination anxiety, and it negatively correlated with pre vaccination level of stress in the normal anxiety group. Gender, marital status, respondents’ level of education, and history of COVID-19 infection had no significant correlation with anxiety or stress at either point of measurement. Overcoming their hesitancy to receive COVID-19 vaccine, individuals with normal levels of anxiety experienced a rise in their distress symptoms following immunization. On the contrary, vaccination seemed to desensitize anxious individuals. Policymakers need to formulate a population-specific plan to increase vaccine preparedness and promote psychological well-being over all during the pandemic.

Preprint ARTICLE | doi:10.20944/preprints202204.0314.v1

The Coronavirus Disease 2019 Spatial Care Path: Home, Community, and Emergency Diagnostic Portals

Gerald J. Kost

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Emergency Use Authorization; endemic; false omission; false omission rate; home testing; point-of-care testing (POCT); positive predictive value geometric mean-squared; prevalence boundary; recursive protocol; tier; visual logistics

Online: 30 April 2022 (08:42:08 CEST)

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Preprint REVIEW | doi:10.20944/preprints202204.0118.v1

SARS-CoV-2-Infection (COVID-19): Clinical Course and Cause(s) of Death

Giuliano Ramadori

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2-infection; dehydration; hypoalbuminemia; pulmonary hypoxia; hyaline memrane; pulmonary engorgement; lung weight; acute respiratory distress syndrome; diffuse alveolar damage (DAD)

Online: 13 April 2022 (08:27:30 CEST)

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ABSTRACT Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.

Preprint REVIEW | doi:10.20944/preprints202204.0078.v1

Big Data in Laboratory Medicine – Ready for AI?

Tobias Blatter, Harald Witte, Upal Nath, Filippo Franchini, Alexander Benedikt Leichtle

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: digitalization; clinical chemistry; artificial intelligence; interoperability; FAIRification

Online: 8 April 2022 (10:52:31 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202203.0360.v1

Development of A Novel Anti-Epcam Monoclonal Antibody for Various Applications

Guanjie Li, Hiroyuki Suzuki, Teizo Asano, Tomohiro Tanaka, Hiroyoshi Suzuki, Mika K Kaneko, Yukinari Kato

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: EpCAM; monoclonal antibody; recombinant antibody; colorectal carcinoma

Online: 28 March 2022 (10:11:34 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202203.0323.v1

ApoA1 Deficiency Reshapes the Phenotypic and Molecular Characteristics of Bone Marrow Adipocytes in Mice

Afroditi Kastrenopoulou, Kyriakos Kypreos, Nicholaos Papachristou, Stavros Georgopoulos, Ioulia Mastora, Ioanna Papadimitriou-Olivgeri, Argyro Spentzopoulou, Dragana Nikitovic, Vassilios Kontogeorgakos, Harry C. Blair, Dionysios J. Papachristou

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Apolipoprotein A-1; High-density lipoprotein; Brown adipose tissue; White adipose tissue; Beige (Hybrid) adipose tissue

Online: 24 March 2022 (05:26:34 CET)

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Preprint REVIEW | doi:10.20944/preprints202203.0301.v1

Acute Heart Failure, 90-day Mortality—and Gravitational Ischemia in the Brain

J. Howard Jaster, Giulia Ottaviani

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Heart Failure; Gravity; Ischemia; Brain

Online: 22 March 2022 (12:38:29 CET)

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During the 90 days following hospitalization for acute heart failure, ejection fraction and type of discharge medications have been shown in clinical trials to have little effect on mortality. We examined the recent literature addressing brain-related etiologies of sudden death following heart failure. Two mechanisms of sudden unexpected death have been suggested to possibly result from 4 significant influences on pathophysiology in the brain. The two causes of death are severe cardiac arrhythmia, and neurogenic pulmonary edema. They are both mediated through the brainstem autonomic nuclei generally, and executed specifically through the dorsal motor nucleus of the vagus nerve. The four significant influences on pathophysiology in the brainstem autonomic nuclei are: 1) Hyper-stimulation of neurons in the solitary tract nucleus, increasing their metabolic requirements; 2) Inadequate blood flow at a vascular watershed terminus; 3) Additionally decreased blood flow following vasoconstriction related to relative hyperventilation and decreased pCO2 levels; 4) Gravitational ischemia in the brain—caused by the weight of the brain mass sitting above the brainstem. Changes in head tilt release gravitational ischemia in the brain. There is no specific head position (relative to gravity) that is considered favorable or unfavorable for an extended period of time (i.e. more than 24 hours). Even a small degree of head elevation, used in managing pulmonary congestion, may increase gravitational ischemia in the posterior fossa and brainstem. In this paper we suggest a new and important research avenue for intervening in cardiac arrhythmias, and preventing their occurrence, through the non-invasive use of head-tilting, and other head repositioning maneuvers. This could potentially help many geriatric patients with heart failure, who have decreased mobility in bed, and who tend to stay in one position longer, thereby increasing gravitational ischemia in the brain.

Preprint ARTICLE | doi:10.20944/preprints202203.0169.v1

Vaccines Associated Cardiac Adverse Events, including SARS-CoV-2 Myocarditis, Elevated Histamine Etiology Hypothesis

Darrell Ricke

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; adverse events; histamine intolerance; myocarditis; pericarditis; tachycardia

Online: 11 March 2022 (12:07:26 CET)

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Preprint ARTICLE | doi:10.20944/preprints202202.0347.v1

Fibrin Strands Will Grow from Soluble Fibrin and Hang Up In an ex vivo Microcirculatory Viscoelastic Model: Is This a Major Cause of Covid-19 Associated Coagulopathy?

Brian S. Bull, Karen L. Hay, Paul C. Herrmann

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Covid-19; fibrin; fibrinogen; fibrinolysis; fibrinolytic shutdown; rotational thromboelastometry (ROTEM); soluble fibrin monomer complex (SFMC); thromboelastography (TEG); thrombosis; viscoelastic

Online: 28 February 2022 (06:58:20 CET)

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Preprint ARTICLE | doi:10.20944/preprints202202.0329.v1

Microfluidic Microcirculation Mimetic as a Tool for the Study of Rheological Characteristics of Red Cells in Patients With Sickle Cell Anaemia

Marcus Inyama Asuquo, Emmanuel Effa, Oluwabukola Gbotosho, Akaninyene Otu, Nicole Tofner, Ameh Soter, Bhayankaram Sruti-Prathivadhi, Noah Zetocha, Chisom Nwakama, William Ohobu Egbe, Jochen Guck, Andrew E. Ekpenyong

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Sickle cell disorder; vaso-occlusive crisis; hydroxyurea; microcirculation; microfluidics; personalized medicine; deformation; transit time.

Online: 25 February 2022 (09:30:03 CET)

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Preprint REVIEW | doi:10.20944/preprints202201.0303.v1

NF-κB Signaling and Inflammation – Drug Repurposing to Treat Inflammatory Disorders?

