Multiple myeloma presenting with external ear canal mass

The manifestations of multiple myeloma are protean and related to bony osteolytic lesions, and to medullar and renal insufficiency. We report a patient who presented with otalgia as the inaugural symptom of multiple myeloma. Local irradiation combined with systemic chemotherapy led to the disappearance of the temporal bone mass and the accompanying symptoms. To date, 24 months after the diagnosis, the patient is still in remission. The literature on otological involvement in multiple myeloma is reviewed. Symptoms are non-specific and include hearing loss, tinnitus, dizziness, facial paralysis, and otalgia. The diagnosis of multiple myeloma should be considered in the presence of a temporal bone mas

SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses

SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses

Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype–phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD

Reversal of SARS-CoV2-Induced Hypoxia by Nebulized Sodium Ibuprofenate in a Compassionate Use Program

Introduction: Sodium ibuprofenate in hypertonic saline (NaIHS) administered directly to the lungs by nebulization and inhalation has antibacterial and anti-inflammatory effects, with the potential to deliver these benefits to hypoxic patients. We describe a compassionate use program that offered this therapy to hospitalized COVID-19 patients. Methods: NaIHS (50 mg ibuprofen, tid) was provided in addition to standard of care (SOC) to hospitalized COVID-19 patients until oxygen saturation levels of > 94% were achieved on ambient air. Patients wore a containment hood to diminish aerosolization. Outcome data from participating patients treated at multiple hospitals in Argentina between April 4 and October 31, 2020, are summarized. Results were compared with a retrospective contemporaneous control (CC) group of hospitalized COVID-19 patients with SOC alone during the same time frame from a subset of participating hospitals from Córdoba and Buenos Aires. Results: The evolution of 383 patients treated with SOC + NaIHS [56 on mechanical ventilation (MV) at baseline] and 195 CC (21 on MV at baseline) are summarized. At baseline, NaIHS-treated patients had basal oxygen saturation of 90.7 ± 0.2% (74.3% were on supplemental oxygen at baseline) and a basal respiratory rate of 22.7 ± 0.3 breath/min. In the CC group, basal oxygen saturation was 92.6 ± 0.4% (52.1% were on oxygen supplementation at baseline) and respiratory rate was 19.3 ± 0.3 breath/min. Despite greater pulmonary compromise at baseline in the NaIHS-treated group, the length of treatment (LOT) was 9.1 ± 0.2 gs with an average length of stay (ALOS) of 11.5 ± 0.3 days, in comparison with an ALOS of 13.3 ± 0.9 days in the CC group. In patients on MV who received NaIHS, the ALOS was lower than in the CC group. In both NaIHS-treated groups, a rapid reversal of deterioration in oxygenation and NEWS2 scores was observed acutely after initiation of NaIHS therapy. No serious adverse events were considered related to ibuprofen therapy. Mortality was lower in both NaIHS groups compared with CC groups. Conclusions: Treatment of COVID-19 pneumonitis with inhalational nebulized NaIHS was associated with rapid improvement in hypoxia and vital signs, with no serious adverse events attributed to therapy. Nebulized NaIHS s worthy of further study in randomized, placebo-controlled trials (ClinicalTrials.gov: NCT04382768).Fil: Salva, Oscar. Clínica Independencia; ArgentinaFil: Doreski, Pablo A.. Fundación Respirar; ArgentinaFil: Giler, Celia S.. Clínica Independencia; ArgentinaFil: Quinodoz, Dario C.. Sanatorio de la Cañada; ArgentinaFil: Guzmán, Lucia G.. Sanatorio de la Cañada; ArgentinaFil: Muñoz, Sonia Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Carrillo, Mariana Norma del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Porta, Daniela Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Ambasch, Germán. Sanatorio Privado Mayo; ArgentinaFil: Coscia, Esteban. Sanatorio Privado Mayo; ArgentinaFil: Tambini Diaz, Jorge L.. Sanatorio Privado Mayo; ArgentinaFil: Bueno, Germán D.. Sanatorio Privado Mayo; ArgentinaFil: Fandi, Jorge O.. Clínica Independencia; ArgentinaFil: Maldonado, Miriam A.. Sanatorio San Roque; ArgentinaFil: Peña Chiappero, Leandro E.. Sanatori San Roque; ArgentinaFil: Fournier, Fernando. Clínica Francesa; ArgentinaFil: Pérez, Hernán A.. Sanatorio Alive; Argentina. University of Maryland; Estados UnidosFil: Quiroga, Mauro A.. Instituto Modelo de Cardiología; ArgentinaFil: Sala Mercado, Javier Agustin. Instituto Modelo de Cardiología; ArgentinaFil: Martínez Picco, Carlos. Clínica del Sol; ArgentinaFil: Beltrán, Marcelo Alejandro. Hospital Dr. Alberto Duhau; ArgentinaFil: Castillo Argañarás, Luis Fernando. Hospital Dr. Alberto Duhau; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ríos, Nicolás Martínez. Quimica Luar Srl; ArgentinaFil: Kalayan, Galia I.. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; ArgentinaFil: Beltramo, Dante Miguel. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Garcia, Nestor Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Provincia de Córdoba. Ministerio de Ciencia y Técnica. Centro de Excelencia en Productos y Procesos de Córdoba; Argentin

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease