Retrospective Analysis of Vaccinated and Unvaccinated COVID-19 Patients Treated with Monoclonal Antibodies (mAb) and Their Emergent Needs (RAVEN).

Strategies to combat COVID-19 include vaccines and Monoclonal Antibody Therapy. While vaccines aim to prevent development of symptoms, Monoclonal Antibody Therapy aims to prevent the progression of mild to severe disease. An increasing number of COVID-19 infections in vaccinated patients raised the question of whether vaccinated and unvaccinated COVID-19 positive patients respond differently to Monoclonal Antibody Therapy. The answer can help prioritize patients if resources are scarce. We performed a retrospective study to evaluate and compare the outcomes and risks for disease progression between vaccinated and unvaccinated COVID-19 patients treated with Monoclonal Antibody Therapy by measuring the number of Emergency Department visits and hospitalizations within 14 days as well as the progression to severe disease, defined through the Intensive Care Unit admissions within 14 days, and death within 28 days from the Monoclonal Antibody infusion. From 3898 included patients, 2009 (51.5%) were unvaccinated at the time of Monoclonal Antibody infusion. Unvaccinated patients had more Emergency Department visits (217 vs. 79, p < 0.0001), hospitalizations (116 vs. 38, p < 0.0001), and progression to severe disease (25 vs. 19, p = 0.016) following treatment with Monoclonal Antibody Therapy. After adjustment for demographics and comorbidities, unvaccinated patients were 2.45 times more likely to seek help in the Emergency Department and 2.70 times more likely to be hospitalized. Our data suggest the added benefit between the COVID-19 vaccine and Monoclonal Antibody Therapy.

Validation of the Menopause Transition Scale (MTS).

OBJECTIVE: All women will experience menopause transition, and a majority will experience symptoms that negatively affect their quality of life. Current validated menopause symptom scales are time consuming, phrased in clinical language, and difficult to adopt for digital use. This study seeks to validate a short novel survey which can be reliably completed without coaching and accurately represents the experience of the menopause transition. METHODS: We developed a patient-centric questionnaire (Menopause Transition Scale, MTS) to examine for symptoms of menopause. Survey responders represented a total of 144 women with at least one symptom of menopause. Survey responders included women affected by cancer aged 30 to 65 (n = 72) and women not affected by cancer aged 45 to 60 (n = 72). Cronbach Alpha was used to examine for internal consistency and dimensionality was assessed using exploratory factor analysis. The cross-validation was analyzed against established patient scales using Spearman correlations or Chi-Square analysis, as appropriate. RESULTS: The MTS questions showed internal consistency with a Cronbach Alpha of 0.63. The individual questions loaded into three unique domains. The MTS overall correlated with validated scales for menopause symptoms, the Menopause-Specific Quality of Life Questionnaire (r = -0.86, P < 0.0001) and Greene Climacteric Scale (r = -0.65, P < 0.0001). Libido correlated with scales (P = 0.0150) and subscales (r = -0.70, P < 0.0001) relating low sexual desire. Energy (r = -0.62, P < 0.0001), Mood (r = -0.48, P < 0.0001), and Hot Flashes/Night Sweats (r = -0.77, P < 0.0001) correlated with scales and subscales related to mood, depression, and vasomotor symptoms. The majority of our responders expressed mild vaginal bleeding. The highest frequency of severe symptoms were low libido and poor energy. CONCLUSIONS: The MTS is a short thorough patient-centric survey that is readily amenable to digital adoption to measure symptoms of menopause as women transition in the out-patient setting. Further study is needed for the longitudinal assessment of symptoms through the transition process and the response of women to therapeutic options.Video Summary: http://links.lww.com/MENO/A938.

Acute Healthcare Utilization of a Multidisciplinary Neurocognitive Dementia Patient Cohort.

BACKGROUND AND PURPOSE: Upon referral from the primary care provider (PCP), dementia is diagnosed either by a neuropsychological evaluation (NPE) or at a multidisciplinary neurocognitive clinic (MNC). Following the NPE, patients continue receiving care from their PCP. In contrast, patients at the MNC are followed by a multidisciplinary care team that provides expertise across specialties in dementia care and education for the patient, family members, and care providers. The purpose of the study was to determine the utilization of acute healthcare services during the 2 years following a diagnosis of dementia in patients from the MNC and NPE. METHODS: A retrospective review was performed of 581 electronic medical records from January 2010 through December 2014 for 2 cohorts of patients diagnosed with dementia 1) by a neuropsychologist or 2) in a MNC. Acute-care hospital admissions, emergency room (ER) visits, and nonroutine PCP visits were identified. Categorical demographics and utilization variables were summarized by frequency. Chi-square analysis was used to analyze demographic characteristics and overall utilization between MNCs and NPE. Utilization in comparison with various demographic characteristics was analyzed using Spearman correlation coefficients and negative binomial regressions. RESULTS: Patients evaluated in the MNC were older, more severely impaired, and lived alone more often compared with NPE patients, but there was no increase in hospital admissions and ER visits. Patients who underwent NPE were 1.58 times more likely to have a nonroutine PCP office visit than patients evaluated in the MNC (p=0.0093). CONCLUSIONS: Performing follow-up in multidisciplinary clinics provides patients with more education and may help to reduce the utilization of healthcare services.