Annabell Roberti, Laura Elizabeth Chaffey, David R Greaves

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Inflammation; NF-κB; drug repurposing; drug development; autoimmunity; COVID-19; multiple sclerosis; rheumatoid arthritis

Online: 20 January 2022 (11:16:25 CET)

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Preprint ARTICLE | doi:10.20944/preprints202201.0162.v1

Possible Role of the Antibiotic-Modified Microbiome in the Development of Hematological Malignancies in European Countries

Gábor Ternák, Károly Berényi, Balázs Németh, Ágnes Szenczi, István Kiss

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: antibiotic cnsumtion; microbiome; hematological malignancies; Hodgkin-lymphoma (HL); Non-Hodgkin lymphoma (NH); multiplex myeloma (MM); leukemia (LEU)

Online: 12 January 2022 (12:53:22 CET)

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Hematological malignancies are considered the fifth most common cancer in the world. Several risk factors and probable etiological agents have been suspected in the pathomechanism of those malignancies as infections, chemicals, irradiation, etc., and recently, the contribution of the altered gut flora, dysbiosis, was identified also as a possible additional factor to the existing ones. Host, and external factors, like antibiotics, which were identified as a major disruptor of the "normal" gut flora, influence the composition of the microbiome. Considering the several-fold differences in antibiotic consumption patterns and the incidence of hematological malignancies in European countries, the hypothesis was raised that the dominant consumption of certain antibiotic classes might influence the incidence of different hematological malignancies through the modification of gut flora. Comparisons were performed between the average antibiotic consumption databases reported yearly by ECDC (2009-2019) and the incidence rate of Hodkin lymphoma (HL), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and leukemia (LEU) estimated for 2020 in 30 European countries. Applying Spearman calculations, significant positive correlation has been found between the incidence of HL and tetracycline (J01A) consumption (r = 0.399, p = 0,029), NHL and narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.580, p = 0,001), MM and tetracycline (r = 0.492, p = 0.006), penicillin (J01C) (r = 0.366, p = 0.047), narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.574, p = 0.001), while strong, significant negative correlation has been recorded between NHL and cephalosporin (r = -0,460, p = 0,011), and quinolone (r = -0,380, p = 0,038). The incidence of LEU did not show any positive or negative association with any antibiotic classes. It is concluded that certain antibiotic classes, in addition to other putative factors, might promote or inhibit the development of different hematological malignancies.

Preprint ARTICLE | doi:10.20944/preprints202201.0032.v1

Dysbiosis in Alzheimer’s Disease Might be Triggered by Certain Classes of Antibiotics with Time-lapse: New Insights in the Pathogenesis?

Gábor Ternák, Márton Németh, Martin Rozanovic, Lajos Bogár

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: antibiotic consumption; gut flora; dysbiosis; Alzheimer disease; dementia; gut-brain axis, mediator molecules

Online: 5 January 2022 (10:44:59 CET)

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Background and objectives: Alzheimer's disease (AD) is a progressive neurodegenerative illness, responsible for 60-70% of all dementias, affecting over 50 million people worldwide, and nearly 11 million in European countries. Several putative factors are identified in the literature as causative agents or risk factors for the development of AD. The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades. Recent studies raised the possible role of dysbiosis in the development of AD which prevents memory loss. The amyloid-β (Aβ) deposition might be considered as an inflammatory reaction to certain molecular products arising from the altered microbiome. Based on the above observations, it has been suspected, that antibiotic consumption patterns of different antibiotic classes might be associated with the prevalence of AD in European countries. Methods: Antibiotic consumption (ECDC) for 1997-2007, 2008-2018, and as the whole 1997-2018 period, have been compared to the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. Results: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the year 1997-2007 (p: 0.044). A similar association was not observed for the entire 22 years (1997-2018) of the average quinolone consumption, and the years 2008-18, indicating 10-20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008-2018 showed a strong positive association with AD prevalence (2018) (p: 0.026) and a positive correlation tendency for the entire 22 years 1997-2018 (p: 0.063), but none for the years 1997-2007 (p: 0.241). Broad-spectrum, beta-lactamase sensitive penicillin (J01CA) consumption showed a positive (non-significant) correlation with the prevalence of AD for the years 2008-2018 (p:0.080).Discussion: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD.

Preprint ARTICLE | doi:10.20944/preprints202112.0453.v1

Detection of Novel Biomarkers in Saliva of Rheumatoid Arthritis Model Mice by Proteomics and Pathological Analysis

Wakako Sakaguchi, Juri Saruta, Shinya Fuchida, Yuko Yamamoto, Masahiro To, Tomoko Shimizu, Mayumi Yakeishi, Keiichi Tsukinoki

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: anti-citrullinated protein antibody (ACPA); alpha-1-antitrypsin (A1AT); DBA/1JJmsSlc mice Proteome analysis; rheumatoid arthritis (RA)

Online: 28 December 2021 (14:44:54 CET)

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Preprint ARTICLE | doi:10.20944/preprints202112.0366.v1

An Integrated Epigenomic and Genomic View on Phyllodes and Phyllodes-Like Breast Tumors

Juergen Hench, Tatjana Vlajnic, Savas Deniz Soysal, Ellen C Obermann, Stephan Frank, Simone Muenst

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: fibroepithelial breast lesions; phyllodes tumors; methylation analysis; copy number alterations; dimension reduction; unsupervised machine learning

Online: 22 December 2021 (12:46:50 CET)

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Preprint ARTICLE | doi:10.20944/preprints202112.0350.v1

HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

Zhangsheng Yang, Milomir O Simovic, Peter R Edsall, Bin Liu, Tomas S Cancio, Andriy I Batchinsky, Leopoldo C Cancio, Yansong Li

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: HMGB1; trauma; hemorrhagic shock; inflammation; multiple organ failure

Online: 22 December 2021 (10:36:56 CET)

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Preprint BRIEF REPORT | doi:10.20944/preprints202112.0327.v1

Predicting and Visualizing STK11 Mutation in Lung Adenocarcinoma Histopathology Slides Using Deep Learning

Runyu Hong, Wenke Liu, David Fenyö

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: keyword; histopathology; deep learning; machine learning; cancer; lung adenocarcinoma; immune; computational pathology

Online: 21 December 2021 (12:28:44 CET)

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Preprint ARTICLE | doi:10.20944/preprints202112.0053.v1

Antibiotic Consumption Patterns in European Countries Might Be Associated with the Prevalence of Diabetes Type-1-2 (T1D, T2D)

Gábor Ternák, Márton Németh, Martin Rozanovic, Lajos Bogár

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: diabetes type-1; T1D; diabetes type-2; T2D; antibiotics; antibiotic classes; microbiome; dysbiosis; prevalence; concordance

Online: 3 December 2021 (12:45:23 CET)

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Abstract: Several publications have raised the issue that the development of diabetes is preceded by alteration of the microbiome (dysbiosis) and hence, the role of environmental factors, triggering dysbiosis, should be considered. Antibiotics are powerful agents inducing dysbiosis and the authors wanted to explore the possible relationship between the consumption of different major classes of antibiotics and the prevalence of diabetes (type-1, /T1D/, type-2 /T2D/) in thirty European countries. According to our hypothesis, if such association exists, the dominant use of certain major antibiotic classes might be reflected in the prevalence of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes (T1D and T2D) estimated for 2019 and featured in the Diabetes Atlas with the average yearly consumption of major antibiotic classes of the previous 10 years (2010-19) extracted from the ECDC yearly reports on antibiotic consumption in Europe. Pearson correlation and variance analysis were used to estimate the possible relationship. Strong, positive (enhancer) associations were found between the prevalence of T1D and the consumption of tetracycline (J01A /p: 0.001/) and the narrow spectrum penicillin (J01CE /p: 0,006/, CF /p: 0.018/). Strong negative (inhibitor) association was observed with broad-spectrum, beta-lactamase resistant penicillin (J01CR /p: 0.003/), macrolide (J01F /p: 0.008/) and quinolone (J01M /p: 0.001/). T2D showed significant positive associations with cephalosporin (J01D /p: 0.048/) and quinolone (J01M /p: 0.025/), and a non-significant negative association was detected with broad-spectrum, beta-lactamase-sensitive penicillin (J01CA /p: 0.67/). Countries with the highest prevalence of diabetes (first 10 positions) showed concordance with the higher consumption of “enhancer” and the lower consumption of “inhibitor” antibiotics (first 10 positions) as indicated by variance analysis. Countries with high prevalence of T1D showed high consumption of tetracycline (p: 0.015), and narrow spectrum, beta-lactamase sensitive penicillin (p: 0.008), and low consumption of “inhibitor” antibiotics (broad-spectrum, beta-lactamase resistant, combination penicillin (p: 0.005), cephalosporin (p: 0.036), and quinolone (p: 0.003). Countries with a high prevalence of T2D consumed more cephalosporin (p: 0.084), quinolone (p: 0.54), and less broad-spectrum, beta-lactamase sensitive penicillin (p: 0.012) than other countries. Conclusion/Interpretation: The development of diabetes-related dysbiosis might be attached to higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics shoving negative (inhibitory) associations. Those groups of antibiotics are different in T1D and T2D

Preprint ARTICLE | doi:10.20944/preprints202111.0313.v1

PRDX6 Alleviates Lipopolysaccharide-Induced Inflammation in Human Gingival Fibroblasts by Regulation of NRF2

Wen-ying Yang, Xiang Meng, Yue-rong Wang, Qing-qing Wang, Xin He, Xiao-yu Sun, Nan Cheng, Lei Zhang

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: PRDX6; inflammation; NRF2; HGFs.

