Correlation between CT imaging and symptom scores in cystic fibrosis associated chronic sinusitis.

PURPOSE: There are limited guidelines for diagnosing and managing chronic rhinosinusitis (CRS) in the cystic fibrosis (CF) population. While CF patients are known to have significant opacification on paranasal computed tomography (CT), limited evidence suggests that CT findings are not indicative of patients' symptom burden and therefore not a reliable indicator for surgical intervention. This provides a diagnostic challenge for otolaryngologists taking care of this patient population. The purpose of this study is to better define the relationship between objective imaging findings and patients' symptom severity in the CF-CRS population with the goal of providing more selective and effective patient care. MATERIALS AND METHODS: In this retrospective cohort study, 67 patients with CF CRS had their CT scans scored according to a modified Lund Mackay CT score (LMCTS), which was compared to their Sinonasal Outcome Test scores (SNOT-22). Total SNOT-22 and individual domains were evaluated. Pearson's correlation was performed. RESULTS: The overall mean SNOT-22 score was 32.3. The mean LMCTS was 17.6. These metrics correlate with relatively low subjective symptom scores in comparison to the high objective presence of sinus disease. While patients had high LMCTS, there was no correlation found between LMCTS and total SNOT-22 or individual SNOT-22 domains. CONCLUSIONS: CT findings in CF CRS patients do not accurately reflect patients' symptom burden and should not be used as a primary driver in the clinical management of these patients.

Characterization of Plasmodium falciparum Atypical Kinase PfPK7- Dependent Phosphoproteome.

PfPK7 is an "orphan" kinase displaying regions of homology to multiple protein kinase families. PfPK7 functions in regulating parasite proliferation/development as evident from the phenotype analysis of knockout parasites. Despite this regulatory role, the functions of PfPK7 in signaling pathways are not known. To better understand PfPK7-regulated phosphorylation events, we performed isobaric tag-based quantitative comparative phosphoproteomics of the schizont and segmenter stages from wild-type and pfpk7 - parasite lines. This analysis identified 3,875 phosphorylation sites on 1,047 proteins. Among these phosphorylation events, 146 proteins with 239 phosphorylation sites displayed reduction in phosphorylation in the absence of PfPK7. Further analysis of the phosphopeptides revealed three motifs whose phosphorylation was down regulated in the pfpk7 - cell line in both schizonts and segmenters. Decreased phosphorylation following loss of PfPK7 indicates that these proteins may function as direct substrates of PfPK7. We demonstrated that PfPK7 is active toward three of these potential novel substrates; however, PfPK7 did not phosphorylate many of the other proteins, suggesting that decreased phosphorylation in these proteins is an indirect effect. Our phosphoproteomics analysis is the first study to identify direct substrates of PfPK7 and reveals potential downstream or compensatory signaling pathways.

Economic Evaluation of Dupilumab Versus Endoscopic Sinus Surgery for the Treatment of Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Dupilumab is a novel monoclonal antibody that recently received US Food and Drug Administration approval for the treatment of chronic rhinosinusitis with nasal polyps. Endoscopic sinus surgery (ESS) has been the mainstay of treatment for patients refractory to initial medical therapy. Data comparing the cost-effectiveness of these treatments are scarce. The objective of this study is to compare the cost-effectiveness of dupilumab and ESS treatment for patients with chronic rhinosinusitis with nasal polyps refractory to medical therapy. METHODS: A cohort-style Markov decision tree economic evaluation with 10-year time horizon was performed. The two comparative treatment strategies were dupilumab therapy or ESS followed by postoperative maintenance therapy. Patients with response to treatment continued with either maintenance or dupilumab therapy; patients with no response underwent ESS. The primary outcome measure was incremental cost per quality-adjusted life-year calculated from Sino-Nasal Outcome Test (SNOT-22) scores. Sensitivity analyses were performed including discounting scenarios and a probabilistic sensitivity analysis. RESULTS: The dupilumab strategy cost $195,164 and produced 1.779 quality-adjusted life-years. The ESS strategy cost $20,549 and produced 1.526 quality-adjusted life-years. This implies an incremental cost of $691,691 for dupilumab for every 1-unit increase in quality-adjusted life-year compared with ESS. Probability sensitivity analysis indicated that ESS was more cost-effective than dupilumab in all iterations. CONCLUSIONS: While dupilumab and ESS may demonstrate similar clinical effectiveness, ESS remains the most cost-effective treatment option and should remain the standard of care for patients with chronic rhinosinusitis with nasal polyps refractory to medical therapy.

Frailty and Hospitalization Burden in Patients With Chronic Heart Failure.

