Genome Sequencing for Diagnosing Rare Diseases.

BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined. METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center. RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments. CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).

Uses of Linguistic Context in Speech Listening: Does Acquired Hearing Loss Lead to Reduced Engagement of Prediction?

Research investigating the complex interplay of cognitive mechanisms involved in speech listening for people with hearing loss has been gaining prominence. In particular, linguistic context allows the use of several cognitive mechanisms that are not well distinguished in hearing science, namely those relating to "postdiction", "integration", and "prediction". We offer the perspective that an unacknowledged impact of hearing loss is the differential use of predictive mechanisms relative to age-matched individuals with normal hearing. As evidence, we first review how degraded auditory input leads to reduced prediction in people with normal hearing, then consider the literature exploring context use in people with acquired postlingual hearing loss. We argue that no research on hearing loss has directly assessed prediction. Because current interventions for hearing do not fully alleviate difficulty in conversation, and avoidance of spoken social interaction may be a mediator between hearing loss and cognitive decline, this perspective could lead to greater understanding of cognitive effects of hearing loss and provide insight regarding new targets for intervention.

Structural instability and linear allocation control in generalized models of substance use disorder.

Substance use disorder (SUD) is a complex disease involving nontrivial biological, psychological, environmental, and social factors. While many mathematical studies have proposed compartmental models for SUD, almost all of these exclusively model new cases as the result of an infectious process, neglecting any SUD that was primarily developed in social isolation. While these decisions were likely made to facilitate mathematical analysis, isolated SUD development is critical for the most common substances of abuse today, including opioid use disorder developed through prescription use and alcoholism developed primarily due to genetic factors or stress, depression, and other psychological factors. In this paper we will demonstrate that even a simple infectious disease model is structurally unstable with respect to a linear perturbation in the infection term - precisely the sort of term necessary to model SUD development in isolation. This implies that models of SUD which exclusively treat problematic substance use as an infectious disease will have misleading dynamics whenever a non-trivial rate of isolated SUD development exists in actuality. As we will show, linearly perturbed SUD models do not have a use disorder-free equilibrium. To investigate management strategies, we implement optimal control techniques with the goal of minimizing the number of SUD cases over time.

Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.

OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice. METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. RESULTS: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today. INTERPRETATION: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.

Ready. Set. Game: Using Nursing Knowledge to Escape the Virtual Room in the Didactic Setting.

ABSTRACT: Most virtual escape rooms are built using Google documents that ask a series of questions; our faculty team wanted to provide a more interactive experience in a large classroom and created a virtual escape room that mimicked the Next Generation NCLEX testing platform. Each room contained a case study with multiple-choice questions. Seventy-three of 98 possible students completed the escape room survey. All recommended this activity to other students, and 91 percent said they preferred the game format more than the lecture format. Virtual escape rooms are interactive, engaging, and can be used successfully to bridge theory to practice.

The impact of the COVID-19 pandemic on the provision & utilisation of primary health care services in Goma, Democratic Republic of the Congo, Kambia district, Sierra Leone & Masaka district, Uganda.

INTRODUCTION: This study aimed to determine whether the COVID-19 pandemic had an impact on essential primary healthcare services at public primary healthcare facilities. METHODS: The number of weekly consultations for antenatal care (ANC), outpatient (OPD), immunisations (EPI), family planning (FP) and HIV services, between January 2018 and December 2020, were collected from 25 facilities in Masaka district, Uganda, 21 in Goma, and 29 in Kambia district, Sierra Leone. Negative binomial regression models accounting for clustering and season were used to analyse changes in activity levels between 2018, 2019 and 2020. RESULTS: In Goma, we found no change in OPD, EPI or ANC consultations, FP was 17% lower in March-July 2020 compared to 2019, but this recovered by December 2020. New diagnoses of HIV were 34% lower throughout 2020 compared to 2019. In Sierra Leone, compared to the same periods in 2019, facilities had 18-29% fewer OPD consultations throughout 2020, and 27% fewer DTP3 doses in March-July 2020. There was no evidence of differences in other services. In Uganda there were 20-35% fewer under-5 OPD consultations, 21-66% fewer MCV1 doses, and 48-51% fewer new diagnoses of HIV throughout 2020, compared to 2019. There was no difference in the number of HPV doses delivered. CONCLUSIONS: The level of disruption varied across the different settings and qualitatively appeared to correlate with the strength of lockdown measures and reported attitudes towards the risk posed by COVID-19. Mitigation strategies such as health communications campaigns and outreach services may be important to limit the impact of lockdowns on primary healthcare services.

