Whole genome sequencing of a German cohort to understand host genetics in COVID-19

Background/Objectives: The disease course upon SARS-CoV-2 infection is highly variable and comprises a range from asymptomatic infection to severe (and even lethal) COVID-19. Genetic factors substantially contribute to this variability, as evidenced by epidemiological studies and recent results from genome-wide association studies (GWAS) as well as sequencing-based approaches. The host genetics group of the German COVID-19 OMICs Initiative (DeCOI) has been founded with the aim to identify additional genetic variants that influence COVID-19 severity through whole genome sequencing (WGS) analyses. Method(s): Until January 2022, WGS has been performed on approximately 1200 individuals affected by COVID-19. Result(s): The most recent data freeze comprised 952 individuals. In this dataset, no carrier of a deleterious protein-altering variant has been detected in TLR7, which is the only conclusive risk gene for severe COVID-19. Applying a gene-based association test of rare variants to the subcohort of European individuals (n = 752, mean age: 56 years, females: 44%), including 199 severely affected individuals, we did not observe any significant association after correction for multiple testing. Exome-wide association analysis of common variants in this subcohort replicated the GWAS-locus on chromosome 3. Conclusion(s): With this ongoing work, we are contributing to international efforts to elucidate the host genetics of COVID-19, also by sharing our summary statistics for meta-analyses. Currently, we are sequencing additional severely affected individuals and we are refining analytical strategies, which will also include the joint analysis of common and rare variants at genomewide scale.

Case Report of Succesful Multidisiplinary Treatment for Patient with Metastatic Lung Cancer and Relapsed/Refractory Chronic Lymphatic Leukemia/Small Lymphocytic Lymphoma

Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.

A survival genome-wide association study to identify variants associated with COVID-19 risk of death

Background/Objectives: SARS-CoV-2 infection clinical manifestations hugely vary among patients, ranging from no symptoms, to life-threatening conditions. This variability is also due to host genetics: COVID-19 Host Genetics Initiative identified six loci associated with COVID-19 severity in a previous case-control genome-wide association study. A different approach to investigate the genetics of COVID-19 severity is looking for variants associated with mortality, e.g. by analyzing the association between genotypes and time-to-event data. Method(s): Here we perform a case-only genome-wide survival analysis, of 1,777 COVID-19 patients from the GEN-COVID cohort, 60 days after infection/hospitalization. Case-only studies has the advantage of eliminating selection biases and confounding related to control subjects. Patients were genotyped using Illumina Infinium Global Screening Arrays. PLINK software was used for data quality check and principal component analysis. GeneAbel R package was used for survival analysis and age, sex and the first four principal components were used as covariates in the Cox proportional hazard model. Result(s): We found four variants associated with COVID-19 patient survival at a nominal P < 1.0 x 10-6. Their minor alleles were associated with a higher mortality risk (i.e. hazard ratios (HR)>1). In detail, we observed: HR=1.03 for rs28416079 on chromosome 19 (P=1.34 x 10-7), HR=1.15 for rs72815354 on chromosome 10 (P=1.66 x 10-7), HR=2.12 for rs2785631 on chromosome 1 (P=5.14 x 10-7), and HR=2.27 for rs2785631 on chromosome 5 (P=6.65 x 10-7). Conclusion(s): The present results suggest that germline variants are COVID-19 prognostic factors. Replication in the remaining HGI COVID-19 patient cohort (EGAS00001005304) is ongoing at the time of submission.

Strong impact of the COVID-19 pandemic on fetal development and chromosomal abnormalities