Online: 17 November 2021 (23:34:15 CET)

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Preprint ARTICLE | doi:10.20944/preprints202111.0309.v1

Transcriptional Analysis-Based Alterations Affecting Neuritogenesis of the Peripheral Nervous System in Psoriasis

Dóra Romhányi, Kornélia Szabó, Lajos Kemény, Endre Sebestyén, Gergely Groma

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: psoriasis; cutaneous nervous system; axon development; myelination

Online: 17 November 2021 (12:54:23 CET)

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Preprint ARTICLE | doi:10.20944/preprints202111.0210.v1

Detection of Klebsiella pneumoniae DNA by PCR-Based CRISPR-lbCas12a System

Shang Wang, Ying Tang, Jiehong Wei, Shan Wang, Guoyu Peng, Yuqing Li, Song Wu

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: CRISPR-Cas, Nucleic acid detection, Klebsiella pneumonia

Online: 11 November 2021 (12:57:06 CET)

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Preprint ARTICLE | doi:10.20944/preprints202111.0124.v1

Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-directed Therapies.

Robert E. E. Brown, Robert L Hunter

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: tuberculosis; secretory antigens; bronchiolar epithelium; alveolar pneumocytes; M2 polarization; COX-2, FAS; Pathogenesis; early lesion

Online: 5 November 2021 (14:50:58 CET)

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Preprint ARTICLE | doi:10.20944/preprints202111.0097.v1

Chronic Histological Outcomes of Indirect Traumatic Optic NEU-Ropathy in Adolescent Mice: Persistent Degeneration and Tem-Porally Regulated Glial Responses

Shelby M. Hetzer, Emily M. Shalosky, Jordyn N. Torrens, Nathan K. Evanson

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: traumatic optic neuropathy; mice; axon injury; TBI; neurodegeneration

Online: 4 November 2021 (09:26:51 CET)

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Preprint ARTICLE | doi:10.20944/preprints202110.0137.v1

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

Supansa Pantoom, Adam Pomorski, Katharina Huth, Christina Hund, Janine Petters, Artur Krezel, Andreas Hermann, Jan Lukas

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Wilson disease; ATPase copper transporting beta; autophagosome-lysosome fusion; HepG2; LC3 interaction region

Online: 8 October 2021 (11:06:51 CEST)

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Preprint REVIEW | doi:10.20944/preprints202110.0118.v1

Pathogenesis of Autoimmune Male Infertility: Juxtacrine, Paracrine and Endocrine Deregulation

Valeriy A. Chereshnev, Svetlana V. Pichugova, Yakov B. Beikin, Margarita V. Chereshneva, Angelina I. Iukhta, Yuri I. Stroev, Leonid P. Churilov

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: male infertility; varicocele; varicocelectomy; spermatozoa; sperm antigens; antisperm autoantibodies; ejaculate; orchitis; autoimmune thyroiditis

Online: 7 October 2021 (11:40:21 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202107.0404.v2

Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-directed Therapies

Robert E. E. Brown, Robert L Hunter

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: tuberculosis; secretory antigens; bronchiolar epithelium; alveolar pneumocytes; M2 polarization; COX-2, FAS; Pathogenesis; early lesion

Online: 29 September 2021 (09:56:22 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202109.0296.v1

Comparative Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii in vitro and in Pregnant Mice Infected with T. gondii Oocysts

Jessica Ramseier, Dennis Imhof, Nicoleta Anghel, Kai Hänggeli, Richard Betteck, Vreni Balmer, Luis-Miguel Ortega-Mora, Roberto Sánchez-Sánchez, Ignacio Ferre, Richard K Haynes, Andrew Hemphill

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: quinolone; decoquinate; Toxoplasma gondii; tachyzoites; bradyzoites; oocysts; vertical transmission; proliferation; resistance

Online: 16 September 2021 (16:41:28 CEST)

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Preprint REVIEW | doi:10.20944/preprints202109.0111.v1

The Utilization and Benefits of Telehealth Services by Health Care Professionals Managing Breast Cancer Patients During the COVID-19 Pandemic

Donovan A. McGrowder, Fabian Miller, Kurt Vaz, Melisa Anderson Cross, Lennox Anderson-Jackson, Sophia Bryan, Lyndon Latore, Rory Thompson, Dwight Lowe, Shelly R. McFarlane, Lowell Dilworth

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: telehealth; teleoncology; telerehabilitation; telemedicine; coronavirus disease; management; video conferencing; web-based platforms; breast cancer patients

Online: 6 September 2021 (17:34:49 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202108.0361.v1

Syndemics of Fluoroquinolone Resistance in N. gonorrhoeae, E. coli and K. pneumoniae: A Global Ecological Analysis

Chris Kenyon

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Neisseria gonorrhoeae; E. coli; K. pneumoniae; Acinetobacter; P. aeruginosa; fluoroquinolones; antimicrobial resistance; stewardship; antibiotic consumption; bystander selection

Online: 17 August 2021 (10:32:27 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202107.0456.v1

Benefits of a Switch From Intermittently Scanned Continuous Glucose Monitoring (isCGM) to Real-time (rt) CGM in Diabetes Type 1 Suboptimal Controlled Patients in Real-life: A One-year Prospective Study

Yannis Préau, Sébastien Galie, Pauline Schaepelynck, Martine Armand, Denis Raccah

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Real-time continuous glucose monitoring; Intermittently scanned continuous glucose monitoring; Type 1 diabetes; Glucose variability; Hypoglycemia; Insulin resistance

Online: 20 July 2021 (14:58:11 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202106.0246.v1

Sudden Unexpected Death Associated with Arrhythmogenic Cardiomyopathy: Study of the Cardiac Conduction System

Giulia Ottaviani, Graziella Alfonsi, Simone G. Ramos, Anna M. Lavezzi, L. Maximilian Buja

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Arrhythmogenic cardiomyopathy; arrhythmogenic right ventricular cardiomyopathy; cardiac conduction system; sudden unexpected cardiac death; autopsy

Online: 9 June 2021 (08:49:09 CEST)

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Working Paper REVIEW

Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

Karen Giménez-Orenga, Elisa Oltra

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: amyotrophic lateral sclerosis; epigenetics; HERV-K; HERV-W; monoclonal antibody; multiple sclerosis; neurodegeneration; temelimab.

Online: 12 April 2021 (12:17:32 CEST)

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Working Paper CASE REPORT

SARS-CoV-2 Infection in the Central Nervous System of a 1-Year-Old Infant

Ismael Carlos Gomes, Karina Karmirian, Julia Oliveira, Carolina Pedrosa, Mayara Abud Mendes, Fernando Colonna Rosman, Leila Chimelli, Stevens Rehen

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2 neuroinvasion; COVID-19; infant; Choroid plexus

Online: 15 March 2021 (13:03:33 CET)

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Preprint ARTICLE | doi:10.20944/preprints202012.0094.v3

“Clinician’s Probability Calculator” to Convert Pre-Test to Post-Test Probability of COVID-19, Based on Method Validation from Each Laboratory

Zoe Brooks, Saswati Das, Tom Pliura

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; SARS-COV-2; False-Positive; False-Negative; Likelihood Ratio; Probability; Calculator; Interpretation

Online: 3 March 2021 (10:08:27 CET)

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Preprint REVIEW | doi:10.20944/preprints202101.0520.v1

Mast Cells Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-inflammatory Cytokines IL-37, IL-38 and IL-1Ra

Pio Conti, Fabrizio Pregliasco, Rosa G. Bellomo, Carla E. Gallenga, Alessandro Caraffa, Spyros K. Kritas, Dorina Lauritano, Gianpaolo Ronconi