Diabetic Ketoacidosis Related to Hypertriglyceridemia-Induced Pancreatitis: A Case Report.

Both diabetic ketoacidosis and acute pancreatitis can result in critical illness. Although not the most common cause of acute pancreatitis, hypertriglyceridemia can account for up to 10% of cases. One source of hypertriglyceridemia is unrecognized diabetes and resultant hyperglycemia. Identifying the underlying cause of acute pancreatitis can guide the most appropriate therapy to resolve this critical illness. This case report addresses the use of insulin infusions to treat hypertriglyceridemia-induced pancreatitis in the setting of concomitant diabetic ketoacidosis.

Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders.

Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A>G;NM_024854.5:c.464A>G;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay and c.1254+1delG elicits in-frame skipping of exon-11. Western blot from cultured fibroblasts shows reduced PYROXD1 protein levels in both probands. Testing urine from BII:1 and six individuals with PYROXD1 myopathy showed elevated levels of deoxypyridinoline, a mature collagen crosslink, correlating with PYROXD1-disorder severity. Urine and serum amino acid testing of the same individuals revealed no reportable changes. In contrast to PYROXD1 knock-out, we find no evidence for disrupted tRNA ligase activity, as measured via XBP1 splicing, in fibroblasts expressing PYROXD1 variants. In summary, we expand the clinical spectrum of PYROXD1-related disorders to include an overlapping connective tissue and myopathy presentation, identify three novel, pathogenic PYROXD1 variants, and provide preliminary evidence that elevated urine DPD crosslinks may provide a clinical biomarker for PYROXD1 disorders. Our results advocate consideration of PYROXD1 variants in the differential diagnosis for undiagnosed individuals presenting with a connective tissue disorder and myopathy.

Case report: Adult-onset limb girdle muscular dystrophy in sibling pair due to novel homozygous LAMA2 missense variant.

Recessive pathogenic variants in the laminin subunit alpha 2 (LAMA2) gene cause a spectrum of disease ranging from severe congenital muscular dystrophy to later-onset limb girdle muscular dystrophy (LGMDR23). The phenotype of LGMDR23 is characterized by slowly progressive proximal limb weakness, contractures, raised creatine kinase, and sometimes distinctive cerebral white matter changes and/or epilepsy. We present two siblings, born to consanguineous parents, who developed adult-onset LGMDR23 associated with typical cerebral white matter changes and who both later developed dementia. The male proband also had epilepsy and upper motor neuron signs when he presented at age 72. Merosin immunohistochemistry and Western blot on muscle biopsies taken from both subjects was normal. Whole exome sequencing revealed a previously unreported homozygous missense variant in LAMA2 [Chr6(GRCh38):g.129297734G>A; NM_000426.3:c.2906G>A; p.(Cys969Tyr)] in the proband. The same homozygous LAMA2 variant was confirmed by Sanger sequencing in the proband's affected sister. These findings expand the genotypic and phenotypic spectrum of LGMDR23.

Compound heterozygous splicing variants expand the genotypic spectrum of EMC1-related disorders.

EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders.

