From COVID-19 to the Common Cold: Novel Host-Targeted, Pan-Respiratory Antiviral Small Molecule Therapeutics

We present a small molecule chemotype, identified by an orthogonal drug screen, exhibiting nanomolar activity against members of all the six viral families causing most human respiratory viral disease, with a demonstrated barrier to resistance development. Antiviral activity is shown in mammalian cells, including human primary bronchial epithelial cells cultured to an air-liquid interface and infected with SARS-CoV-2. In animals, efficacy of early compounds in the lead series is shown by survival (for a coronavirus) and viral load (for a paramyxovirus). The drug target is shown to include a subset of the protein 14-3-3 within a transient host multi-protein complex containing components implicated in viral lifecycles and in innate immunity. This multi-protein complex is modified upon viral infection and largely restored by drug treatment. Our findings suggest a new clinical therapeutic strategy for early treatment upon upper respiratory viral infection to prevent progression to lower respiratory tract or systemic disease. One Sentence SummaryA host-targeted drug to treat all respiratory viruses without viral resistance development.

Reduced 2-year aneurysm retreatment and costs among patients treated with flow diversion versus non-flow diversion embolization: A Premier Healthcare Database retrospective cohort study.

INTRODUCTION: The use of endovascular treatments, including Pipeline embolization devices (PEDs) and coiling approaches (non-PEDs), has played an increasingly important role in the treatment of intracranial aneurysms. Despite multiple studies evaluating PEDs, a real-world evaluation of follow-up outcomes and costs remains to be completed. METHODS: The Premier Healthcare Database (PHD), 2010-2017, was queried to identify patients with unruptured intracranial aneurysms treated endovascularly. Rates of readmission, retreatment, and cost at the same hospital were compared between patients who underwent PED and non-PED endovascular treatments of their aneurysms. One-to-three (PED-to-non-PED) propensity score (PS) matching was performed to adjust for potential case selection bias into the PED cohort, with covariates including age group, sex, Charlson Comorbidity Index (CCI) group, payor, region, and randomized hospital identifier. RESULTS: A total of 679 patients underwent PED placement and 8432 had non-PED treatments. Prior to PS matching, there were significant but minor differences in age (56.7±12.8 vs. 58.2±12.6 years, p = 0.004) and sex (male 16.6% vs. 24.4%, p<0.0001) for PED and non-PED, respectively, but no differences in CCI (p = 0.08), length of stay (p = 0.88), or rate of routine discharge (p = 0.21). All-cause readmission/emergency department reevaluation rates in the two cohorts were similar at 30, 90, and 180 days and 1 and 2 years. Our results identified a significantly lower retreatment rate for PEDs at all follow-up time points over a 2-year period (range: 0.9-8.1%) compared with non-PED treatments (range: 1.7-11.6%). These findings remained consistent after PS matching: all-cause readmission/reevaluation rates were significantly lower in patients treated with PED at 90 days, 180 days, 1 year, and 2 years (p<0.001). Although the initial treatment costs were higher for PED at time of treatment (p<0.001), cumulative follow-up emergency department visit and readmission costs (inclusive of patients with no readmission and/or no retreatment) were significantly lower for patients with initial PED relative to non-PED treatment at 2 years (p = 0.021). CONCLUSIONS: These results suggest that PEDs may potentially reduce downstream retreatment rates and costs. Further work is required to improve identification of patient subgroups that could benefit from PED over non-PED treatments both initially and during follow-up.

Early-Onset X-Linked Retinitis Pigmentosa in a Heterozygous Female Harboring an Intronic Donor Splice Site Mutation in the Retinitis Pigmentosa GTPase Regulator Gene.

PURPOSE: To report a heterozygous female presenting with an early-onset and severe form of X-linked retinitis pigmentosa (XLRP). PATIENTS AND METHODS: This is a case series presenting the clinical findings in a heterozygous female with XLRP and two of her family members. Fundus photography, fundus autofluorescence, ocular coherence tomography, and visual perimetry are presented. RESULTS: The proband reported here is a heterozygous female who presented at the age of 8 years with an early onset and aggressive form of XLRP. The patient belongs to a four-generation family with a total of three affected females and four affected males. The patient was initially diagnosed with retinitis pigmentosa (RP) at the age of 4 years. Genetic testing identified a heterozygous donor splice site mutation in intron 1 (IVS1 + 1G > A) of the retinitis pigmentosa GTPase regulator gene. The father of the proband was diagnosed with RP when he was a young child. The sister of the proband, evaluated at the age of 6 years, showed macular pigmentary changes. CONCLUSIONS: Although carriers of XLRP are usually asymptomatic or have a mild disease of late onset, the proband presented here exhibited an early-onset, aggressive form of the disease. It is not clear why some carrier females manifest a severe phenotype. A better understanding of the genetic processes involved in the penetrance and expressivity of XLRP in heterozygous females could assist in providing the appropriate counseling to affected families.

Familial trends in a population with macular holes.

PURPOSE: To determine if patients with macular hole report an increased family history of macular hole compared with control patients and compare the report of family history between patients with unilateral and bilateral macular holes. METHODS: This was a multicenter case-control study. Charts of patients coded with diagnosis of macular hole were reviewed, and the diagnosis of idiopathic full-thickness macular hole was ascertained in 166 patients. The control group comprised 136 patients without macular hole or trauma who presented with senile cataract. Family history was obtained from all patients through a telephone interview. RESULTS: Six of 166 (3.6%) macular hole patients surveyed reported a history of macular hole in a primary relative compared with none of 136 (0.0%) control patients (odds ratio is infinity, with 95% confidence interval 1.295 to infinity); however, this finding may be explained by confounders such as age and number of family members. Two of the 142 (1.4%) patients with unilateral holes versus 4 of the 24 (16.7%) patients with bilateral holes reported a family history (odds ratio is 0.0714, with 95% confidence interval 0.0063 to 0.5537), and this finding remains significant when logistic regression is performed to evaluate variables of age and number of family members as potential confounders. CONCLUSION: There is an increased report of familial occurrence of macular hole in patients with macular holes compared with control patients; however, logistic regression relates this finding to variables of age and number of family members. Patients with bilateral macular holes are more likely to report a family history of macular hole than patients with unilateral macular holes, and this finding remains significant in the presence of age and number of family members. These findings may suggest a familial component to macular hole.