Background/Objectives: To date, not many studies have been conducted to examine the role of COVID-19 on gestation and fetal development. During COVID-19, pregnant women had difficulty accessing prenatal screening and care due to pandemics restrictions and lockdowns. In this retrospective study we aimed to assess the effect of the SARS-CoV-2 outbreak on fetal development in both prenatal and postnatal outcomes pre-and pre-COVID-19 pandemics in Northern Cyprus. Method(s): A total number of 61 aborted materials were karyotyped during the pre-pandemic period (January 2017 and March 2020) whereas 24 samples were analysed during the peripandemic period (March 2020-November 2021). On the other hand, 25 new-borns blood samples during the pre-pandemic and 44 samples during the pre-pandemic period were analysed. Result(s): No statistically significant difference found in health and abnormal aborted material karyotypes between two periods. On the other hand, a statistical significance was observed in postnatal chromosomal abnormalities (P = 0.04) after two long pandemic lockdowns, which are known as the first and the second waves, dramatically indicating that no baby with Down syndrome was between 2017-2020 whereas seven babies with Down Syndrome were born as consequences of without taking precaution against lockdowns. Conclusion(s): Overall, prenatal care is failed which resulting increased postnatal chromosomal abnormality due to heavy flight restrictions, economic inflation instability, limited access to medical services during COVID-19 pandemic lockdowns in Northern Cyprus.

Gain and loss of function CFTR alleles modulate COVID-19 clinical outcome

Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.

Mild Androgen Insensitivity Syndrome presenting in male with infertility and sexual difficulties

Androgen insensitivity syndrome has a wide spectrum of presentations. It results from a mutation in androgen receptor (AR) gene. It ranges from mild androgen insensitivity syndrome (MAIS) which is the mildest form to complete androgen insensitivity syndrome (CAIS). In case of MAIS, the abnormality that can be observed appears to be male infertility and sexual difficulties including premature ejaculation and erectile dysfunction. In this case report, we discuss a case of MAIS in a 37-year-old male who presented with infertility, premature ejaculation, and secondary erectile dysfunction.Copyright © 2023, Ibn Sina Trust. All rights reserved.

The eXtraordinarY BABIES STUDY: EARLY SOCIAL COMMUNICATION SKILLS IN INFANTS WITH SEX CHROMOSOME TRISOMY (SCT)

Purpose of Study: The eXtraordinarY Babies Study is a natural history study of health and neurodevelopment in infants with a prenatal diagnosis of SCT. Given the increased risk for social difficulties and autism in SCT in later childhood and beyond, the study explores trajectories of early social communication development to identify early predictors of outcomes, and relationship of social communication skills to developmental profiles. Methods Used: A subset of 56 participants (XXY=43, XYY=4, XXX=9) from the eXtraordinarY Babies Study completed the Autism Diagnostic Observation Schedule- 2nd edition (ADOS-2), Toddler Module as part of the 12-month visit and The Bayley-3 Scales of Infant and Toddler Development. The ADOS-2 provides ratings of 0 (typical development), 1 (mild atypicality), and 2 (atypical) for communication, social interaction, and other behavior items, and an algorithm classifies total score into categories of: Little-No Concern, Mild-Moderate Concern, Moderate-Severe Concern. Analyses were limited to those who completed the assessment prior to COVID19 mask/shield requirements. Summary of Results: High rates of delayed or atypical development of early social communication skills were identified, with >75% of the sample showing scores of 1 or 2 in frequency of babbling, spontaneous vocalizations, gesture use, and pointing. 58% of the sample showed unusual eye contact and vocalizations. Over 50% received atypical scores on items assessing the quality of eye contact. Participants showed few restricted and repetitive behaviors. Results of ADOS-2 total scores: Little-no concern 50%, Mild-Moderate concern 35.7%, Moderate-severe concern 14.3%. No one was assigned a clinical diagnosis of ASD. For this group, Bayley-3 results showed average Cognitive (scaled score 10.8 sd1.9) and Fine motor skills (9.3 sd2.3), followed by lower Receptive (8.2 sd2.4) and Expressive Language (8.9 sd3.0) and below average Gross Motor skills (7.9 sd2.6). Receptive language scores negatively correlated with ADOS-2 Social Affect (r= -.38, p = < .001) and Overall Total (r= -.41, p = < .001). Conclusion(s): Even at an early age, toddlers with SCT are at increased risk for language, communication, and social interaction delays. While no participants were diagnosed with ASD at 12 months of age, social communication deficits known to be "red flags" for later diagnosis of ASD were seen in a subset of young children with SCT. Prospective follow-up will allow us to determine the trajectory of these deficits and those that may predict higher risk for more significant clinical symptoms.