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: mast cell; psoriasis; inflammation; cytokine; Il-37; IL-38; IL-1Ra

Online: 25 January 2021 (15:57:19 CET)

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Working Paper CASE REPORT

SARS-CoV-2 Infection in the Central Nervous System of a 1-Year-Old Infant

Ismael Carlos Gomes, Karina Karmirian, Julia Oliveira, Carolina Pedrosa, Fernando Colonna Rosman, Leila Chimelli, Stevens Rehen

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2 neuroinvasion; COVID-19; infant; Choroid plexus

Online: 2 December 2020 (11:45:50 CET)

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Preprint REVIEW | doi:10.20944/preprints202009.0420.v1

SARS-CoV-2 S Protein Binding hACE2: Viral Entry, Pathogenesis, Prognosis, and Potential Therapeutic Targets

Lobna Al-Zaidan, Sarra Mestiri, Afsheen Raza, Maysaloun Merhi, Varghese Inchakalody, Queenie Fernandez, Nassiba Taib, Shahab Uddin, Said Dermime

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; SARS-CoV-2; ACE2 receptor; spike glycoprotein; S glycoprotein immunogenic sequences; ACE2 polymorphism

Online: 18 September 2020 (04:56:02 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202009.0390.v1

A Novel Purification Procedure for Active Recombinant Human DPP4 and the Inability of DPP4 to Bind SARS-CoV-2

Cecy Xi, Arianna Arianna Di Fazio, Naveed Nadvi, Karishma Patel, Michelle Xiang, Hui Emma Zhang, Chandrika Deshpande, Jason Low, Xiaonan Trixie Wang, Yiqian Chen, Brenna Osborne, Ana Julia Vieira de Ribeiro, Geoffrey McCaughan, Bret Church, Joel Mackay, Mark Gorrell

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Recombinant protein; Protease; DPP4; Covid-19

Online: 17 September 2020 (08:44:17 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202009.0280.v1

Altered Spatial Composition of the Immune Cell Repertoire in the Bone Marrow Stem Cell Niche in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

Marcus Bauer, Christoforos Vaxevanis, Haifa Kathrin Al-Ali, Nadja Jaekel, Christin Le Hoa Naumann, Judith Schaffrath, Achim Rau, Barbara Seliger, Claudia Wickenhauser

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: MDS; immune cell repertoire; prognosis; multiplex immunohistochemistry; stem cell niche

Online: 13 September 2020 (11:51:13 CEST)

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Preprint REVIEW | doi:10.20944/preprints202009.0076.v1

Why COVID-19 Transmission is More Efficient and Aggressive than Viral Transmission in Previous Coronavirus Epidemics?

Fatma Elrashdy, Elrashdy M. Redwan, Vladimir N Uversky

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: severe acute respiratory syndrome coronavirus 2; SARS-CoV-2; coronavirus disease 2019; COVID-19; viral infection; virus-host interaction

Online: 4 September 2020 (03:19:43 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202009.0066.v1

Saphenous Vein Graft between Brachial Artery and Cephalic Vein in Antebrachial Arteriovenous Anastomosis – Simulation of the Procedure

Lilija Banceviča, Dzintra Kažoka, Aleksandrs Maļcevs, Māra Pilmane

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: arteriovenous graft; hemodialysis; vascular access; anastomosis

Online: 3 September 2020 (09:26:44 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202009.0038.v1

Diabetes Induced Renal Complications by Leukocyte Activation of Nuclear Factor κ-B and its Regulated Genes Expression

Noura Darwish, Yousif Elnahas, Fatmah AlQahtany

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: NF-κB; IL-1β; IL-6; VEGF; TNF-α; FN; ICAM-1; VCAM-1

Online: 2 September 2020 (09:46:10 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202009.0035.v1

Isolation and Molecular Characterization of Enteroviruses from Great Apes and Humans in the Republic of Congo: Recombination within Enterovirus C Serotypes

Inestin Amona, Hacène Medkour, Jean Akiana, Bernard Davoust, Mamadou Lamine Tall, Clio Grimaldier, Celine Gazin, Christine Zandotti, Anthony Levasseur, Bernard La Scola, Didier Raoult, Florence Fenollar, Henri Banga-Mboko, Oleg Mediannikov

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: enterovirus; nonhuman primates; humans; genetic recombination; emergence; Republic of Congo

Online: 2 September 2020 (08:49:42 CEST)

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Working Paper ARTICLE

Specialized Pro-resolving Endogenous Lipid Mediators and Resolution of the Inflammatory Process

Claudio G. Gallo, Sirio Fiorino, Giovanni Posabella, Donato Antonacci, Antonio Tropeano, Emanuele Pausini, Carlotta Pausini, Tommaso Guarniero, Marco Zancanaro

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Inflammation; Cytokine Storm; ⍵-3; ⍵-6; SPMs; Resolvins

Online: 30 August 2020 (16:47:53 CEST)

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Inflammation is an essential protective response against injury or infection. Physiological inflammation eliminates the pathogen, promotes tissue repair and healing. An exaggerated, out of control inflammation, however, can become pathological. Inflammation can generate secondary cell damage, inflame the vessels (endothelitis), activate coagulation processes. Among these pathogenetic factors (cell damage, inflammation, endothelitis, coagulopathies), self-amplification mechanisms can be created, spreading beyond the initial site, up to Multiple Organ Failure (MOF) and host death. If the inflammation does not resolve in a physiological way, the remodeling of the tissues can be maladaptive and lead to the onset of chronic inflammatory degenerative diseases. Diseases such as sepsis, burns, polytrauma, severe forms of influenza or COVID-19, are characterized by a condition of hyperinflammation, associated with a condition of immunosuppression. The initial events triggered by the pathogen (cell damage, interferon response in the case of viruses) ignite the inflammation by activating the inflammasome, the transcription factor NFkB, the release of pro-inflammatory eicosanoids (Prostaglandins, Leukotrienes, Thromboxanes) by neutrophils and macrophages. Hence, the cells of the innate immune system produce pro-inflammatory cytokines. Indeed, the ‘’eicosanoid storm’’ precedes the ‘’cytokine storm’’. Eicosanoids are a group of potent endogenous lipid mediators derived from omega-6 fatty acids Arachidonic Acid (AA). Eicosanoids include a group of molecules with pro-inflammatory (Prostaglandins, Leukotriens) and pro-coagulant (Thromboxanes) action. In addition, Arachidonic Acid (AA) is the source of Lipoxins (LXs). Lipoxins belong to a group of molecules collectively referred to as specialized pro-solving mediators (SPMs) which also include molecules derived from w-3 eicosapentaenoic acid (EPA): Resolvins (ReV-E sieres) and w-3 docohexanoic (DHA): Resolvins D-series (ReV D-series); Protectins (PTs); Maresins (MaRs). SPMs are important for the resolution phase of inflammation to take place properly. Their deficiency could be involved in both acute uncontrolled inflammation and chronic inflammation. The active regulation of the acute inflammatory process, integrating the precursors of Specialized Pro-resolving Mediators (SPMs), such as ⍵-6 and ⍵-3 in balanced ratio, or the SPMs themselves, could be a complementary therapeutic approach useful for taming the "storm of cytokines '' which characterizes exaggerated forms of inflammation. ⍵-3 and ⍵-6 are part of already widely used, readily available, inexpensive and safe supplements. Resolvins have already been included in clinical trials for various other inflammatory diseases (eye diseases, periodontal diseases).

