Association of Baseline Frailty Status and Age With Postoperative Complications After Cochlear Implantation: A National Inpatient Sample Study.

OBJECTIVE: To conduct a national registry-based evaluation of the independent associations of chronological age and frailty, as measured by 5- and 11-factor modified frailty index (mFI-5, mFI-11) score, on postoperative outcomes of participants undergoing cochlear implantation (CI). STUDY DESIGN: Cross-sectional analysis. SETTING: Multicenter national database. PARTICIPANTS: Adults 18 years or older who underwent CI during 2001 to 2018. MAIN OUTCOME MEASURES: Any postoperative complications (determined as the presence of major, minor, or implant-specific), extended hospital length of stay (eLOS) (≥75th percentile of study population), and nonhome discharge destination. RESULTS: There were 5,130 participants included with a median age of 60 years (interquartile range, 44-73 y) and slight female predominance (53.5%). Under mFI-5 scoring, there were 2,979 (58.1%) robust (mFI-5 = 0), 1710 (33.3%) prefrail (mFI-5 = 1), 362 (7.1%) frail (mFI-5 = 2), and 78 (1.5%) severely frail (mFI-5 ≥ 3) participants. Three hundred twenty-eight (6.49%) participants experienced a postoperative complication, with 320 (6.2%) discharged to a nonhome destination. Multivariate analysis showed no statistically significant correlation between increasing participant age or frailty status and postoperative complications; however, increasing baseline frailty tier showed an independent association with risk of eLOS (severely frail: odds ratio, 4..83; 95% confidence interval, 3.00-7.75; p < 0.001) and nonhome discharge (severely frail: odds ratio, 6.51; 95% confidence interval, 3.81-11.11; p < 0.001). The mFI-11 showed very similar trends. CONCLUSION: Among those evaluated, this study demonstrates that CI is a low-risk procedure in participants of all ages. Increasing frailty does not predispose to postoperative complications. However, frail patients are at additional risk for an eLOS and nonhome discharge. Short follow-up time, hospital-coding errors, and selection bias of more robust patients may limit the true results of this study.

An Algorithm for Classifying Patients Most Likely to Develop Severe Coronavirus Disease 2019 Illness.

OBJECTIVES: To develop an algorithm that predicts an individualized risk of severe coronavirus disease 2019 illness (i.e., ICU admission or death) upon testing positive for coronavirus disease 2019. DESIGN: A retrospective cohort study. SETTING: Cleveland Clinic Health System. PATIENTS: Those hospitalized with coronavirus disease 2019 between March 8, 2020, and July 13, 2020. INTERVENTIONS: A temporal coronavirus disease 2019 test positive cut point of June 1 was used to separate the development from validation cohorts. Fine and Gray competing risk regression modeling was performed. MEASUREMENTS AND MAIN RESULTS: The development set contained 4,520 patients who tested positive for coronavirus disease 2019 between March 8, 2020, and May 31, 2020. The validation set contained 3,150 patients who tested positive between June 1 and July 13. Approximately 9% of patients were admitted to the ICU or died of coronavirus disease 2019 within 2 weeks of testing positive. A prediction cut point of 15% was proposed. Those who exceed the cutoff have a 21% chance of future severe coronavirus disease 2019, whereas those who do not have a 96% chance of avoiding the severe coronavirus disease 2019. In addition, application of this decision rule identifies 89% of the population at the very low risk of severe coronavirus disease 2019 (< 4%). CONCLUSIONS: We have developed and internally validated an algorithm to assess whether someone is at high risk of admission to the ICU or dying from coronavirus disease 2019, should he or she test positive for coronavirus disease 2019. This risk should be a factor in determining resource allocation, protection from less safe working conditions, and prioritization for vaccination.

Diagnostic Utility of CT and MRI for Mycotic Aneurysms: A Meta-Analysis.

OBJECTIVE. The purpose of this meta-analysis was to assess the diagnostic performance of CT and MRI in detecting mycotic aneurysm, an infection of high mortality and morbidity. MATERIALS AND METHODS. The PubMed, Cochrane, and Embase databases were searched from January 1, 1980, through June 30, 2019, for diagnostic studies assessing both sensitivity and specificity of CT or MRI for detecting mycotic aneurysms, and studies were pooled by use of random-effects models and freely available meta-analysis software. RESULTS. Among 1507 articles searched, 15 studies of CT (13 studies) or MRI (five studies) for aortic and cerebral mycotic aneurysms were included. The studies evaluated 622 imaging examinations for 249 mycotic aneurysms. The pooled sensitivities and specificities of CT for all mycotic aneurysms were 0.82 (95% CI, 0.77-0.87) and 0.93 (95% CI, 0.89-0.95) and of MRI were 0.79 (95% CI, 0.61-0.91) and 0.89 (95% CI, 0.81-0.95). CT and MRI had pooled sensitivities and specificities of 0.84 (95% CI, 0.78-0.89) and 0.92 (95% CI, 0.89-0.95) for aortic and 0.71 (95% CI, 0.54-0.85) and 0.90 (95% CI, 0.83-0.95) for cerebral mycotic aneurysms. Heterogeneity and publication bias were observed in some pooled analyses. CONCLUSION. CT and MRI had moderately high sensitivities and specificities for mycotic aneurysms. Study heterogeneity, publication bias, and modest sample size were important limitations, warranting larger and higher-quality studies.

Development and validation of a model for individualized prediction of hospitalization risk in 4,536 patients with COVID-19.

BACKGROUND: Coronavirus Disease 2019 is a pandemic that is straining healthcare resources, mainly hospital beds. Multiple risk factors of disease progression requiring hospitalization have been identified, but medical decision-making remains complex. OBJECTIVE: To characterize a large cohort of patients hospitalized with COVID-19, their outcomes, develop and validate a statistical model that allows individualized prediction of future hospitalization risk for a patient newly diagnosed with COVID-19. DESIGN: Retrospective cohort study of patients with COVID-19 applying a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm to retain the most predictive features for hospitalization risk, followed by validation in a temporally distinct patient cohort. The final model was displayed as a nomogram and programmed into an online risk calculator. SETTING: One healthcare system in Ohio and Florida. PARTICIPANTS: All patients infected with SARS-CoV-2 between March 8, 2020 and June 5, 2020. Those tested before May 1 were included in the development cohort, while those tested May 1 and later comprised the validation cohort. MEASUREMENTS: Demographic, clinical, social influencers of health, exposure risk, medical co-morbidities, vaccination history, presenting symptoms, medications, and laboratory values were collected on all patients, and considered in our model development. RESULTS: 4,536 patients tested positive for SARS-CoV-2 during the study period. Of those, 958 (21.1%) required hospitalization. By day 3 of hospitalization, 24% of patients were transferred to the intensive care unit, and around half of the remaining patients were discharged home. Ten patients died. Hospitalization risk was increased with older age, black race, male sex, former smoking history, diabetes, hypertension, chronic lung disease, poor socioeconomic status, shortness of breath, diarrhea, and certain medications (NSAIDs, immunosuppressive treatment). Hospitalization risk was reduced with prior flu vaccination. Model discrimination was excellent with an area under the curve of 0.900 (95% confidence interval of 0.886-0.914) in the development cohort, and 0.813 (0.786, 0.839) in the validation cohort. The scaled Brier score was 42.6% (95% CI 37.8%, 47.4%) in the development cohort and 25.6% (19.9%, 31.3%) in the validation cohort. Calibration was very good. The online risk calculator is freely available and found at https://riskcalc.org/COVID19Hospitalization/. LIMITATION: Retrospective cohort design. CONCLUSION: Our study crystallizes published risk factors of COVID-19 progression, but also provides new data on the role of social influencers of health, race, and influenza vaccination. In a context of a pandemic and limited healthcare resources, individualized outcome prediction through this nomogram or online risk calculator can facilitate complex medical decision-making.

Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study-Asian Subgroup Analysis.

INTRODUCTION: The primary analysis of a global phase 3 study that evaluated the efficacy and safety of denosumab versus zoledronic acid for preventing skeletal-related events (SREs) in adults with newly diagnosed multiple myeloma (MM) indicated that denosumab was noninferior to zoledronic acid for time to first on-study SREs. Here we present a subgroup analysis to evaluate efficacy and safety in Asian patients. METHODS: Patients were randomized 1:1 to receive denosumab 120 mg subcutaneously or zoledronic acid intravenously 4 mg every 4 weeks in a double-blind, double-dummy fashion. All patients received standard-of-care first-line antimyeloma treatment. Each patient received either study drug until an estimated 676 patients experienced at least one on-study SRE and the primary efficacy and safety analyses were completed. RESULTS: Of 1718 total enrolled patients, 196 Asian patients (denosumab, n = 103; zoledronic acid, n = 93) were included in this subgroup analysis. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% and 50.5%, respectively (HR [95% CI], 0.77 [0.48-1.26]). All 194 patients receiving at least one dose of study drug experienced at least one treatment-emergent AE. The most common AEs reported in either group (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), and pyrexia (38.2%, 41.3%). Treatment-emergent renal toxicity occurred in 9/102 (8.8%) and 20/92 (21.7%) patients, respectively. Similar rates of positively adjudicated osteonecrosis of the jaw (7 [6.9%] vs 5 [5.4%]) and treatment-emergent hypocalcemia (19 [18.6%] vs 17 [18.5%]) were reported in the denosumab and zoledronic acid groups, respectively. CONCLUSION: Efficacy and safety outcomes from this Asian subgroup were comparable to those of the full study population. Overall, this analysis supports denosumab as an additional treatment option for standard of care for Asian patients with newly diagnosed MM with lytic bone lesions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01345019.

Individualizing Risk Prediction for Positive Coronavirus Disease 2019 Testing: Results From 11,672 Patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is sweeping the globe. Despite multiple case-series, actionable knowledge to tailor decision-making proactively is missing. RESEARCH QUESTION: Can a statistical model accurately predict infection with COVID-19? STUDY DESIGN AND METHODS: We developed a prospective registry of all patients tested for COVID-19 in Cleveland Clinic to create individualized risk prediction models. We focus here on the likelihood of a positive nasal or oropharyngeal COVID-19 test. A least absolute shrinkage and selection operator logistic regression algorithm was constructed that removed variables that were not contributing to the model's cross-validated concordance index. After external validation in a temporally and geographically distinct cohort, the statistical prediction model was illustrated as a nomogram and deployed in an online risk calculator. RESULTS: In the development cohort, 11,672 patients fulfilled study criteria, including 818 patients (7.0%) who tested positive for COVID-19; in the validation cohort, 2295 patients fulfilled criteria, including 290 patients who tested positive for COVID-19. Male, African American, older patients, and those with known COVID-19 exposure were at higher risk of being positive for COVID-19. Risk was reduced in those who had pneumococcal polysaccharide or influenza vaccine or who were on melatonin, paroxetine, or carvedilol. Our model had favorable discrimination (c-statistic = 0.863 in the development cohort and 0.840 in the validation cohort) and calibration. We present sensitivity, specificity, negative predictive value, and positive predictive value at different prediction cutoff points. The calculator is freely available at https://riskcalc.org/COVID19. INTERPRETATION: Prediction of a COVID-19 positive test is possible and could help direct health-care resources. We demonstrate relevance of age, race, sex, and socioeconomic characteristics in COVID-19 susceptibility and suggest a potential modifying role of certain common vaccinations and drugs that have been identified in drug-repurposing studies.

Comparative assessment of nanomaterial definitions and safety evaluation considerations.

Nanomaterials continue to bring promising advances to science and technology. In concert have come calls for increased regulatory oversight to ensure their appropriate identification and evaluation, which has led to extensive discussions about nanomaterial definitions. Numerous nanomaterial definitions have been proposed by government, industry, and standards organizations. We conducted a comprehensive comparative assessment of existing nanomaterial definitions put forward by governments to highlight their similarities and differences. We found that the size limits used in different definitions were inconsistent, as were considerations of other elements, including agglomerates and aggregates, distributional thresholds, novel properties, and solubility. Other important differences included consideration of number size distributions versus weight distributions and natural versus intentionally-manufactured materials. Overall, the definitions we compared were not in alignment, which may lead to inconsistent identification and evaluation of nanomaterials and could have adverse impacts on commerce and public perceptions of nanotechnology. We recommend a set of considerations that future discussions of nanomaterial definitions should consider for describing materials and assessing their potential for health and environmental impacts using risk-based approaches within existing assessment frameworks. Our intent is to initiate a dialogue aimed at achieving greater clarity in identifying those nanomaterials that may require additional evaluation, not to propose a formal definition.

Is it time to refine? An exploration and simulation of optimal antibiotic timing in general surgery.

BACKGROUND: Postoperative infections increase morbidity, resource use, and costs. Our objective was to examine whether within guideline recommendations an optimal time exists for an initial dose of antibiotic to reduce postoperative infections in general surgery, and to simulate the magnitude of a reduction in infections should an optimal time be implemented. STUDY DESIGN: The population consisted of 6,731 patients who underwent 7,095 general surgery procedures between January 5, 2006 and June 25, 2012. Patients with pre-existing infections, such as pneumonia and sepsis, and patients with no recorded use of antibiotics were excluded, as were patients on vancomycin and surgical procedures longer than 4 hours in duration. The final analysis dataset included 4,453 patients. The National Surgical Quality Improvement Program was used for perioperative variables and outcomes. The end point was a composite of wound disruption; superficial, deep, organ space, surgical site infections; and sepsis. Semi-parametric logistic regression was used to study the association between antibiotic timing and infection. RESULTS: There were 444 (10%) patients with a primary end point of infectious complication. A nonlinear "bowl-shaped" relationship between duration of interval from antibiotic administration and surgical incision and infection was observed; lowest risk corresponding to administration time close to incision was 4 minutes before incision (95% one-sided CI, 0-18 minutes). The model suggested optimal timing would result in an 11.3% reduction in the primary infection end point. CONCLUSIONS: Risk of infectious complications decreased as antibiotic administration moved closer to incision time. These data suggest an opportunity to reduce infections by 11.3% by targeting initial antibiotic administration closer to incision.

Challenges of interferon-γ release assay conversions in serial testing of health-care workers in a TB control program.

BACKGROUND: Clinical data with use of serial interferon-γ release assay (IGRA) testing in US health-care workers (HCWs) are limited. METHODS: A single-center, retrospective chart review was done from 2007 to 2010 of HCWs who underwent preemployment QuantiFERON-TB Gold In-Tube testing. Demographic data, bacille Calmette-Guérin history, prior tuberculin skin test result if done, and baseline and serial IGRA values were obtained. The number of IGRA converters and reverters and their subsequent management by infectious disease physicians were reviewed. Quantitative IGRA-negative values were not available. RESULTS: A total of 7,374 IGRAs were performed on newly hired HCWs. Of these tests, 486 (6.6%) were positive at baseline, 305 (4.1%) were indeterminate, and 6,583 (89.3%) were negative. From 2007 to 2010, 52 of 1,857 HCWs (2.8%) with serial IGRA tests were identified as converters, with a serial IGRA median value of 0.63 IU/mL. Seventy-one percent of HCWs with IGRA conversion had values ≤ 1 IU/mL. None of the converters had active TB or were part of an outbreak investigation. CONCLUSIONS: Clinical significance of most QuantiFERON-TB Gold In-Tube conversions in serial testing remains a challenging task for clinicians. The use of a single cutoff point criterion for IGRA may lead to overdiagnosis of new TB infections. Clinical assessment and evaluation may help to prevent unnecessary therapy in these cases. The criteria for defining conversions and reversions by establishing new cutoffs needs to be evaluated further, especially in HCWs.

PEDOT-CNT Composite Microelectrodes for Recording and Electrostimulation Applications: Fabrication, Morphology, and Electrical Properties.

Composites of carbon nanotubes and poly(3,4-ethylenedioxythiophene, PEDOT) and layers of PEDOT are deposited onto microelectrodes by electropolymerization of ethylenedioxythiophene in the presence of a suspension of carbon nanotubes and polystyrene sulfonate. Analysis by FIB and SEM demonstrates that CNT-PEDOT composites exhibit a porous morphology whereas PEDOT layers are more compact. Accordingly, capacitance and charge injection capacity of the composite material exceed those of pure PEDOT layers. In vitro cell culture experiments reveal excellent biocompatibility and adhesion of both PEDOT and PEDOT-CNT electrodes. Signals recorded from heart muscle cells demonstrate the high S/N ratio achievable with these electrodes. Long-term pulsing experiments confirm stability of charge injection capacity. In conclusion, a robust fabrication procedure for composite PEDOT-CNT electrodes is demonstrated and results show that these electrodes are well suited for stimulation and recording in cardiac and neurophysiological research.

Antigen mining with iterative genome screens identifies novel diagnostics for the Mycobacterium tuberculosis complex.

The definition of antigens for the diagnosis of human and bovine tuberculosis is a research priority. If diagnosis is to be used alongside Mycobacterium bovis BCG-based vaccination regimens, it will be necessary to have reagents that allow the discrimination of infected and vaccinated animals. A list of 42 potential M. bovis-specific antigens was prepared by comparative analysis of the genomes of M. bovis, M. avium subsp. avium, M. avium subsp. paratuberculosis, and Streptomyces coelicolor. Potential antigens were tested by applying them in a high-throughput peptide-based screening system to M. bovis-infected and BCG-vaccinated cattle and to cattle without prior exposure to M. bovis. A response hierarchy of antigens was established by comparing responses in infected animals. Three antigens (Mb2555, Mb2890, and Mb3895) were selected for further study, as they were strongly recognized in experimentally infected animals but with low or no frequency in BCG-vaccinated and naïve cows. Interestingly, all three antigens were recognized in animals vaccinated against Johne's disease, suggesting the presences of epitopes cross-reacting with M. avium subsp. paratuberculosis antigens. Eight peptides from the three antigens studied in detail were identified as immunodominant and were characterized in terms of major histocompatibility complex class II restriction element usage and shown to be restricted through both DR and DQ molecules. Reasons for antigenic cross-reactivity with M. avium subsp. paratuberculosis and refinement of the in silico strategy to predict such cross-reactivity from the primary protein sequence will be discussed. Evaluation of the peptides identified from the three dominant antigens by use of larger field studies is now a priority.

Revisiting the evolution of Mycobacterium bovis.

Though careful consideration has been placed towards genetic characterization of tubercle bacillus isolates causing disease in humans, those causing disease predominantly among wild and domesticated mammals have received less attention. In contrast to Mycobacterium tuberculosis, whose host range is largely specific to humans, M. bovis and "M bovis-like" organisms infect a broad range of animal species beyond their most prominent host in cattle. To determine whether strains of variable genomic content are associated with distinct distributions of disease, the DNA contents of M. bovis or M. bovis-like isolates from a variety of hosts were investigated via Affymetrix GeneChip. Consistent with previous genomic analysis of the M. tuberculosis complex (MTC), large sequence polymorphisms of putative diagnostic and biological consequence were able to unambiguously distinguish interrogated isolates. The distribution of deleted regions indicates organisms genomically removed from M. bovis and also points to structured genomic variability within M. bovis. Certain genomic profiles spanned a variety of hosts but were clustered by geography, while others associated primarily with host type. In contrast to the prevailing assumption that M. bovis has broad host capacity, genomic profiles suggest that distinct MTC lineages differentially infect a variety of mammals. From this, a phylogenetic stratification of genotypes offers a predictive framework upon which to base future genetic and phenotypic studies of the MTC.