Integrating Bioethics and Neonatal Palliative Care in a Pandemic: The Scope of Advocacy and Online Collaboration for Exceptional Life-Sustaining Medical and Surgical Interventions in a Regional Neonatal Intensive Care Unit

Purpose of Study: The regional NICU is an essential healthcare resource for families of newborns with serious life-threatening illnesses. Mechanical ventilation, cardiovascular therapies, therapeutic hypothermia, and neonatal surgeries are common life-sustaining interventions. Our NICU serves an underprivileged population in a resource poor environment and several ethical questions frequently emerge when facing extremes of innovative therapies. The pandemic and rapidly changing institutional protocols accentuated challenges faced by frontline NICU teams caring for newborns at risk for devastating illnesses and death. Concurrently, evolving paradigms in neonatal ethics required urgent and high quality palliative care in a background of racial and socioeconomic inequities, restrictive visitation policies, and limited healthcare resources. The purpose of this study was to ensure that neonates and their families receive ethically sound care, timely referrals for innovative therapies, and specialized palliative care in the strained and uncertain environment of the COVID-19 pandemic. Methods Used: The key steps consisted of structured and impromptu discussion forums for specialized palliative care and medical ethics, perinatal case conferences and pediatrics grand rounds on virtual platforms, educational webinars for interdisciplinary teams, and improved electronic communication. Online collaboration and innovative combinations of in-person and virtual meetings were utilized for urgently Incorporating clinical updates. Summary of Results: 1. A neonate with severe HIE and postnatally diagnosed congenital diaphragmatic hernia required emergent ECMO center referral. NICU providers utilized a structured bioethics and palliative care framework for providing family support and discussing the prognostication challenges of acute illnesses. 2. Many important bioethical questions emerged while caring for infants with life-threatening chromosomal abnormalities. Ethical tension was addressed by teaching tools, quality of life and pediatrics ethics conversations, mitigation of moral distress, contemporary clinical and surgical experience, community engagement, and family perspectives. 3. Ethical conflicts are central in the decision to resuscitate neonates born between 22 and 23 weeks of gestation. To provide urgent prenatal consultations and attend high risk deliveries, we collaborated across geographically distant healthcare systems, unified management strategies and analyzed outcomes data. 4. NEC in several extremely preterm babies had devastating outcomes and the team respected each family's voice with compassionate, shared decision-making for both curative care surgeries and palliative care. Conclusion(s): The new workflows, telephone and video conferences, and redirection to telehealth based family meetings did not change important outcomes during the pandemic. Advocacy and education for integrating bioethics and palliative care were vital facets of neonatal critical care in a resource poor and ever-changing pandemic environment.

Association of Toll-Like Receptor 7 and 8 Polymorphisms with Covid-19 Severity

Objectives: Toll-like receptors (TLRs) are an important family of receptors that recognize infectious agents and play an important role in the innate immune system. TLRs are a potential candidate to control infection in the early stages of the disease and to produce vaccines against SARS-CoV-2. In addition, studies have suggested that TLR polymorphisms are also associated with antiviral responses against SARS-CoV-2. Therefore, we aimed to investigate the relationship of TLR7 and TLR8 polymorphisms with COVID-19 disease prognosis. Materials-Methods: A total of 120 COVID-19 patients, including 40 outpatients, 40 patients with mild and moderate clinical status, hospitalized and severe pneumonia, and 40 patients followed in the intensive care unit (ICU), were included in the study. The classification of disease severity was made according to WHO criteria. TLR7 (rs179009), TLR8 -129 C/G (rs3764879) and TLR8 Met1Val (rs3764880) polymorphisms were genotyped using the PCR-RFLP method. Result(s): Since TLR7 and TLR8 are located on the X chromosome, men and women were analyzed separately. There was no significant difference between the groups in terms of 3 polymorphisms in males. On the other hand, in women, individuals carrying AG genotype and G allele for TLR8 Met1Val polymorphism were found at a higher rate in patients hospitalized in ICU than in patients followed in the service (p <0.05). In terms of the other two polymorphisms, no significant difference was found between the groups in women. Conclusion(s): We suggest that the AG genotype and G allele of TLR8 Met1Val polymorphism can be considered as an important risk factor that increases the severity of the disease in women.