Frailty is associated with increased mortality and hospitalizations in patients with heart failure (HF). However, there is little evidence regarding the burden of morbidity. In this study, we aimed to assess the association between frailty and recurrent all-cause HF hospitalizations in patients with stable chronic HF. This was an observational and prospective study that enrolled HF outpatients followed in a specialized HF unit of a single tertiary care center from 2017 to 2019. Frailty was assessed by Fried criteria. Robustness, prefrailty, and frailty were defined as 0, 1 to 2, and ≥3, respectively. The independent association between frailty status and recurrent hospitalizations was assessed through Famoye's bivariate Poisson regression model, and risk estimates were expressed as incidence rate ratios (IRR). A total of 277 patients were included. The mean age was 74 ± 10 years, 118 were women (42.6%), and 131 patients (47.3%) had left ventricular ejection fraction ≥50. According to Fried's score 61 patients (22%) were robust, 95 patients (34%) were prefrail, and 121 patients (44%) were frail. After a median follow-up of 2.21 (1.6 to 2.8) years, 52 patients (19%) died. We registered 348 all-cause hospitalizations in 144 patients (52%) and 178 HF hospitalizations in 108 patients (39%). Compared with robust patients, frailty was associated with a higher risk of all-cause and HF recurrent hospitalizations in multivariable analysis (IRR 2.01, 95% confidence interval 1.14 to 3.57, p = 0.017 and IRR 2.25, 95% confidence interval 1.16-4.36, p = 0.016, respectively). In conclusion, in patients with chronic HF, frailty identifies patients with an increased risk of total and recurrent all-cause and HF hospitalizations.

Bending oxygen saturation index and risk of worsening heart failure events in chronic heart failure.

AIMS: Bendopnea is a clinical symptom of advanced heart failure with uncertain prognostic value. We aimed to evaluate whether bendopnea and the change in oxygen saturation when bending forward (bending oxygen saturation index [BOSI]) are associated with adverse outcomes in ambulatory chronic heart failure (CHF) patients. METHODS AND RESULTS: We prospectively evaluated 440 subjects with symptomatic CHF. BOSI was defined as the difference between sitting and bending oxygen saturation (SpO2 ). The endpoint was the total number of worsening heart failure (WHF) events (heart failure hospitalization or urgent heart failure visit requiring parenteral diuretic therapy). The mean age was 74 ± 10 years, 257 (58.6%) were male, and 226 (51.4%) had a left ventricular ejection fraction <50%. Bendopnea was present in 94 (21.4%) patients, and 120 (27.3%) patients had a BOSI ≥-3%. The agreement between BOSI ≥-3% and bendopnea was moderate (Gwet's AC 0.482, p < 0.001). At a median (p25%-p75%) follow-up of 2.17 years (0.88-3.16), we registered 441 WHF events in 148 patients. After multivariable adjustment, BOSI was independently associated with the risk for total WHF episodes (overall, p < 0.001). Compared to improvement/no change in SpO2 when bending (BOSI 0%), those with BOSI ≥-3% showed an increased risk of WHF events (incidence rate ratio [IRR] 2.16, 95% confidence interval [CI] 1.67-2.79; p < 0.001). In contrast, bendopnea was not associated with the risk of total WHF episodes (IRR 1.04, 95% CI 0.83-1.31; p = 0.705). CONCLUSIONS: In ambulatory and stable CHF patients, BOSI ≥-3% and not bendopnea was independently associated with an increased risk of total (first and recurrent) WHF episodes. Awareness of SpO2 while assessing bendopnea may be a useful tool for predicting heart failure decompensations.

Aberrant Epidermal Growth Factor Receptor RNA Splice Products Are Among the Most Frequent Somatic Alterations in Clear Cell Renal Cell Carcinoma and Are Associated with a Poor Response to Immunotherapy.

BACKGROUND: Accumulating evidence suggests that alternative RNA splicing has an important role in cancer development and progression by driving the expression of a diverse array of RNA and protein isoforms from a handful of genes. However, our understanding of the clinical significance of cancer-specific RNA splicing in renal cell carcinoma (RCC) is limited. OBJECTIVE: To characterize and validate a novel oncogene RNA splicing event discovered in patients with RCC and to correlate expression with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Using DNA and RNA sequencing, we identified a novel epidermal growth factor receptor (EGFR) splicing alteration (EGFR_pr20CTF) in RCC tumor tissue. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We confirmed the frequency and specificity of the EGFR_pr20CTF variant by analyzing cohorts of patients from our institution (n = 699) and The Cancer Genome Atlas (TCGA; n = 832). Furthermore, we analyzed its expression in tumor tissue and a human kidney cancer cell line using reverse transcriptase-polymerase chain reaction. Variant expression was also correlated with survival and response to systemic therapy. RESULTS AND LIMITATIONS: EGFR_pr20CTF expression was identified in 71.7% (n = 71/99) of patients with RCC in our institutional cohort and in 56.7% (n = 279/492) of patients in the TCGA cohort. EGFR_pr20CTF was found to be specific to clear cell renal cell carcinoma (ccRCC), occurring in <0.2% of non-RCC tumors (n = 2/1091). High levels of EGFR_pr20CTF correlated with lower survival at 48 mo following immunotherapy (p = 0.036). The average survival in patients with high EGFR_pr20CTF expression was <16 mo. CONCLUSIONS: The EGFR_pr20CTF RNA splice variant occurs frequently, is specific to patients with advanced ccRCC, and is associated with a poor response to immunotherapy. PATIENT SUMMARY: Cancer-specific RNA alternative splicing may portend a poor prognosis in patients with advanced clear cell renal cell carcinoma. Further investigation will help clarify whether EGFR_pr20CTF can be used as a biomarker for this patient population.