Working Paper ARTICLE

Population-Based Reductionist Measures Cannot Prevent SARS-CoV-2 Induced Global Health Crisis: A Compelling Need To Improve Personal Resistance to the Virus

Jianqing Wu, Ping Zha

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; COVID-19; public health intervention; disease severity; personal survival strategy; randomized control trials; epidemiological model; junk science; mind and body; reductionist

Online: 24 August 2020 (03:11:34 CEST)

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To predict how the COVID-19 pandemic progresses, we developed a systematic method for predicting disease outcomes. In the method, we evaluate how personal disease outcomes are mainly affected by viral concentration and exposure time and four defense mechanisms: human innate immunity/host response, acquired immune response, inflammation resolution and micro circulation, and the available space in the thorax cage. By considering how pandemic measures affect viral exposure and those mechanisms, we found many pandemic measures are misused or abused to deliver long-term adverse impacts. We noted that lifestyles have been changed as a result of movement restriction measures. By using the method, we found that altered lifestyles are predicted to raise infection rate, disability and death risks in the future. We show that a person can use personal, environmental, emotional factors to reduce infection rate and death risk. To prove the validity of this finding, we extensively examined medical research models, holistic and reductionist models, epidemiological models, disease risk factors, etc, and found that population methods are unfit for studying holistic health, statistical population does not exist in most clinical trials, mathematical models were misused for studying disease properties for a population, mathematical equations for modeling personal diseases are beyond human ability to solve, statistical models are misused, population-derived treatments are inherently dangerous to patients, vaccines have limited benefits due to unique lung structure and rapid RNA mutation, and immune system damage is caused by fast viral replication rate. We found that altering biological properties to improve the defense mechanisms could prevent a super majority of deaths and prevent the virus from reaching a point to damage the immune system. For vulnerable persons, such measure is a viable strategy for surviving from the pandemic. As a whole, holistic personalized medicine is more powerful than population-based reductionist treatment by one to several orders of magnitudes. We urge people do their parts to force the medical establishment to abandon population treatment models that are responsible for failure of medicine and dissemination of misleading and factually wrong information on the effectiveness of medical treatments.

Working Paper ARTICLE

COVID-19: Role of the Interferons

Claudio G. Gallo, Sirio Fiorino, Giovanni Posabella, Donato Antonacci, Antonio Tropeano, Emanuele Pausini, Carlotta Pausini, Tommaso Guarniero, Marco Zancanaro

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; SARS CoV-2; IFN-⍺; IFN-β; IFN-λ

Online: 2 August 2020 (11:31:40 CEST)

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COVID-19 disease, caused by the SARS-CoV2 virus, is a potentially fatal disease that represents a serious public health and economic problem worldwide. The SARS-CoV2 virus infects the lower respiratory tract and can cause pneumonia in humans. ARDS is the leading cause of death in COVID-19 disease. One of the main characteristics of ARDS is the cytokine storm, an uncontrolled systemic inflammatory response resulting from the release of pro-inflammatory cytokines and chemokines and growth factors, by immune cells. The other important aspect of the disease is represented by the involvement of the vascular organ that undergoes endothelitis. Hyperinflammation and endothelitis contribute in various ways to trigger coagulation disorders with diffuse micro thrombotic and thromboembolic phenomena. Lastly, multiple organ failure may occur (MOF). Since so far there is no approved treatment, there is an urgent need to reposition known treatments, considered safe, to be included in trials. Naturally produced interferons represent the body's first line of defense against viruses. Pharmacological forms, obtained by means of genetic recombination techniques, have long been approved and used to treat numerous pathologies. Interferons are divided into three families, within which some subfamilies are distinguishable. Only IFN-II comprises a single isoform which has completely different aspects and functions. The IFN I and III, however, each comprise different subfamilies (17 subfamilies the IFN-I and 4 subfamilies the IFN-III), share many aspects, representing the body's first antiviral response, but play different roles. The use of IFNs has been studied in two severe hCoV (Human Coronavirus) diseases, closely related to COVID-19 disease, such as SARS and MERS. Numerous in vitro and in vivo studies have been conducted, often in combination with other antivirals. The results have been controversial. The positive results in vitro and in experimental animals were often not replicable in humans. The possible positioning of these molecules in the right window of therapeutic opportunity requires that the complex dialogue between IFN, inflammasome, cytokines, pro-inflammatory chemokines, growth factors and barrier function be shed light.

Preprint ARTICLE | doi:10.20944/preprints202007.0484.v1

Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers

Hye Sung Kim, Hyun Joo Song, In Ho Jeong, Bo Gun Jang

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Gastric cancer; Submucosal invasion; Intestinal stem cell; Cancer stem cell; Prognosis

Online: 21 July 2020 (12:34:02 CEST)

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Working Paper ARTICLE

COVID-19, What Could Sepsis, Severe Acute Pancreatitis, Gender Differences and Aging Teach Us?

Claudio Gallo, Sirio Fiorino, Giovanni Posabella, Donato Antonacci, Antonio Tropeano, Emanuele Pausini, Carlotta Pausini, Tommaso Guarniero, Marco Zancanaro

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; Sepsis; Inflammation

Online: 19 July 2020 (15:11:24 CEST)

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Severe COVID-19 disease is characterised by an exaggerated inflammatory response, called cytokine storm, accompanied by a condition of immune depression. Even sepsis is characterised by an exaggerated inflammatory response, called SIRS (Systemic Inflammatory Response Syndrome), accompanied by a condition of immune depression called CARS (compensatory anti-inflammatory response syndrome). Clinical studies reveal that most sepsis patients who did not die during the hyper inflammatory response (SIRS) subsequently succumbed to the condition of immune depression (CARS). Severe acute pancreatitis begins with local inflammation that induces systemic inflammatory response syndrome (SIRS), accompanied and followed by a compensatory anti-inflammatory response (CARS). In COVID-19 disease, the male response to SARS CoV-2 virus is typically characterised by a robust inflammatory response. Instead, a cell-mediated immune response is dominant in women. This means that the male sex tends to have a more robust hyper inflammatory response than the female one. Furthermore, in women the condition of immune depression is less represented, therefore they are more protected. Sepsis, severe acute pancreatitis and COVID-19 disease evolve between two fundamental aspects: hyper inflammation and immunodepression. The experience gained over years of studies of sepsis and severe acute pancreatitis suggests that therapies should be differentiated according to the evolutionary stage of the disease. The goal is to save the lives of most patients with COVID-19 disease. The identification of critical points, suitable for designing the windows of therapeutic opportunity, may allow the use of therapeutic interventions, in the COVID-19 disease, which are effective (there are no approved drugs yet), safe (without significant side effects), targeted (based on the evolutionary phase of the disease) personalized, (based on sex, co-morbidities, age, etc.) and timely (based on signs, symptoms, laboratory parameters and instrumental investigations).

Preprint ARTICLE | doi:10.20944/preprints202007.0287.v1

Cytomegalovirus-Associated Venous and Arterial Thrombotic Disease

Amar Kelkar, Brian Loc, Michael Tarantino, Anita Rajasekhar, Huaping Wang, John Farrell

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Acquired Coagulation Disorders; Arterial thrombosis; prophylaxis; diagnosis; and treatment; Infections in immunocompromised hosts; Viral Infection; Venous thromboembolism; prophylaxis; diagnosis; treatment

Online: 14 July 2020 (03:48:03 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202007.0268.v1

Rapid Senectome and Alternative Splicing miRNAs Changes with the Relaxation Response: A One Year Follow-Up Study

Carlo Dal Lin, Mariela Marinova, Laura Brugnolo, Giorgio Rubino, Mario Plebani, Sabino Iliceto, Francesco Tona

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: cardiovascular disease; inflammation; aging; senectome, telomerase; alternative splicing; relaxation response; microRNA

Online: 12 July 2020 (16:57:10 CEST)

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Working Paper ARTICLE

COVID-19: Role of the Inflammasome

Claudio G. Gallo, Sirio Fiorino, Giovanni Posabella, Donato Antonacci, Antonio Tropeano, Emanuele Pausini, Carlotta Pausini, Tommaso Guarniero, Marco Zancanaro

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; Inflammasome; Interleukin 1β; Inflammation; Innate Immune System

Online: 12 July 2020 (08:17:56 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202006.0279.v2

COVID-19 Testing – Impact of Prevalence, Sensitivity, and Specificity on Patient Risk and Cost

Zoe C. Brooks, Saswati Das

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID19; risk; clinical; metrics; cost; false-positive; false-negative; prevalence; sensitivity; specificity

Online: 9 July 2020 (15:57:30 CEST)