Post-Transplantation Cyclophosphamide for the Prevention of Graft-Versus-Host Disease Should Not Limit Transplantation for Acute Lymphoblastic Leukemia in People with Trisomy 21

Introduction: Use of hematopoietic cell transplantation (HCT) in patients with trisomy 21 (+21) is infrequent given concerns about increased toxicity with cytotoxic chemotherapy.1 Due to increasing evidence of benefit from post-HCT cyclophosphamide (PTCy) for graft-vs.-host disease (GVHD) prophylaxis and lack of prior descriptions in patients with +21,2-4 we report on 2 patients with +21 and acute lymphoblastic leukemia (ALL) who underwent HCT with PTCy. Method(s): Retrospective data were collected from 2 patients with ALL and +21 who underwent allogeneic HCT with PTCybased GVHD prophylaxis from 2019 to 2021. Data collected included age, disease risk, HCT-CI, GVHD incidence, and survival. Result(s): Patient 1 is a 22-year-old male and patient 2 a 25-year-old female. Both had Ph-negative, B-cell ALL. Patient 1 had ETV6/RUNX1 rearrangement, del 12p, gain of X, and he had recurrence of measurable residual disease (MRD) after initial MRD-negative CR with two lines of therapy pre-HCT. Patient 2 had normal cytogenetics and relapsed disease with 4 prior lines of therapy. Both achieved MRD-negativity pre-HCT. Both received fludarabine and melphalan conditioning, and patient 1 also received thiotepa 2.5 mg/kg. PTCy was given on days +3 and 4 at 50 mg/kg with sirolimus and tacrolimus for GVHD prophylaxis. Patient 1 had a haploidentical donor and received one dose of rabbit ATG (1 mg/kg) on day +5. Patient 2 had a matched unrelated donor. There was no significant delay in engraftment of ANC (day 16-19) or platelets (day 15-16). Patient 2 developed acute GVHD at day 30 (stage I skin, stage II GI) that resolved with steroids which were tapered off by day 96 without recurrence. Sirolimus stopped at day 79 (pt 1) and 103 (pt 2) and tacrolimus was stopped at day 274 (pt 1) and 469 (pt 2). Patient 1 developed a sirolimus-induced pericardial effusion at day 84 which did not recur after sirolimus discontinuation. Patient 2 developed moyamoya 8 months post-HCT during tacrolimus taper without other GVHD symptoms. Response to steroids was noted, so tacrolimus was restarted for residual neurological deficit. Neither patient developed chronic GVHD or left ventricular ejection fraction decline, and neither patient had disease relapse at follow-up of 30 and 16 months respectively. Patient 2 developed COVID pneumonia 16 months post-HCT and died while in CR. Patient 1 remains alive, in CR, and off immunosuppression nearly 3 years post HCT. Conclusion(s): Allogeneic HCT with PTCy at standard doses did not appear prohibitively toxic in patients with +21 when administered after reduced-intensity conditioning. In this case series, GVHD rates seemed consistent with larger series in patients without +21. Moyamoya development is associated with autoimmunity in patients with +21 and hence may have been GVHD-related5. Trisomy 21 should not be a barrier to patients otherwise eligible for HCT, even with PTCy prophylaxis.Copyright © 2023 American Society for Transplantation and Cellular Therapy

Epigenetic features, methods, and implementations associated with COVID-19

The infection and life cycle of severe acute respiratory syndrome coronavirus 2 are widely studied, yet multiple gaps exist in the knowledge that affects therapeutic developments against coronavirus disease 2019 (COVID-19). Predominantly caused by a respiratory virus, COVID-19 is not restricted to the respiratory tract but affects multiple organs of the body including the cardiovascular, neurological, immunological, and renal systems. COVID-19 affects all age groups, although the elderly population inherently presenting with multiple comorbidities are disproportionately affected. The majority of the patients experience mild symptoms, although moderate, severe, and critical symptoms occur in a smaller group of patients. Interestingly, the effects of the disease can be acute or chronic and present an ongoing health care challenge. Epigenetic mechanisms of COVID-19 (DNA methylation, histone posttranslational modifications, histone citrullination, etc.) are an emerging field and present enormous potential toward the medical management of COVID-19. Angiotensin converting enzyme 2, an important protein in the cardiovascular system, is a receptor for viral entry into cells, and the epigenetic processes that regulate this protein have been widely studied. Identification of the epitranscriptomic profile has led to the identification of putative biomarkers for disease diagnosis and trials of novel epidrugs for targeted therapy. © 2023 Elsevier Inc. All rights reserved.