Systematic review of outcomes for endoscopic sinus surgery and subsequent aspirin desensitization in aspirin-exacerbated respiratory disease.

OBJECTIVE: To review and evaluate outcomes of patients with aspirin-exacerbated respiratory disease (AERD) following endoscopic sinus surgery and subsequent aspirin desensitization. METHODS: Electronic searches of OVID MEDLINE (1948 to September 10, 2019), EMBASE (1980 to September 10, 2019), and PubMed were performed on September 10, 2019. A systematic review of the literature was performed using the 2009 PRISMA guidelines. Studies with both preoperative and postoperative data for patients with AERD who underwent sinus surgery and aspirin desensitization were considered appropriate for inclusion. Publications were written in English and included patients aged 18 years or older. RESULTS: Six studies met inclusion criteria for this systematic review. The primary outcome measure was change in symptom profile measured by patient-reported quality of life scores. The results demonstrate statistically significant improvement in symptoms following endoscopic sinus surgery, with sustained improvement following aspirin desensitization. Revision surgery rates were significantly lower in patients maintained on aspirin therapy. CONCLUSION: This review suggests that surgery followed by aspirin desensitization results in improvement in both subjective and objective outcome measures. The adjunctive use of aspirin desensitization allows for long-term stability in symptom scores. Recurrence of polyps and worsening symptoms requiring revision surgery occurs when aspirin maintenance therapy is interrupted.

The evidence-based preoperative assessment for the otolaryngologist.

There is a narrow window of opportunity between surgical scheduling and the operative date to optimize patients for an elective surgical procedure. Traditionally, preoperative care has involved extended routine testing batteries with intermittent referrals for medical clearance. These traditions are costly, inefficient, and yield no clear reduction in perioperative morbidity and mortality. Evidence, which has evolved over the past decade, suggests that optimal preoperative care requires a patient-centric, personalized, and often multidisciplinary approach. We present an up-to-date overview of this literature with a focus on the otolaryngologic surgical population. An algorithmic approach to preoperative patient assessment is also proposed in hopes of both optimizing patient outcome and streamlining routine clinical workflow. Laryngoscope, 130:38-44, 2020.

A test of the stress-buffering hypothesis of social support among bariatric surgery patients.

BACKGROUND: The buffering effect of social support against a range of stress-related health outcomes has been well-documented; however, no previous work has examined the applicability of this model to bariatric surgery outcomes. OBJECTIVES: The present study sought to address whether social support interacts with stress in predicting postsurgical outcomes, as well as whether these associations may vary by sex. SETTING: Teaching hospital, United States. METHODS: Data were collected using retrospective chart review (n = 548). Stress, patient sex, and social support were explored as predictors of curvilinear weight loss trajectories during the first year after surgery using growth curve modeling. RESULTS: Attendance at follow-up appointments was poor, with 250 patients at 6 months and 187 at 12 months. On average, these patients lost 27% of their total weight between baseline and the 12-month follow-up. Overall, weight-related emotional support appeared to be most relevant to weight loss/maintenance in this population; cohabitating with a spouse or significant other and attendance at support group meetings did not predict weight loss or show any significant interactions with stress. CONCLUSIONS: The present study found only partial support for the stress-buffering model of social support among bariatric surgery patients. Such findings have important implications for assessment and follow-up care after bariatric surgery, as well as for future research in this area.

Protected cytoskeletal-related proteins: Towards a resolution of contradictions regarding the role of the cytoskeleton in cancer.

Initial reports of the role of the cytoskeleton in cancer indicated that tumor cells with a more disorganized cytoskeleton were more tumorigenic. These reports were based on stains for the F-actin cytoskeleton, for example, using phalloidin or anti-F-actin antibody reagents, and gave a basic impression of F-actin-based cytoskeletal integrity. Later developments emphasized the significance of the cytoskeletal elements in cell migration, presumably associated with either basement membrane invasion or metastasis, or both, with several specific proteins implicated in the formation of cell invadopodia. With the advent of genomics approaches, it has become clear that cytoskeletal related proteins are indeed common targets of mutagenesis in cancer and commonly rank among the most mutated proteins in cancers, presumably due to large coding region sizes and the significant stochastic component to human mutagenesis. This cytoskeletal genomics result is consistent with the loss of cytoskeleton integrity as a hallmark of tumor development, but raises the question of whether such mutational sensitivity relates to the migration and invadopodia aspects of tumor progression. In the present study, the authors report that it is possible to identify a set of cytoskeletal related proteins protected from mutation, in comparison to the commonly mutated cytoskeleton related proteins in certain, but not all cancer, datasets.