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Preprint REVIEW | doi:10.20944/preprints202007.0142.v1

COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

Corlia Grobler, Jhade Bredenkamp, Mireille Grobbelaar, Sipho Maphumulo, Jaco Laubscher, Janami Steenkamp, Douglas Kell, Etheresia Pretorius

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; fibrin(ogen); D-dimer; von Willebrand Factor; P-selectin; bleeding; thrombocytopenia; thrombosis

Online: 8 July 2020 (10:44:08 CEST)

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Preprint REVIEW | doi:10.20944/preprints202006.0339.v1

New Coronavirus Disease (COVID-19): Clinical Symptoms Other Than Pneumonia with Emphasis on Thrombosis

Takuma Hayashi, Kaoru Abiko, Masaki Mandai, Nobuo Yaegashi, Ikuo Konishi

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: ACE2; COVID-19; SARS-CoV-2; alveolar macrophage; thrombus; thrombosis

Online: 28 June 2020 (10:34:52 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202006.0279.v1

COVID-19 Testing – Impact of Prevalence, Sensitivity, and Specificity on Patient Risk and Cost

Zoe C. Brooks, Saswati Das

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID19; risk; clinical; metrics; cost; false-positive; false-negative; prevalence; sensitivity; specificity

Online: 21 June 2020 (15:12:43 CEST)

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Preprint REVIEW | doi:10.20944/preprints202006.0183.v1

Preventing Mortality in COVID-19 Patients: Which Cytokine to Target in a Raging Storm?

Ligong Lu, Hui Zhang, Meixiao Zhan, Jun Jiang, Hua Yin, Danielle Dauphars, Shi-You Li, Yong Li, You-Wen He

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; SARS-CoV-2; mortality; cytokine storm; cytokine release syndrome; chemokine; inflammation; immunopathology; IL-6; IL-1; CCL2; CCL5

Online: 14 June 2020 (15:44:38 CEST)

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Preprint COMMUNICATION | doi:10.20944/preprints202006.0115.v1

Capillary Regression, A Key Pathogenic Feature of COVID-19 Infection?

George E. Davis, Courtney T. Griffin

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: capillary regression; COVID-19; pro-inflammatory mediators; interleukin-1 beta; tumor necrosis factor; thrombin

Online: 9 June 2020 (04:12:30 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202006.0049.v1

miR-148b Differentiates Tubular Atrophy/Interstitial Fibrosis Histopathological Stages in IgA Nephropathy

Santosh Kumar, Priscilla C, Sreejith Parameswaran, Deepak Shewade, Pragasam Viswanathan, Rajesh Ganesh

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: IgAN; miR-148b; let-7b; Tubular atrophy; Interstitial fibrosis; MEST-C

Online: 5 June 2020 (14:06:53 CEST)

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Preprint BRIEF REPORT | doi:10.20944/preprints202005.0429.v1

Mechanical Ventilation Stimulates Expression of the SARS-Cov-2 Receptor ACE2 in the Lung and May Trigger a Vicious Cycle

Sui Huang, Arja Kaipainen, Michael Strasser, Sergio Baranzini

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: mechanical stress; vicious cycle; midkine; ARDS; GTEx

Online: 26 May 2020 (11:26:52 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202005.0364.v1

The Molecular Basis of Gender Variations in Mortality Rates Associated with the Novel Coronavirus (COVID-19) Outbreak

Ibrahim Y. Hachim, Mahmood Y. Hachim, Iman Mamdouh Talaat, Vanessa M. López-Ozuna, Narjes Saheb Sharif-Askari, Rabih Halwani, Qutayba Hamid

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; gender; transcriptomics; RAS; hydrolase activity; sex-based immunological differences

Online: 23 May 2020 (06:03:25 CEST)

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Since the outbreak of the novel coronavirus disease (COVID-19) at the end of 2019, the clinical presentation of the disease showed a great heterogeneity with a diverse impact between different subpopulations. Emerging evidence from different parts of the world showed significantly poor outcome among males compared to female patients. A better understanding of the molecular mechanisms behind this difference might be a fundamental step for a more effective and targeted response to the outbreak. For that reason, here we try to investigate the molecular basis of the gender variations in mortality rates related to COVID-19 infection. To achieve this, we used our in-house pipeline to process publicly available lung transcriptomic data from 141 females compared to 286 males. After excluding Y specific genes, our results showed a shortlist of 73 genes that are differentially expressed between the two groups. Our results showed downregulation of a group of genes that are involved in the regulation of hydrolase activity including (AGTR1, CHM, DDX3X, FGFR3, SFRP2, and NLRP2), which is also believed to be essential for lung immune response and antimicrobial activity in the lung tissues in males compared to females. In contrast, our results showed an upregulation of angiotensin II receptor type 1 (AGTR1), a member of the renin-angiotensin system (RAS) that plays a role in angiotensin-converting enzyme 2 (ACE2) activity modulation. Interestingly, recent reports and experimental animal models highlight an important role of this receptor in SARS-Coronavirus lung damage as well as pulmonary edema, suggesting a possible role of its blockers like losartan and olmesartan as potential therapeutic options for COVID-19 infection. Finally, our results also showed a differential expression of different genes that are involved in the immune response including the NLRP2 and PTGDR2, further supporting the notion of the sex-based immunological differences. Taken together, our results provide an initial evidence of the molecular mechanisms that might be involved in the differential outcomes observed between both genders during the COVID-19 outbreak. This might be essential for the discovery of new targets and more precise therapeutic options to treat COVID-19 patients from different clinical and epidemiological characteristics with the aim of improving their outcome.

Preprint ARTICLE | doi:10.20944/preprints202005.0310.v1

Parametric Nasopharyngeal Swab for Sampling COVID-19 and Other Respiratory Viruses: Open Source Design, SLA 3-D Printing and UV Curing System

Nicole Gallup, Adam M. Pringle, Shane Oberloier, Nagendra G. Tanikella, Joshua M. Pearce

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: open hardware; COVID-19; medical hardware; nasopharyngeal swab; nasal swab; UV curing; SLA; RepRap; 3-D printing; additive manufacturing

Online: 19 May 2020 (04:21:41 CEST)

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Working Paper ARTICLE

COVID-19 Perfect Storm (Part II): Role of Vitamins as Therapy or Preventive Strategy in Aged People

Sirio Fiorino, Claudio Gallo, Maddalena Zippi, Sergio Sabbatani, Roberto Manfredi, Renzo Moretti, Elisa Fogacci, Caterina Maggioli, Francesca Travasoni Loffredo, Enrico Giampieri, Ivan Corazza, Christoph Dickmans, Claudio Denitto, Michele Cammarosano, Michele Battilana, Paolo Emilio Orlandi, Francesco Del Forno, Francesco Miceli, Michela Visani, Giorgia Acquaviva, Paolo Leandri, Elio Jovine, Roberto Iovine, Dario de Biase

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS; CoV-2; COVID-19; vitamins; therapeutic strategy

Online: 18 May 2020 (12:51:05 CEST)

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Working Paper REVIEW

COVID-19 Perfect Storm (Part I): Cytokine Release Syndrome in Aged People

Sirio Fiorino, Claudio Gallo, Maddalena Zippi, Sergio Sabbatani, Roberto Manfredi, Renzo Moretti, Elisa Fogacci, Caterina Maggioli, Francesca Travasoni Loffredo, Enrico Giampieri, Ivan Corazza, Christoph Dickmans, Claudio Denitto, Michele Cammarosano, Michele Battilana, Paolo Emilio Orlandi, Francesco Del Forno, Francesco Miceli, Michela Visani, Giorgia Acquaviva, Paolo Leandri, Elio Jovine, Roberto Jovine, Dario de Biase

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS; CoV-2; COVID-19; immune system; cytokine

Online: 18 May 2020 (12:46:48 CEST)

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Preprint HYPOTHESIS | doi:10.20944/preprints202005.0262.v1

C1-INH and the Contact System in COVID-19-Associated Coagulopathy

Timothy M. Thomson, Emily Toscano, Ernesto Casis, Rosanna Paciucci

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; coagulopathy; C1-INH

Online: 16 May 2020 (04:19:07 CEST)

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Preprint BRIEF REPORT | doi:10.20944/preprints202003.0338.v3

Yin-Yang Balance of ACE/ACE2 Pathways: The Rational for Administration of ACE2 Pathway Inhibitors in Patients Infected by SARS-CoV-2

Loris Zamai

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Severe Acute Respiratory Syndrome Coronavirus-2; (soluble) ACE2; eosinophil; asthma; IL-10; Lung fibrosis; hypercapnic acidosis; hypoxia; infarction; hypertension; cardiac dysfunction; respiratory distress; coagulopathy; Angiotensin; renin; Ang (1-7); Ang (1-9); Mas receptor; AT2 receptor

Online: 6 May 2020 (04:40:25 CEST)

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Preprint REVIEW | doi:10.20944/preprints202004.0525.v1

The Epidemiology, Evolution, Transmission and Therapeutics of COVID-19 Outbreak: An Update on the Status

Karan Singh Labana, Amit Kumar Mittal, Akash Gujral

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; evolution of SARS-CoV-2; replication; emerging disease 2019 and diagnostic tools

Online: 30 April 2020 (10:39:54 CEST)

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an etiologic agent of the respiratory disease in humans that is known as coronavirus disease 2019 (COVID19). The first outbreak of the disease was initially documented in Wuhan, Hubei Province, China in late December 2019 where people had experienced SARS pneumonia-like symptoms with unknown etiology. Since then it has been observed that COVID-19 positive patients have been showing mild to severe upper respiratory illness symptoms. The type of virus is known to make its transfer from animals to humans and for the concerned virus; researchers have claimed its origin from bat coronavirus at whole-genome level with a 96 % sequence identity. The COVID-19 virus is very contagious and communicable in nature and has been spread throughout the globe since its first outbreak in China. On March 9, 2020, WHO declared it as a Pandemic, and within a month it was already reported to have shown its presence in 213 countries and territories or areas. As of April 29, 2020, this novel virus infected 3,218,183 people and caused 228,029 mortalities worldwide with a variable mortality rate from 3-13 % across the planet and also varied by age and gender. Diagnosis of the disease is a key component in understanding and controlling the spread of the virus and several techniques have been devised including RT-PCR, ELISA, and sequencing-based approaches. To cure COVID-19 patients as of now we do not have proven to be a safe and effective treatment. Therapeutic options currently under investigation in various parts of the world. However, there are various effective therapeutic targets to repurpose the present antiviral therapy for developing potential interventions against SARS-CoV-2. Boosting the immune system can also help to prevent and spread of COVID-19 using various medication and exercises. In this review, our goal to summarize and discussed the present scientific advancements to fight against this novel pandemic.

Preprint ARTICLE | doi:10.20944/preprints202004.0418.v1

Introducing the Q-strip to Quantitatively Measure Nocturnal Perspiration as a Parameter and Predictor: A Review of Literature

Kasper Jolink, Loussi Bedrosian

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Diagnosis; Health sensing system; Nocturnal perspiration; Parameter; Pathology; Predictor; Q-strip; Subjective measurement; Sweat pattern; Symptoms; Prodromal; biomarker

Online: 23 April 2020 (15:26:39 CEST)

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Working Paper ARTICLE

The Rationale for a Multi-Step Therapeutic Approach Based On Antivirals and Drugs with Immunomodulatory Activity in Patients With Coronavirus-Sars2-Induced Disease of Different Severity

Sirio Fiorino, Maddalena Zippi, Claudio Gallo, Debora Sifo, Sergio Sabbatani, Roberto Manfredi, Edoardo Rasciti, Leonardo Rasciti, Enrico Giampieri, Ivan Corazza, Paolo Leandri, Dario de Biase

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS; Covid-19; Vitamins; Therapy

Online: 23 April 2020 (05:44:52 CEST)

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Preprint HYPOTHESIS | doi:10.20944/preprints202004.0360.v1

Early Oxygen Inhalation to Prevent SARS-CoV-2-Induced Acute Respiratory Distress Syndrome

Shu Yuan, Si-Cong Jiang, Zi-Lin Li

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; acute respiratory distress syndrome; hypoxic pulmonary vasoconstriction; alveolar edema; early low-flow oxygen

Online: 20 April 2020 (08:30:29 CEST)

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Preprint REVIEW | doi:10.20944/preprints202004.0284.v1

COVID-19: Look to the Future, Learn from the Past

Zhangkai J. Cheng, Zhigang Liu, Ruixi Zeng, Lifeng Tian, Zhifeng Duan, Hakon Hakonarson, Hui-Qi Qu, Qing Zhang, Liteng Yang, Gang Cheng

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: coronavirus; epidemiology; 2019-nCoV; COVID-19

Online: 16 April 2020 (16:00:00 CEST)

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Preprint REVIEW | doi:10.20944/preprints202004.0238.v1

NETs By-products and Extracellular DNA May Play a Key Role in COVID-19 Pathogenesis: Incidence on Patient Monitoring and Therapy

Alain Thierry, Benoit ROCH

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Covid; NET; neutrophils; circulating DNA; therapy; innate immune response

Online: 15 April 2020 (09:55:34 CEST)

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Neutrophils play an important role as the first line of innate immune defense. One function of neutrophils, called neutrophil extracellular traps (NETs), has been discovered recently. NETs are extensive fibrous structures released extracellularly from activated neutrophils in response to infection. They are composed of cytosolic protein assembled on a scaffold of released chromatin. These structures suppress the dissemination of micro-organisms in blood by trapping them mechanically, and by exploiting coagulant function to segregate them within the circulation. In addition, NET components (DNA, histone, and granule proteins) also contribute to the triggering of an inflammatory process. NET function, however, can be regarded as a double-edged sword. On one hand, NET formation is an efficient strategy for neutralizing invading micro-organisms. On the other hand, NET can be harmful to the host, as its exposed by-products that are toxic to endothelial cells and parenchymal tissue. We present here the analogous biological and physiological features of the harmful positive amplification loop between inflammation and tissue damage induced by NETosis dysregulation and Coronavirus Disease-2019 (COVID-19) pathogenesis. Considering the rapid evolution of this disease symptoms and its lethality, we hypothesize that COVID-19 progresses under an amplifier loop, leading to an massive, uncontrolled inflammation process. We also describe the correlations of COVID-19 symptoms and biological features with those consecutive to uncontrolled NET formation causing various sterile or infectious diseases. General clinical conditions, and numerous pathological and biological features, are analogous with NETs deleterious effects. We postulate that Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) induces a disproportionate virus-induced NET release, and that this plays a key role in COVID-19 pathogenesis. While neutrophils are the principal starting point for extracellular and circulating DNA release, targeting NETs rather than neutrophils themselves may stand for an effective strategy. This paper offers an in-depth review of NET formation, function and pathogenic dysregulation, as well as of current and future therapies to control NET unbalance. As such, it enables us also to suggest new therapeutic strategies to fight COVID-19. In combination with or independent of the latest tested approaches, we propose that, in the short term, deoxyribonuclease I (DNase-1) treatment should be evaluated; we also advocate a significant increase in research on the development of toll-like receptors (TLR) and C-type Lectin like receptors (CLEC) inhibitors, and on anti-IL26 therapies.