Lethal NARS2-Related Disorder Associated With Rapidly Progressive Intractable Epilepsy and Global Brain Atrophy.

BACKGROUND: Infantile epileptic encephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy. METHODS: We describe two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants. RESULTS: Brain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months. CONCLUSIONS: NARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.

Quantifying and Trending the Thermal Signal as an Index of Perfusion in Patients Sedated with Propofol.

We examined the feasibility of a thermal imager smart phone attachment as a potential proxy of skin perfusion by assessing shifts in skin temperature following administration of the vasodilatory anesthetic propofol. Four limb distal extremity thermal images were taken before propofol administration and at 5-min intervals thereafter during monitored anesthesia. The study enrolled 60 patients with ages ranging from 1.3 to 18 years (mean 10.7 years old) from April 2016 to January 2017. Five minutes following propofol administration, the median temperature differential (delta temperature) between the core and extremity skin significantly decreased in both upper and lower extremities, 7.9 to 3.6 °C (p < 0.0001) and 12.1 to 6.9 °C (p < 0.0001), respectively. By 10 min, the median delta temperatures further decreased significantly in the upper (p = 0.0068) and lower extremities (p = 0.0018). There was a concordant decrease in mean blood pressure (MBP). These trends reverted back when the subject awoke. There was no significant difference between the four operators who used the camera (p = 0.0831). Blood pressure and time temperature change was the only value of significance. Mobil thermal imaging represents a non-invasive modality to assess perfusion in real time. Further studies are required to validate the clinical utility.

Implementing an Oxygen Supplementation and Monitoring Protocol on Inpatient Pediatric Bronchiolitis: An Exercise in Deimplementation.

AIM: Our goal in this study is to evaluate the effectiveness of our oxygen (O2) protocol to reduce length of stay (LOS) for children hospitalized with bronchiolitis. METHODS: In this retrospective cohort study, the outcomes of children ≤ 24 months old that were admitted with bronchiolitis and placed on the O2 protocol were compared to historical controls. The primary outcome was hospital length of stay. Secondary outcomes were duration of O2 supplementation, rates of pediatric intensive care unit transfer, and readmission. RESULTS: Groups were not significantly different in age, gender, and rates of respiratory distress score assessment. Significantly more severely ill patients were in the O2 protocol group. There were no significant differences between control and O2 protocol groups with regard to mean LOS, rates of pediatric intensive care unit transfer, or seven-day readmission rates. By multiple regression analysis, the use of the O2 protocol was associated with a nearly 20% significant decrease in the length of hospitalization (p = 0.030). CONCLUSION: Use of O2 supplementation protocol increased LOS in the more ill patients with bronchiolitis but decreased overall LOS by having a profound effect on patients with mild bronchiolitis.

Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts.

Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition. However, treatment with nanomolar levels of mTOR inhibitor renders these cells as sensitive to MEK inhibition as a melanoma cell line with mutant BRAF. Similar results were observed in B-Raf wild-type melanoma cells as well as in vivo, where treatment of canine AS tumorgrafts with MEK and mTOR inhibitors was more effective than monotherapy. Our data show that a low dose of an mTOR inhibitor can dramatically enhance angiosarcoma and melanoma response to MEK inhibition, potentially widening the field of applications for MEK-targeted therapy.

Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma.

Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease.

MEK genomics in development and disease.

The mitogen-activated protein kinase kinases (the MAPK/ERK kinases; MKKs or MEKs) and their downstream substrates, the extracellular-regulated kinases have been intensively studied for their roles in development and disease. Until recently, it had been assumed any mutation affecting their function would have lethal consequences. However, the identification of MEK1 and MEK2 mutations in developmental syndromes as well as chemotherapy-resistant tumors, and the discovery of genomic variants in MEK1 and MEK2 have led to the realization the extent of genomic variation associated with MEKs is much greater than had been appreciated. In this review, we will discuss these recent advances, relating them to what is currently understood about the structure and function of MEKs, and describe how they change our understanding of the role of MEKs in development and disease.

Sec3-containing exocyst complex is required for desmosome assembly in mammalian epithelial cells.

The Exocyst is a conserved multisubunit complex involved in the docking of post-Golgi transport vesicles to sites of membrane remodeling during cellular processes such as polarization, migration, and division. In mammalian epithelial cells, Exocyst complexes are recruited to nascent sites of cell-cell contact in response to E-cadherin-mediated adhesive interactions, and this event is an important early step in the assembly of intercellular junctions. Sec3 has been hypothesized to function as a spatial landmark for the development of polarity in budding yeast, but its role in epithelial cells has not been investigated. Here, we provide evidence in support of a function for a Sec3-containing Exocyst complex in the assembly or maintenance of desmosomes, adhesive junctions that link intermediate filament networks to sites of strong intercellular adhesion. We show that Sec3 associates with a subset of Exocyst complexes that are enriched at desmosomes. Moreover, we found that membrane recruitment of Sec3 is dependent on cadherin-mediated adhesion but occurs later than that of the known Exocyst components Sec6 and Sec8 that are recruited to adherens junctions. RNA interference-mediated suppression of Sec3 expression led to specific impairment of both the morphology and function of desmosomes, without noticeable effect on adherens junctions. These results suggest that two different exocyst complexes may function in basal-lateral membrane trafficking and will enable us to better understand how exocytosis is spatially organized during development of epithelial plasma membrane domains.