Predictors of Respiratory Support Use in Emergency Department Patients With COVID-19-Related Respiratory Failure.

BACKGROUND: Given the known downstream implications of choice of respiratory support on patient outcomes, all factors influencing these decisions, even those not limited to the patient, warrant close consideration. We examined the effect of emergency department (ED)-specific system factors, such as work load and census, on the use of noninvasive versus invasive respiratory support. METHODS: We conducted a multi-center retrospective cohort study of all adult subjects with severe COVID-19 requiring an ICU admission from 5 EDs within a single urban health care system. Subject demographics, severity of illness, and the type of respiratory support used were obtained. Using continuous measures of ED census, boarding, and active management, we estimated ED work load for each subjects' ED stay. The subjects were categorized by type(s) of respiratory support used: low-flow oxygen, noninvasive respiratory support (eg, noninvasive ventilation [NIV] and/or high-flow nasal cannula [HFNC]), invasive mechanical ventilation, or invasive mechanical ventilation after trial of NIV/HFNC. We used multivariable logistic regression to examine system factors associated with the type of respiratory support used in the ED. RESULTS: A total of 634 subjects were included. Of these, 431 (70.0%) were managed on low-flow oxygen alone, 108 (17.0%) on NIV/HFNC, 54 (8.5%) on invasive mechanical ventilation directly, and 41 (6.5%) on NIV/HFNC prior to invasive mechanical ventilation in the ED. Higher severity of illness and underlying lung disease increased the odds of requiring invasive mechanical ventilation compared to low-flow oxygen (odds ratio 1.05 [95% CI 1.03-1.07] and odds ratio 3.47 [95% CI 1.37-8.78], respectively). Older age decreased odds of being on invasive mechanical ventilation compared to low-flow oxygen (odds ratio 0.96 [95% CI 0.94-0.99]). As ED work load increased, the odds for subjects to be managed initially with NIV/HFNC prior to invasive mechanical ventilation increased 6-8-fold. CONCLUSIONS: High ED work load was associated with higher odds on HFNC/NIV prior to invasive mechanical ventilation.

A phase I study of cabazitaxel in combination with platinum and 5-fluorouracil (PF) in locally advanced squamous cell carcinoma of head and neck (LA-SCCHN).

BACKGROUND: There is a clinical need to improve outcomes for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), especially in Human Papilloma Virus (HPV) negative and HPV positive subtypes with a significant history of tobacco use. In animal models bearing SCCHN, Cabazitaxel showed an excellent response rate compared to docetaxel and might prove useful in treatment of patients. The primary objective of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of cabazitaxel when combined with cisplatin and 5-fluorouracil (PF) in induction chemotherapy (IC) for patients with SCCHN. Cabazitaxel-PF IC administered in 3 cycles (each 21 days) followed by concurrent chemoradiation (CRT) or surgery has been evaluated to assess overall response rate (ORR) and progression-free survival (PFS) in this population. METHODS: This phase I study employed a standard 3+3 design. DLT was defined as grade 4 or 5 toxicity or grade 3 toxicity lasting >7days. Out of 40 consented patients with stage IV, curable, previously untreated, LA-SCHHN and poor prognosis, 35 (32M, 3F) were enrolled and evaluated for toxicity: 19 oropharynx, 10 larynx, 2 oral cancer, 1 nasopharynx and 3 hypopharynx. Five dose levels of cabazitaxel (10, 12.5, 15, 17.5 and 20mg/m2) were tested in combination with cisplatin 100mg/m2 and 5-fluorouracil (5-FU) 800mg/m2/d×4days. Dose escalation for cabazitaxel was terminated upon the occurrences of 2 DLTs and the establishment of MTD. Cabazitaxel was then further escalated with cisplatin 75mg/m2 and 5-FU 800mg/m2/d×4days in the subsequent 3 dose levels (17.5, 20 and 22.5mg/m2). In the expansion cohort, 9 patients were enrolled at the 22.5mg/m2 dose level. Following 3 cycles of IC, patients were evaluated for clinical, radiographic, and pathologic response to cabazitaxel-PF before beginning CRT or surgery. RESULTS: There were two DLTs (grade 4 hyperuricemia; neutropenic fever, sepsis, and grade 4 thrombocytopenia) among 2 patients in cohort 5 at the dose of 20mg/m2 of cabazitaxel. There were no DLTs reported with cohorts using a lower dose of cisplatin, even in the expansion cohort. The study was stopped at the dose of 22.5mg/m2 in accordance with the initial study design. With 33 evaluable patients for response, the Overall Response Rate (ORR) rate was 57.6%: 9.1% Complete Responses (CR) and 48.5% Partial Responses (PR) were noted. CONCLUSIONS: The recommended phase II dose for cabazitaxel in combination with cisplatin 75mg/m2 and 5-FU 800mg/m2/d×4days is 22.5mg/m2 and for cisplatin 100mg/m2 and 5-FU 800mg/m2/d×4days is 17.5mg/m2. With a median follow-up of 39months, PFS for the entire non-metastatic population at 3years was approximately 58%.

Risk Factors Leading to Free Flap Failure: Analysis From the National Surgical Quality Improvement Program Database.

BACKGROUND: The objective of this study was to identify risk factors for free flap failure among various anatomically based free flap subgroups. METHODS: The 2005 to 2012 American College of Surgeons National Surgical Quality Improvement Program database was queried for patients undergoing microvascular free tissue transfer based on current procedural terminology codes. Univariate analysis was performed to identify any association between flap failure and the following factors: age, gender, race, body mass index (BMI), diabetes, smoking, alcohol use, hypertension, intraoperative transfusion, functional health status, American Society of Anesthesiologists class, operative time, and flap location. Factors yielding a significance of P < 0.20 were included in multivariate logistic regression models in order to identify independent risk factor significance for flap failure. Furthermore, patients were stratified based on recipient site (breast, head and neck, trunk, or extremity), and analysis was repeated in order to identify risk factors specific to each location. RESULTS: A total of 1921 of 2103 patients who underwent microvascular free flap reconstruction met inclusion criteria. Multivariate logistic regression identified BMI (adjusted odds ratio [AOR] = 1.07, P = 0.004) and male gender (AOR = 2.16, P = 0.033) as independent risk factors for flap failure. Among the "breast flaps" subgroup, BMI (AOR = 1.075, P = 0.012) and smoking (AOR = 3.35, P = 0.02) were independent variables associated with flap failure. In "head and neck flaps," operative time (AOR = 1.003, P = 0.018) was an independent risk factor for flap failure. No independent risk factors were identified for the "extremity flaps" or "trunk flaps" subtypes. CONCLUSIONS: BMI, smoking, and operative time were identified as independent risk factors for free flap failure among all flaps or within flap subsets.

A Comparison of Postoperative Outcomes in Immediate Versus Delayed Reconstruction After Mastectomy.

OBJECTIVE: The objective of this study was to evaluate the frequency of various postoperative complications in patients undergoing either immediate or delayed breast reconstruction after mastectomy for malignancy. METHODS: The ACS-NSQIP 2005-2012 database was queried for patients who underwent mastectomy for the treatment of breast malignancy. These mastectomy cases were then stratified, generating "mastectomy alone" and "mastectomy with immediate reconstruction" cohorts. Database analysis also identified "delayed-reconstruction" oncologic patients. All patients undergoing reconstruction were then stratified into the tissue expander/implant or flap-based reconstruction group. The frequency of postoperative complications was assessed. A multiplicative risk model was used to calculate the probability of postoperative complications after undergoing a mastectomy alone, followed by reconstruction on a different date. These values were compared with the frequency of postoperative complications in the "mastectomy with immediate reconstruction" cohort, and 1-sample binomial tests were performed to determine statistical significance. RESULTS: A total of 49,450 cases that underwent either mastectomy alone (n = 30,226), mastectomy with immediately tissue expander/implant reconstruction (n = 13,513), mastectomy with immediate flap reconstruction (n = 2854), delayed tissue expander/implant reconstruction (n = 2047), or delayed flap reconstruction (n = 810) were identified. When compared with a delayed reconstructive model, immediate reconstruction after mastectomy was associated with increased flap or tissue expander/implant failure. However, delayed reconstructive modalities were associated with increased postoperative medical and surgical complications. Finally, in flap-based reconstruction, the incidence of return to the operating room was higher in delayed reconstruction than in immediate reconstruction. CONCLUSIONS: Awareness of complications associated with each reconstructive modality will allow both surgeons and patients to effectively decide upon reconstructive options.

Conservation of HIV-1 T cell epitopes across time and clades: validation of immunogenic HLA-A2 epitopes selected for the GAIA HIV vaccine.

HIV genomic sequence variability has complicated efforts to generate an effective globally relevant vaccine. Regions of the viral genome conserved in sequence and across time may represent the "Achilles' heel" of HIV. In this study, highly conserved T-cell epitopes were selected using immunoinformatics tools combining HLA-A2 supertype binding predictions with relative global conservation. Analysis performed in 2002 on 10,803 HIV-1 sequences, and again in 2009, on 43,822 sequences, yielded 38 HLA-A2 epitopes. These epitopes were experimentally validated for HLA binding and immunogenicity with PBMCs from HIV-infected patients in Providence, Rhode Island, and/or Bamako, Mali. Thirty-five (92%) stimulated an IFNγ response in PBMCs from at least one subject. Eleven of fourteen peptides (79%) were confirmed as HLA-A2 epitopes in both locations. Validation of these HLA-A2 epitopes conserved across time, clades, and geography supports the hypothesis that such epitopes could provide effective coverage of virus diversity and would be appropriate for inclusion in a globally relevant HIV vaccine.