Preprint REVIEW | doi:10.20944/preprints202004.0077.v2

The Pathophysiology of Virulence of the COVID-19

Joseph De Soto, Shazia Hakim, Frederick Boyd

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; native American Indian; treatment; ACE2 receptor; pathophysiology; virulence

Online: 15 April 2020 (08:08:52 CEST)

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Background: On Dec 19, 2019, the public health department of China reported that an outbreak of pneumonia was caused by a novel Coronavirus. The virulence of the new virus COVID-19 was much greater than either the SARs and MERSs viruses and on March 11, 2020, the World Health Department (WHO) declared a worldwide pandemic. Understanding the pathophysiology of virulence of the SARS-COV-2 virus is absolutely necessary for understanding the transmission, virulence factors, reduce risk factors, clinical presentation, predict outcomes of the disease and provide guidance for any current or future treatment protocols. Methodology: A comprehensive PubMed search was performed during December 20, 2019 and April 03, 2020, utilizing the words: Wuhan Virus, COVID-19, SARs coronavirus, ACE2, S-protein, virulence, clinical presentation, epidemiology, genome, treatment, structure, MERs, pathogenesis and/or pathology alone and in combination with other terms. Each paper was evaluated by three content experts for quality, reproducibility, credibility and reputation of the journal. Results: The SARS-COV-2 virus is much more virulent than either the SAR’s or MER’s virus and its ability to cause serious disease inversely corresponds to the person’s ability to produce T-cells which declines linearly with age. The ACE2 receptor binding site does not vary among different ethnic groups but do in ACE-2 expression levels. This variance in expression level may explain for different infectivity rates among men and women and predict and explain different susceptibilities to infection by different ethnic groups. Furthermore, by understanding the underlying pathophysiology one can explain and provide guidance to the clinical effectiveness of any treatment. Conclusions: The underlying pathophysiology of COVID-19 explains not only the virulence, and clinical presentation, but, explains at a molecular level the comorbidity risk factors such as hypertension, sex, and age. Ethnic and anatomic expression patterns of ACE-2 and associated pathophysiology suggests that Native Americans and Asians may be particularly susceptible to this disease.

Preprint REVIEW | doi:10.20944/preprints201907.0211.v2

HIV-1: Tackling the Obstacles that Limit the Effectiveness of CRISPR-Cas9 Gene Editing of the T Cell Co-receptor CCR5

Tatiana Hillman

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: HIV-1; CRISPR-Cas9; T-cells; lipid nanoparticles; gut-associated-lymphoid tissue; Co-receptors; Probiotics; GI Tract,; Gene Editing

Online: 13 April 2020 (10:57:52 CEST)

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HIV-1 is a complicated and perplexing virus. It infects T cells, reverse transcribes its RNA into DNA, utilizes its host DNA machinery to replicate its HIV-DNA, translates the HIV-DNA into proteins, assembles itself for a budding escape from the T cell, and rapidly mutates its conformation. Partially, due to its complexity, there remains no cure for HIV or AIDs. However, recently with the discovery of TALENs, the use of zinc fingers, and most of all the applications of CRISPR-Cas9 technology, has given researchers new hope in finding alternative gene therapies and treatments for diseases. With more focus on CRISPR-Cas9, this new and novel technology uses a guiding RNA, sgRNA, to lead a Cas9 nuclease to its target for deletion or to change that DNA site. CRISPR-Cas9 can delete point mutations and multiple DNA sites. Because CRISPR can alter DNA sequences, several scientists have conducted research into CRISPR, possibly treating more diseases such as cancer, diabetes, and even HIV. HIV-1 drew the focus of a researcher named Dr. Ebina in 2013 when he was the first to design and apply CRISPR-Cas9 to genes found in the binding sites of HIV-1, inhibiting HIV-1 gene expression. Since 2013, several other researchers have blocked HIV replication and infection through CRISPR-Cas9 targeting the receptors of T cells called the CC chemokine receptor 5 or CCR5. HIV-1 binds to the CD4 receptor of T cells, which consists of co-receptors CCR5 and CXCR4. If CCR5 expression can be removed, the HIV virus cannot bind to T-cells, blocking the initial attachment stage, and discontinuing the infection. However, there remain obstacles and issues for the CRISPR deletion of CCR5 for treating HIV-1. The issues include: 1) finding new and safe methods of CRISPR-Cas9 delivery, 2) clearing the latent HIV reservoirs, 3) improving the sgRNA design to avoid off-target mutations or deletions, and 4) effectively analyze the viral escape of HIV from CRISPR-Cas9 modifications. Therefore, the purpose of this review is to discuss possible techniques for removing the obstacles that can lessen the potential of CRISPR to delete CCR5, repressing HIV-1 into long-term remission or a functional cure.

Preprint HYPOTHESIS | doi:10.20944/preprints202004.0143.v1

Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

Massimiliano Bonafè, Francesco Prattichizzo, Angelica Giuliani, Gianluca Storci, Jacopo Sabbatinelli, Fabiola Olivieri

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; COVID-19; IL-6; inflamm-aging; immune senescence; host-directed therapies

Online: 9 April 2020 (08:38:22 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202004.0030.v1

Intra-Cystic (In Situ) Mucoepidermoid Carcinoma: A Clinico-Pathological Study of 14 Cases

Saverio Capodiferro, Giuseppe Ingravallo, Luisa Limongelli, Mauro Giuseppe Mastropasqua, Angela Tempesta, Gianfranco Favia, Eugenio Maiorano

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: salivary glands, minor salivary glands, salivary gland carcinoma, mucoepidermoid carcinoma, in situ carcinoma, intra-cystic carcinoma

Online: 8 April 2020 (14:46:41 CEST)

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Aims: To report on the clinico-pathological features of a series of 12 intra-oral mucoepidermoid carcinomas showing exclusive intra-cystic growth. Methods and methods: All mucoepidermoid carcinomas diagnosed in the period 1990-2012 were retrieved, the original histological preparations were reviewed to confirm the diagnosis, and from selected cases, showing exclusive intra-cystic neoplastic component, additional sections were cut at 3 subsequent 200m intervals and stained with Hematoxylin-Eosin, PAS and Alcian Blue, to possibly identify tumor invasion of the adjacent tissues, which could have been overlooked in the original histological preparations. Also, pertinent findings collected from the clinical charts and follow-up data were analyzed. Results: We identified 14 intraoral mucoepidermoid carcinomas treated by conservative surgery and with a minimum follow up of 5 years. The neosplasm were located in the hard palate (9 cases), the soft palate (2), the cheeck (2) and the retromolar trigone (1). In all instances histological examination was revealed the presence of a single cystic space, containing clusters of columnar, intermediate, epidermoid, clear and mucous-producing cells, the latter exhibiting distinct intra-cytoplasmic mucin production, as confirmed by PAS and Alcian Blue stains. The cysts were entirely circumscribed by fibrous connective tissue and no solid areas or infiltrating tumour clusters were detected. Conservative surgical resection was performed in all cases and no recurrences or nodal metastases were observed during the follow up period. Conclusions: Mucoepidermoid carcinomas showing prominent (>20%) intra-cystic proliferation currently are considered low-grade tumours. In addition, we also unveil the possibility that mucoepidermoid carcinomas, at least in their early growth phase, may display an exclusive intra-cystic fashion and might be considered as in situ carcinomas, unable to infiltrate adjacent tissues or metastasize.

Working Paper ARTICLE

Investigation of the Health Effects of Workers Exposed to Respirable Crystalline Silica during Outdoor and Underground Construction Projects in Greece

Dimitrios Keramydas, Petros Bakakos, Manos Alchanatis, Ioannis Konstantakopoulos, Petros Papalexis, Kyriaki Tavernaraki, Vasileios Dracopoulos, Antonios Papadakis, Eugenia Pantazi, Nektaria Sidiropoulou, Georgios Chelidonis, Elias Chaidoutis, Theodoros C. Constantinidis, Dimosthenis Chochlakis, Nikolaos Kavantzas, Efstratios Patsouris, Andreas Ch. Lazaris

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: ilicosis; silicon powder; crystalline silica (SiO2); construction workers; occupational exposure; occupational exposure limit; occupational hygiene

Online: 8 April 2020 (04:22:26 CEST)

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Preprint REVIEW | doi:10.20944/preprints202004.0103.v1

Safe Laboratory Practices in the Light of Covid-19 Pandemic: Way Forward in a Resource Limited Setting

Kevin Odega, Ehijie Iyamah, Ephraim Ibadin, Festus Idomeh, Deborah odega

Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Coronavirus; SARS-CoV-2; Medical Laboratory; Resource-limited setting, Good Laboratory Practice (GLP)

Online: 7 April 2020 (12:11:35 CEST)

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MEDICINE & PHARMACOLOGY