Advanced significance analysis of microarray data based on weighted resampling: a comparative study and application to gene deletions in Mycobacterium bovis.

MOTIVATION: When analyzing microarray data, non-biological variation introduces uncertainty in the analysis and interpretation. In this paper we focus on the validation of significant differences in gene expression levels, or normalized channel intensity levels with respect to different experimental conditions and with replicated measurements. A myriad of methods have been proposed to study differences in gene expression levels and to assign significance values as a measure of confidence. In this paper we compare several methods, including SAM, regularized t-test, mixture modeling, Wilk's lambda score and variance stabilization. From this comparison we developed a weighted resampling approach and applied it to gene deletions in Mycobacterium bovis. RESULTS: We discuss the assumptions, model structure, computational complexity and applicability to microarray data. The results of our study justified the theoretical basis of the weighted resampling approach, which clearly outperforms the others.

Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect.

BACKGROUND: Mesenchymal stem cells from adult bone marrow are multipotent cells capable of forming bone, cartilage, and other connective tissues. In a previous study, we demonstrated that autologous mesenchymal stem cells could repair a critical-sized bone defect in the dog. The objective of this study was to determine whether the use of allogeneic mesenchymal stem cells could heal a critical-sized bone defect in the femoral diaphysis in dogs without the use of immunosuppressive therapy. METHODS: A critical-sized segmental bone defect, 21 mm in length, was created in the mid-portion of the femoral diaphysis of twelve adult dogs that weighed between 22 and 25 kg. Each defect was treated with allogeneic mesenchymal stem cells loaded onto a hollow ceramic cylinder consisting of hydroxyapatite-tricalcium phosphate. A complete mismatch between donor stem cells and recipient dogs was identified by dog leukocyte antigen typing prior to implantation. The healing response was evaluated histologically and radiographically at four, eight, and sixteen weeks after implantation. The radiographic and histological results at sixteen weeks were compared with the historical data for the control defects, which included defects that had been treated with a cylinder loaded with autologous mesenchymal stem cells, defects treated with a cylinder without mesenchymal stem cells, and defects that had been left untreated (empty). The systemic immune response was evaluated by the analysis of recipient serum for production of antibodies against allogeneic cells. RESULTS: For defects treated with allogeneic mesenchymal stem cell implants, no adverse host response could be detected at any time-point. Histologically, no lymphocytic infiltration occurred and no antibodies against allogeneic cells were detected. Histologically, by eight weeks, a callus spanned the length of the defect, and lamellar bone filled the pores of the implant at the host bone-implant interface. Fluorescently labeled allogeneic cells were also detected. At sixteen weeks, new bone had formed throughout the implant. These results were consistent with those seen in implants loaded with autologous cells. Implants loaded with allogeneic or autologous stem cells had significantly greater amounts of bone within the available pore space than did cell-free implants at sixteen weeks (p < 0.05). CONCLUSIONS: The results of this study demonstrated that allogeneic mesenchymal stem cells loaded on hydroxyapatite-tricalcium phosphate implants enhanced the repair of a critical-sized segmental defect in the canine femur without the use of immunosuppressive therapy. No adverse immune response was detected in this model.

Detection of Legionella pneumophila by real-time PCR for the mip gene.

A real-time PCR assay for the mip gene of Legionella pneumophila was tested with 27 isolates of L. pneumophila, 20 isolates of 14 other Legionella species, and 103 non-Legionella bacteria. Eight culture-positive and 40 culture-negative clinical specimens were tested. This assay was 100% sensitive and 100% specific for L. pneumophila.