Pattern of self-reported adverse events related to COVID-19 vaccines in Saudi Arabia: A nationwide study.

Background: Vaccination against coronavirus disease 2019 (COVID-19) is the most effective way to end the pandemic. Any development of adverse events (AEs) from various vaccines should be reported. We therefore aimed to explore major and minor AEs among vaccinated individuals in Saudi Arabia. Methods: This is a nationwide report based on the Saudi Arabian Ministry of Health (MOH) registry. It included those who received COVID-19 vaccines from 17th December 2020 to 31st December 2021. The study included spontaneous self-reported adverse effects to COVID-19 vaccines where the study participants used a governmental mobile app (Sehhaty) to report their AEs following vaccination using a checklist option that included a selection of side-effects. The primary outcome was to determine AEs reported within 14 days of vaccination which included injection site itching, pain, reaction, redness, swelling, anxiety, dizziness, fever, headache, hoarseness, itchiness, loss of consciousness, nausea, heartburn, sleep disruption, fatigue, seizures, anaphylaxis, shortness of breath, wheezing, swelling of lips, face, and throat, loss of consciousness, and admissions into the intensive care unit (ICU). Results: The study included a total number of 28,031 individuals who reported 71,480 adverse events (AEs); which were further classified into minor and major adverse events including ICU admissions post vaccination. Of the reported AEs, 38,309 (53. 6%) side-effects were reported following Pfizer-BioNTech, 32,223 (45%) following Oxford-AstraZeneca, and 948 (1.3%) following Moderna. The following reported AEs were statistically significant between the different vaccine types: shortness of breath\difficulty of breathing, dizziness, fever above 39°C, headache, hoarseness, injection site reactions, itchiness, nausea, sleep disruption, fatigue, wheezing, swelling of lips/face and\or throat, and loss of consciousness (p-value < 0.05). Fever and seizure were the only statistically significant AEs amongst the number of vaccine doses received (p-value < 0.05). Ten ICU admissions were reported in the 14 days observation period post-COVID-19 vaccination with the following diagnoses: acute myocardial infarction, pneumonia, atherosclerosis, acute respiratory failure, intracranial hemorrhage, grand mal seizure, Guillain-Barré syndrome, abnormal blood gas levels, and septic shock. Conclusion: This study demonstrated that the most prevalent SARS-CoV-2 vaccine side-effects among adults in Saudi Arabia were mild in nature. This information will help reduce vaccine hesitancy and encourage further mass vaccination to combat the COVID-19 pandemic, especially as booster doses are now available. Further studies are warranted to obtain a better understanding of the association between risk factors and the experiencing of side-effects post vaccination.

Demographic Characteristics, Comorbidities, and Length of Stay of COVID-19 Patients Admitted Into Intensive Care Units in Saudi Arabia: A Nationwide Retrospective Study.

Background: This study aimed to describe the demographic characteristics and determine the risk factors associated with disease severity and length of hospital and intensive care unit (ICU) stay in a cohort of COVID-19 patients admitted into ICU in Saudi Arabia. Methods: This was a national, multi-center, retrospective cross-sectional study of all COVID-19 cases admitted into different ICUs in Saudi Arabia between March 2020 and September 202l. Demographic, clinical features, comorbidities, and length of stay (LOS) data were retrieved from the national Health Electronic Surveillance Network (HESN) and Taqassi databases at the Saudi Ministry of Health (MOH) for subsequent analyses. We used multiple linear regression models to determine risk factors associated with critical outcomes (including LOS in ICU) among COVID-19 cases. Results: A total of 12,436 COVID-19 patients were included in this study, with a mean age of 59.57 ± 18.30 years and 7,679 (62%) were <65 years old. COVID-19 was more common in males (N = 7,686, 61.9%) and Saudi nationals (N = 8,516, 68.5%). The clinical characteristic findings showed that 36.3% of patients required invasive ventilation whilst 65.4% received tracheostomies for ventilation, and 4% were on dialysis. Our analysis revealed that 2,978 (23.9%) patients had one comorbidity, 4,977 (47.4%) had two or more comorbidities, and diabetes (48.2%) was the most prevalent comorbidity, followed by hypertension (44.2%), and chronic cardiovascular disease (10.5%). Thirteen variables emerged as significant predictors of LOS in ICU using multiple linear regression analyses, with invasive ventilation as the strongest predictor of LOS in the ICU (beta = -0.68, p = 0.001) and hospital admission (beta = -0.65, p = 0.001). Conclusions: COVID-19 continues to affect millions of people around the world, with a mortality rate of about 2-3% of all infected patients. Our analysis revealed that comorbidities such as chronic kidney disease, cardiovascular disease, diabetes, and older age were significant risk factors associated with a poorer prognosis and longer duration of stay in hospitals and ICU.

SARS-CoV-2 Reinfection Rate and Outcomes in Saudi Arabia: A National Retrospective Study.

BACKGROUND: The characterization of reinfection with SARS-CoV-2 has been a subject of concern and controversy, especially with the surge of infections with highly transmissible variants worldwide. METHODS: This retrospective national study used comorbidities, vaccination status, SARS-CoV-2 variants of concern, and demographics data to profile participants who were reinfected with SARS-CoV-2, defined as having two reverse transcriptase-polymerase chain reaction-positive SARS-CoV-2 tests within at least 90 days apart. A multivariate logistic regression model assessed the risk factors associated with reinfection . Two control groups were selected: nonreinfected participants reporting a positive test (control group one) and those reporting a negative test (control group two). RESULTS: Between March 2020 and December 2021, 4454 reinfected participants were identified in Saudi Arabia (0.8%, 95% confidence interval [CI] 0.7-0.8). The majority (67.3%) were unvaccinated (95% CI 65.9-68.7) and 0.8% (95% CI 0.6-1.1) had severe or fatal SARS-CoV-2 disease. COVID-19 vaccines were 100% effective against mortality in reinfected individuals who received at least one dose, whereas it conferred 61% (odds ratio [OR] 0.4, 95% CI 0.1-1.0) additional protection against severe disease after the first dose and 100% after the second dose. In the risk factor analysis, reinfection was highly associated with comorbidities, such as HIV (OR 2.5, 95% CI 1.3-5.2; P = 0.009), obesity (OR 2.3, 95% CI 1.3-3.9; P = 0.003), pregnancy (OR 3.2, 95% CI 1.4-7.4; P = 0.005), and working in health care facilities (OR 6.1, 95% CI 3.1-12.9; P <0.0001). The delta variant (B.1.617.2) was the most frequent variant of concern among the reinfected cohort. CONCLUSION: This in-depth study of the reinfection profile identified risk factors and highlighted the associated SARS-CoV-2 variants. Results showed that naturally acquired immunity to SARS-CoV-2 through multiple reinfections together with vaccine-induced immunity provided substantial protection against severe SARS-CoV-2 disease and mortality.

KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas.

Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree.

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.

Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.