Sex chromosome complement and sex steroid signaling underlie sex differences in immunity to respiratory virus infection.

Epidemiological studies have revealed sex differences in the incidence and morbidity of respiratory virus infection in the human population, and often these observations are correlated with sex differences in the quality or magnitude of the immune response. Sex differences in immunity and morbidity also are observed in animal models of respiratory virus infection, suggesting differential dominance of specific immune mechanisms. Emerging research shows intrinsic sex differences in immune cell transcriptomes, epigenomes, and proteomes that may regulate human immunity when challenged by viral infection. Here, we highlight recent research into the role(s) of sex steroids and X chromosome complement in immune cells and describe how these findings provide insight into immunity during respiratory virus infection. We focus on the regulation of innate and adaptive immune cells by receptors for androgen and estrogens, as well as genes with a propensity to escape X chromosome inactivation. A deeper mechanistic knowledge of these pathways will help us to understand the often significant sex differences in immunity to endemic or pandemic respiratory pathogens such as influenza viruses, respiratory syncytial viruses and pathogenic coronaviruses.

Optimal approach to T-cell ALL

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patient's risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.Copyright © 2022 by The American Society of Hematology.

Male fertility: a review of the publications July - September 2021.

The article provides an overview of the most significant publications on the topic of male infertility. The main selection criteria were considered the practical significance of the article, as well as the impact factor of the journal in which it was published according to the SCImago Journal Rank (SJR). As a result, we formed a list of 10 articles published in the III quarter (July - September) of 2021. The review included articles concerning the following issues: the ability of oocytes to repair damaged DNA-chains of sperm cells, the effectiveness of ICSI in AZF-c microdeletions, the advanced paternal age, artificial intelligence in reproductive clinics, genetic causes of infertility, the effect of surgical treatment of varicocele concerning DNA fragmentation, the role of ICSI in the frequency of chromosomal abnormalities in offspring, the safety of COVID-19 vaccination for spermatogenesis, as well as the novel WHO 6 manual for semen investigation.Copyright © 2021 Vestnik Urologii. All rights reserved.

Molecular Study of ACE2 Gene Polymorphism of COVID-19 Infection among the Kurdish Population in Kurdistan Region- Iraq.

Coronavirus Disease 2019 (COVID-19) is a current pandemic infection of the human respiratory system, which is caused by which caused by Sever Acute respiratory syndrome virus 2 (SARS-CoV-2). The infection was classified by World Health Organization (WHO) as a universal pandemic in February 2020; there have been 494.587.638 confirmed cases and 6.170.283 deaths. The present study investigated the molecular genetics of the Angiotensin Converting Enzyme 2 (ACE2) gene in correlation to COVID-19 patients in the Kurdish population. Eighty-six individuals were clinically diagnosed with COVID-19 and control groups. After the genomic DNA extraction these participants the target 1, 2 and 8 exons of the ACE2 gene were amplified using the PCR technique, and then the Sanger sequencing technique was performed to analyze genetic variants of the ACE2 gene in 70 DNA samples of COVID-19 hospital patients at Emergency Hospital in Erbil city, Sarchnar Hospital in Sulaymaniyah city, Lalav Hospital in Duhok city and Wafa Hospital in Halabja city from Kurdistan Region of Iraq. The current study was designed into two groups control group and a patient group. The patient group was divided into two subgroups, severe and mild patients of different ages and genders. As a result, there were no mutations at the positions 1, 2 and 8 exons sequences, while single nucleotide polymorphisms (SNPs) were detected and identified three different types of mutation at intron position: twenty-six of c.12405 del T, two of c.12407 T>G, and two of c.12406 G>A in a total 86 participants. This result shows that genetic difference does not impact the COVID-19 infection severity among the Kurdish population regarding ACE2 gene polymorphism.

Unusual X chromosome inactivation maintenance in female alveolar type 2 cells is correlated with increased numbers of X-linked escape genes and sex-biased gene expression.

Sex differences exist for many lung pathologies, including COVID-19 and pulmonary fibrosis, but the mechanistic basis for this remains unclear. Alveolar type 2 cells (AT2s), which play a key role in alveolar lung regeneration, express the X-linked Ace2 gene that has roles in lung repair and SARS-CoV-2 pathogenesis, suggesting that X chromosome inactivation (XCI) in AT2s might impact sex-biased lung pathology. Here we investigate XCI maintenance and sex-specific gene expression profiles using male and female AT2s. Remarkably, the inactive X chromosome (Xi) lacks robust canonical Xist RNA "clouds" and less enrichment of heterochromatic modifications in human and mouse AT2s. We demonstrate that about 68% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI. There are genome-wide expression differences between male and female AT2s, likely influencing both lung physiology and pathophysiologic responses. These studies support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease.

Safety of and antibody response to the BNT162b2 COVID-19 vaccine in adolescents and young adults with underlying disease

Background: Data are limited regarding the safety of and antibody response to the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid vaccine in adolescents and young adults with underlying disease. Methods: This prospective observational study enrolled patients age 12–25 years with chronic underlying disease who received 2 doses of BNT162b2. A 18-item questionnaire was used to assess adverse events within 7 days post-vaccination, and data regarding severe adverse events were collected from electronic medical records. An antibody titer for the receptor-binding domain of the spike protein in SARS-CoV-2 was used to assess antibody response after the second vaccine dose. Results: Study participants were 429 patients (241 [56.2%] age 12–15 years;188 [43.8%] age 16–25 years). The most common underlying diseases were genetic or chromosomal abnormalities and/or congenital anomalies, followed by endocrine or metabolic diseases;32% of participants were immunocompromised. Severe adverse events were observed after the second dose in 1 (0.4%) patient age 12–15 years and in 2 (1.1%) patients age 16–25 years;all patients recovered. Seropositivity after the second vaccine dose was 99.0%. The geometric mean antibody titer was higher in patients age 12–15 years versus 16–25 years (1603.3 [1321.8–1944.7] U/mL vs. 949.4 [744.2–1211.0] U/mL). Compared with immunocompetent patients, immunocompromised patients had a lower antibody titer (2106.8 [1917.5–2314.7] U/mL vs. 467.9 [324.4–674.8] U/mL). Conclusions: Vaccination with BNT162b2 was acceptably safe and immunogenic for adolescents and young adults with underlying disease. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

RNA INTERFERENCE IS THE BASIS OF HUMAN ANTIVIRAL DEFENSE.

Comparative analysis of antiviral protective mechanisms in protozoa and RNA interference of multicellular organisms has revealed their similarity, also providing a clue to understanding the adaptive immunity. In this article, we present the latest evidence on the importance of RNA-guided gene regulation in human antiviral defense. The role of neutralizing antibodies and interferon system in viral invasion is considered. The new concept has been introduced, i.e., antiviral protection of any living organism is based on the intracellular RNA-guided mechanisms. Simple and effective defense against viruses is that spacer segment of the viral DNA is inserted into the cellular chromosomes. Upon re-infection, the RNA transcript of the spacer directs nuclease enzymes against the foreign genome. This is a really adaptive immune defense that any cell potentially possesses. In humans, the interferon system provides an additional tool for early suppression of viral infections which shifts the cells to the alert regimen, thus preventing further spread of infection. The main task of the human central immune system is to maintain integrity and combat foreign organisms. Accordingly, a suitable index of acquired antiviral immunity should be a presence of specific spacer markers in DNA samples from reconvalescent persons, rather than detection of neutralizing antibodies, B and T memory cells. This article is addressed primarily to general medical community, and its practical conclusions are as follows: 1. Presence or absence of specific antibodies to SARS-CoV-2 is not a prognostic sign of the disease. Detection of specific antibodies in blood simply reflects the fact that the person has contacted with the viral agent. Absence of antibodies does not mean a lack of such contact, and the persons with high titers of specific antibodies are not protected from re-infection with SARS-CoV-2. 2. PCR testing: The PCR results may remain "false positive" in those subjects who have had COVID-19, if the genetic material is taken from the site of initial virus contraction (mainly, nasopharynx). In our opinion, negative PCR tests for COVID-19 in blood plasma and urine will be a more correct index for the absence of the disease, even with positive PCR tests from the nasopharyngeal samples. 3. It is necessary to draw attention of general practitioners to potential usage of retinol in prevention and treatment of COVID-19, given the importance of RLR receptors in recognition of viral RNAs and positive experience of vitamin A administration in measles, another dangerous viral disease. Copyright © 2022, SPb RAACI.

Mineralizing angiopathy: an underrecognized clinicoradiologic entity

Case Report: Initial History/Presentation: A term vaccinated 7-month-old male with a history of eczema presents with two hours of right-sided hemiplegia and hemidystonia. Parents deny loss of consciousness, altered mental status, or facial symptoms. He has no known history of recent or remote head trauma. Patient may have had COVID two months prior when he had upper respiratory symptoms, with his mother testing COVID+ at that time. Of note, he received a Moderna COVID vaccination one day prior to onset of symptoms. Physical Exam: Pertinent exam findings include CN II-XII intact, right-sided upper and lower extremity strength 3/5, sensation intact, and truncal ataxia while seated. Physical exam is otherwise unremarkable. Diagnostic Evaluation: Initial lab work revealed leukocytosis (20.9), but otherwise a reassuring CMP, triglycerides, HDL, and LDL. PTT was elevated, but normal on recheck. Protein C antigen and activity were low, but deemed non-concerning by hematology. All other hypercoagulable labs were normal. On imaging, CT Brain showed linear calcifications in bilateral basal ganglia suggestive of mineralizing angiopathy. HisCTA head/neckwas negative.MRI Brain revealed an acute infarct of the body/tail of the left caudate nucleus, posterior limb of internal capsule, and posterior putamen. Clinical Course/Follow-up: Our patient was started on Aspirin 4 mg/kg daily. Throughout the course of his 3-day inpatient stay, he had mild improvement of right-sided strength and function, and continued improvement upon follow-up with his pediatrician. Given the short interval between receiving his COVID vaccination and onset of symptoms, his case was reported to the Vaccine Adverse Event Reporting System. Conclusion(s): From a radiological perspective, mineralizing angiopathy is an uncommon but familiar finding seen in up to 5% of all neonatal head ultrasounds and increasing to nearly 20% in preterm infants. It is most commonly associated with infection, hypoxia, and chromosomal abnormalities but is usually of minimal clinical significance. However, there are numerous reports of basal ganglia and thalamic strokes following minor head trauma in children with mineralizing angiopathy. For radiologists, this association is important to recognize and relay to the primary team so targeted history and MRI, if indicated, may be obtained to expedite definitive diagnosis and initiation of treatment to preserve precious brain tissue. Without a history of head trauma, in this case, stroke provocation is unclear, and other infectious or inflammatory disorders could appear similarly if they induced vasospasm or blood pressure lability. A short-interval timeframe between COVID vaccine administration and symptom onset is likely incidental, but research to exclude or illicit any link may be of benefit. Findings of mineralizing angiopathy on CT in the appropriate clinical setting should prompt further evaluation with emergent MRI to determine the presence of basal ganglia or thalamic stroke. Copyright © 2023 Southern Society for Clinical Investigation.

The Risk of COVID-19 in People Having a Particular Set of Gene

These risk factors of advancing age, male gender and co-existing health conditions like cancer, cardiovascular diseases, diabetes and obesity do not fully explain why some people have no or mild symptoms whereas others have severe symptoms. Genomewide association study (GWAS) identify a 3p21.31 gene cluster as a genetic susceptibility locus in patients with COVID-19 with respiratory failure. They also found a higher risk among persons with blood group A and protective effect for blood group O than among patients with other blood groups. The particular haplotype in a region of chromosome 3 is contributed to modern humans by neandertals. Another Neanderthal haplotype on chromosome 12 is associated with a 22% reduction in relative risk of becoming severely ill with COVID-19. The ApoE e4e4 homozygous genotype was found to increase the risk of severe COVID-19. Change in angiotensin converting enzyme (ACE) 2 gene was also found to be associated with increased risk of COVID-19, cardiovascular and pulmonary conditions. Copyright © 2021, Kathmandu University. All rights reserved.