Healthcare providers' attitudes towards delay in cancer treatment during COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic has created unprecedented obstacles leading to delays in treatment for older adults with cancer. Due to limited resources at the height of the pandemic, healthcare providers were constantly faced with ethical dilemmas regarding postponing or rescheduling care for their patients. MATERIALS AND METHODS: Two survey-based studies were conducted at different time-points during the pandemic looking at factors affecting oncology care providers' attitudes towards delay in treatment for older adults with cancer. Eligible participants were recruited by email sent through professional organizations' listservs, email blasts, and social media. Change in provider attitude over time was analyzed by comparing responses from the 2020 and 2021 surveys. Data analysis included descriptive statistics and chi-squares. RESULTS: In 2020, 17.5% of respondents were strongly considering/considering postponing cancer treatment for younger patients (age 30 and below), while 46.2% were considering delaying treatment for patients aged >85. These responses were in stark contrast to the results of the 2021 survey, where only 1.4% of respondents strongly considered postponing treatment for younger patients, and 13.5% for patients aged >85. DISCUSSION: All recommendations to postpone treatment for older adults with cancer must be made after mutual discussion with the patient. Throughout the COVID-19 pandemic, oncology care providers had to consider multiple factors while treating patients, frequently making most decisions without appropriate institutional support.

Newborn Screening for the Diagnosis and Treatment of Duchenne Muscular Dystrophy.

A pilot newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) study proposes to assess the feasibility of the screening procedure, temporal course of the various steps of screening, and the public acceptability of the program. This is particularly vital to ascertain as DMD is considered a 'non-treatable' disease and thus does not fit the traditional criteria for newborn screening. However, modern perspectives of NBS for DMD are changing and point to possible net benefits for children and their families undertaking NBS for DMD. The aim of this workshop was to establish pathways for the successful implementation and evaluation of a pilot NBS for DMD program in Australia. Consensus was reached as to the rationale for, potential benefits, risks, barriers and facilitators of screening, alongside the establishment of screening protocols and clinical referral pathways.

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.

Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort. Methods: GS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants. Results: We successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19). Conclusion: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.

A systematic approach to developing NP-led student health services clinic on a regional university campus.

BACKGROUND: Universities are communities with specific health care needs, and rural campuses often do not have access to student health services (SHS). PROBLEM: Lack of basic services can increase health risks for students and the greater community. METHODS: A theory-informed quality improvement project utilizing an organizational assessment, study survey, and proof-of-concept intervention designed to demonstrate feasibility and acceptability of a SHS clinic. INTERVENTION: An NP-directed influenza immunization clinic was conducted on a small rural college campus in southeastern United States. RESULTS: Seventy-eight students received influenza vaccinations, demonstrating to local stakeholders the feasibility and acceptability of SHS for primary preventative services. Ninety-seven percent of these students expressed a high likelihood that they would obtain the vaccine again. CONCLUSIONS: Results of this study can be used as an exemplar to guide health care initiatives focused on college students in rural communities.

Cerebral blood flow is associated with markers of neurodegeneration in Huntington's disease.

INTRODUCTION: The ultimate cause of neuronal death in Huntington's disease (HD) is still uncertain. Apart from impairment in systems handling abnormal proteins, other mechanisms might contribute to neurodegeneration and progression of HD. Decreased cerebral blood flow (CBF) has been described in other neurodegenerative disorders and may play a role in HD. OBJECTIVES: To investigate CBF changes in HD gene carriers. METHODS: A group of 39 HD gene carriers (18 premanifest and 21 manifest HD) and 16 controls underwent a comprehensive clinical evaluation and a brain magnetic resonance imaging protocol that included pseudo-continuous arterial spin labeling to quantify CBF. Regions of interest (ROI) analyses were performed to compare CBF in controls vs premanifest HD vs manifest HD. Correlation analyses were performed to ascertain the relationship between CBF and clinical and biomarkers data. RESULTS: We found a decrease in CBF in bilateral caudate and putamen of patients with manifest HD in comparison with controls. CBF of premanifest HD carriers in the same ROIs was midway between controls and the HD patients, with differences not reaching statistical significance. Lower CBF in caudate and putamen was associated with worse motor symptoms, functionality, and cognitive performance. CBF was also associated with markers of neurodegeneration: higher CBF in caudate and putamen significantly correlated to higher volumes in the same ROI and to lower levels of neurofilament light chain. CONCLUSION: As CBF changes in caudate and putamen nuclei were associated with markers of neurodegeneration and with clinical outcomes, decreased CBF and oxygen supply could emerge as a relevant mechanism contributing to degeneration in HD.

A genetic basis is identified in 74% cases of paediatric hyperCKaemia without weakness presenting to a tertiary paediatric neuromuscular centre.

Paediatric hyperCKaemia without weakness presents a clinical conundrum. Invasive investigations with low diagnostic yields, including muscle biopsy, may be considered unjustifiable. Improved access to genome-wide genetic testing has shifted first-line investigations towards genetic studies in neuromuscular disease. This research aims to provide an evidence-based diagnostic approach to paediatric hyperCKaemia without weakness, a current gap in the literature. We identified 47 individuals (10-months to 16-years-old; 34 males, 13 females) from 43 families presenting with hyperCKaemia on two or more occasions, without weakness, from The Children's Hospital at Westmead Neuromuscular Clinic Database. Clinical features, investigations and outcomes were analysed via retrospective chart review. Genetic testing has been performed in 34/43. Genetic variants explaining hyperCKaemia were identified in 25/34 (74%) using multiplex ligation-dependent probe amplification, massive parallel sequencing, single gene testing and exome sequencing. Pathogenic/likely pathogenic variants were identified in 19 neuromuscular disease genes and six metabolic myopathy genes. Individuals with metabolic diagnoses had higher peak creatine kinase levels that sometimes normalized. Conversely, creatine kinase levels remained persistently elevated those with neuromuscular diagnoses. In summary, a genetic cause is found in most paediatric patients with hyperCKaemia without weakness informing clinical management and counselling. Thus, we propose a diagnostic algorithm for this cohort.

Prevalence, parameters, and pathogenic mechanisms for splice-altering acceptor variants that disrupt the AG exclusion zone.

Predicting the pathogenicity of acceptor splice-site variants outside the essential AG is challenging, due to high sequence diversity of the extended splice-site region. Critical analysis of 24,445 intronic extended acceptor splice-site variants reported in ClinVar and the Leiden Open Variation Database (LOVD) demonstrates 41.9% of pathogenic variants create an AG dinucleotide between the predicted branchpoint and acceptor (AG-creating variants in the AG exclusion zone), 28.4% result in loss of a pyrimidine at the -3 position, and 15.1% result in loss of one or more pyrimidines in the polypyrimidine tract. Pathogenicity of AG-creating variants was highly influenced by their position. We define a high-risk zone for pathogenicity: > 6 nucleotides downstream of the predicted branchpoint and >5 nucleotides upstream from the acceptor, where 93.1% of pathogenic AG-creating variants arise and where naturally occurring AG dinucleotides are concordantly depleted (5.8% of natural AGs). SpliceAI effectively predicts pathogenicity of AG-creating variants, achieving 95% sensitivity and 69% specificity. We highlight clinical examples showing contrasting mechanisms for mis-splicing arising from AG variants: (1) cryptic acceptor created; (2) splicing silencer created: an introduced AG silences the acceptor, resulting in exon skipping, intron retention, and/or use of an alternative existing cryptic acceptor; and (3) splicing silencer disrupted: loss of a deep intronic AG activates inclusion of a pseudo-exon. In conclusion, we establish AG-creating variants as a common class of pathogenic extended acceptor variant and outline factors conferring critical risk for mis-splicing for AG-creating variants in the AG exclusion zone, between the branchpoint and acceptor.

SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice.

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease.

Rationale: The incidence and sites of mucus accumulation and molecular regulation of mucin gene expression in coronavirus (COVID-19) lung disease have not been reported. Objectives: To characterize the incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Methods: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected human bronchial epithelial (HBE) cultures were used to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. Measurements and Main Results: MUC5B and variably MUC5AC RNA concentrations were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the subacute/chronic disease phase after SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of subjects with COVID-19 in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days after inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days after inoculation. SARS-CoV-2 infection of HBE cultures induced expression of epidermal growth factor receptor (EGFR) ligands and inflammatory cytokines (e.g., IL-1α/ß) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways or administration of dexamethasone reduced SARS-CoV-2-induced mucin expression. Conclusions: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation after SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease.