Virginia Mason Franciscan Health

In patients with symptomatic paroxysmal atrial fibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmic drug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established.

Innovation and technological change are the main drivers of companies' productivity and growth. But public information on companies' efforts to innovate (namely, their investment in science and technology and the consequences of that investment) is generally scant and not timely. To alleviate this impediment to the valuation of companies' performance and prospects, we examined the ability of a new set of publicly available patent-related measures to reflect science- and technology-based companies' potential and growth. We tested the ability of the patent-related measures to predict stock returns and market-to-book ratios. Our empirical results indicate that patent measures reflecting the volume of companies' research activity, the impact of companies' research on subsequent innovations, and the closeness of research and development to science are reliably associated with the future performance of R&D-intensive companies in capital markets.

Importance: Functional impairment and pain are common indications for the initiation of lumbar spine surgery, but information about expected improvement in these patient-reported outcome (PRO) domains is not readily available to most patients and clinicians considering this type of surgery. Objective: To assess population-level PRO response after lumbar spine surgery, and develop/validate a prediction tool for PRO improvement. Design, Setting, and Participants: This statewide multicenter cohort was based at 15 Washington state hospitals representing approximately 75% of the state's spine fusion procedures. The Spine Surgical Care and Outcomes Assessment Program and the survey center at the Comparative Effectiveness Translational Network prospectively collected clinical and PRO data from adult candidates for lumbar surgery, preoperatively and postoperatively, between 2012 and 2016. Prediction models were derived for PRO improvement 1 year after lumbar fusion surgeries on a random sample of 85% of the data and were validated in the remaining 15%. Surgical candidates from 2012 through 2015 were included; follow-up surveying continued until December 31, 2016, and data analysis was completed from July 2016 to April 2017. Main Outcomes and Measures: Functional improvement, defined as a reduction in Oswestry Disability Index score of 15 points or more; and back pain and leg pain improvement, defined a reduction in Numeric Rating Scale score of 2 points or more. Results: A total of 1965 adult lumbar surgical candidates (mean [SD] age, 61.3 [12.5] years; 944 [59.6%] female) completed baseline surveys before surgery and at least 1 postoperative follow-up survey within 3 years. Of these, 1583 (80.6%) underwent elective lumbar fusion procedures; 1223 (77.3%) had stenosis, and 1033 (65.3%) had spondylolisthesis. Twelve-month follow-up participation rates for each outcome were between 66% and 70%. Improvements were reported in function, back pain, and leg pain at 12 months by 306 of 528 surgical patients (58.0%), 616 of 899 patients (68.5%), and 355 of 464 patients (76.5%), respectively, whose baseline scores indicated moderate to severe symptoms. Among nonoperative patients, 35 (43.8%), 47 (53.4%), and 53 (63.9%) reported improvements in function, back pain, and leg pain, respectively. Demographic and clinical characteristics included in the final prediction models were age, sex, race, insurance status, American Society of Anesthesiologists score, smoking status, diagnoses, prior surgery, prescription opioid use, asthma, and baseline PRO scores. The models had good predictive performance in the validation cohort (concordance statistic, 0.66-0.79) and were incorporated into a patient-facing, web-based interactive tool (https://becertain.shinyapps.io/lumbar_fusion_calculator). Conclusions and Relevance: The PRO response prediction tool, informed by population-level data, explained most of the variability in pain reduction and functional improvement after surgery. Giving patients accurate information about their likelihood of outcomes may be a helpful component in surgery decision making.

In 2001, the Society of Critical Care Medicine published practice model guidelines that focused on the delivery of critical care and the roles of different ICU team members. An exhaustive review of the additional literature published since the last guideline has demonstrated that both the structure and process of care in the ICU are important for achieving optimal patient outcomes. Since the publication of the original guideline, several authorities have recognized that improvements in the processes of care, ICU structure, and the use of quality improvement science methodologies can beneficially impact patient outcomes and reduce costs. Herein, we summarize findings of the American College of Critical Care Medicine Task Force on Models of Critical Care: 1) An intensivist-led, high-performing, multidisciplinary team dedicated to the ICU is an integral part of effective care delivery; 2) Process improvement is the backbone of achieving high-quality ICU outcomes; 3) Standardized protocols including care bundles and order sets to facilitate measurable processes and outcomes should be used and further developed in the ICU setting; and 4) Institutional support for comprehensive quality improvement programs as well as tele-ICU programs should be provided.

Background: Epidemiological observational studies have investigated the relationship between rheumatoid arthritis(RA) and pre-eclampsia, but no consistent conclusions were obtained due to various limitations. Hence, we conducted a two-sample mendelian randomization analysis to evaluate the potential causal effect of RA on pre-eclampsia. Methods: Summary-level statistics for RA were derived from a large-scale meta-analysis of datasets of genome-wide association studies(GWAS) which involved 14,361 cases and 43,923 controls. Moreover, summary statistics for pre-eclampsia or eclampsia were sourced from the Finn biobank which contained 3,903 cases and 114,735 controls. The inverse variance weighting (IVW) as well as other four effective methods including MR-Egger, weighted median, weighted mode, and simple mode were applied to deduce the potential causal relationships between RA and pre-eclampsia comprehensively. Results: The two-sample MR analysis suggested a strong causal relationship between RA and pre-eclampsia[OR,1.05;95%CI, 1.01-1.09;p<0.05]. The OR estimates obtained from the weighted mode[OR,1.09;95%CI,1.03-1.15;p<0.01] and weighted median[OR,1.07;95%CI, 1.01-1.14;p<0.05] were similar to those from the IVW method, but there was no significant association observed in MR Egger and simple mode analysis. Conclusion: This MR analysis provides evidence of a positive causal association between RA and pre-eclampsia genetically. Our findings highlight the importance of more intensive prenatal care and early intervention among pregnant women with RA to prevent potential adverse obstetric outcomes. Moreover, our study provides clues for risk factor identification and early prediction of pre-eclampsia.

OBJECTIVES: In 2014, the Tele-ICU Committee of the Society of Critical Care Medicine published an article regarding the state of ICU telemedicine, one better defined today as tele-critical care. Given the rapid evolution in the field, the authors now provide an updated review. DATA SOURCES AND STUDY SELECTION: We searched PubMed and OVID for peer-reviewed literature published between 2010 and 2018 related to significant developments in tele-critical care, including its prevalence, function, activity, and technologies. Search terms included electronic ICU, tele-ICU, critical care telemedicine, and ICU telemedicine with appropriate descriptors relevant to each sub-section. Additionally, information from surveys done by the Society of Critical Care Medicine was included given the relevance to the discussion and was referenced accordingly. DATA EXTRACTION AND DATA SYNTHESIS: Tele-critical care continues to evolve in multiple domains, including organizational structure, technologies, expanded-use case scenarios, and novel applications. Insights have been gained in economic impact and human and organizational factors affecting tele-critical care delivery. Legislation and credentialing continue to significantly influence the pace of tele-critical care growth and adoption. CONCLUSIONS: Tele-critical care is an established mechanism to leverage critical care expertise to ICUs and beyond, but systematic research comparing different models, approaches, and technologies is still needed.

BACKGROUND: Depression is associated with an increased risk of a series of cardiovascular diseases and with increased symptom burden in patients with atrial fibrillation. The aim of this study was to determine the association between depression as well as antidepressant treatment and the risk of incident atrial fibrillation. DESIGN: A nationwide register-based study comparing the atrial fibrillation risk in all Danes initiating antidepressant treatment from 2000 to 2013 ( N = 785,254) with that in a 1:5-matched sample from the general population. METHODS: Cox regression was used to estimate adjusted hazard ratios (aHRs) and associated 95% confidence intervals (95% CIs), both after initiation of treatment and in the month before when patients were assumed to have medically untreated depression. RESULTS: Antidepressant treatment was associated with a three-fold higher risk of atrial fibrillation during the first month (aHR = 3.18 (95% CI: 2.98-3.39)). This association gradually attenuated over the following year (aHR = 1.37 (95% CI: 1.31-1.44) 2-6 months after antidepressant therapy initiation, and aHR = 1.11 (95% CI: 1.06-1.16) 6-12 months after). However, the associated atrial fibrillation risk was even higher in the month before starting antidepressant treatment (aHR = 7.65 (95% CI: 7.05-8.30) from 30 to 15 days before, and aHR = 4.29 (95% CI: 3.94-4.67) the last 15 days before). Overall, 0.4% of patients were diagnosed with atrial fibrillation from 30 days before to 30 days after antidepressant treatment. CONCLUSIONS: Antidepressant users had a substantially increased atrial fibrillation risk, particularly before treatment initiation. Whether this mirrors a causal relation between depression and atrial fibrillation may have large consequences for public health and should be discussed.

Importance: Positive margins following breast-conserving surgery (BCS) are often identified on standard pathology evaluation. Intraoperative assessment of the lumpectomy cavity has the potential to reduce residual disease or reexcision rate following standard of care BCS in real time. Objective: To collect safety and initial efficacy data on the novel pegulicianine fluorescence-guided system (pFGS) when used to identify residual cancer in the tumor bed of female patients undergoing BCS. Design, Setting, and Participants: This prospective single-arm open-label study was conducted as a nonrandomized multicenter controlled trial at 16 academic or community breast centers across the US. Female patients 18 years and older with newly diagnosed primary invasive breast cancer or ductal carcinoma in situ DCIS undergoing BCS were included, excluding those with previous breast cancer surgery and a history of dye allergies. Of 283 consecutive eligible patients recruited, 234 received a pegulicianine injection and were included in the safety analysis; of these, 230 were included in the efficacy analysis. Patients were enrolled between February 6, 2018, and April 10, 2020, and monitored for a 30-day follow-up period. Data were analyzed from April 10, 2020, to August 5, 2021. Interventions: Participants received an injection of a novel imaging agent (pegulicianine) a mean (SD) of 3.2 (0.9) hours prior to surgery at a dose of 1 mg/kg. After completing standard of care (SOC) excision, pFGS was used to scan the lumpectomy cavity to guide the removal of additional shave margins. Main Outcomes and Measures: Adverse events and sensitivity, specificity, and reexcision rate. Results: Of 234 female patients enrolled (median [IQR] age, 62.0 [55.0-69.0] years), 230 completed the trial and 1 patient with a history of allergy to contrast agents had an anaphylactic reaction and recovered without sequelae. Correlation of pFGS with final margin status on a per-margin analysis showed a marked improvement in sensitivity over standard pathology assessment of the main lumpectomy specimen (69.4% vs 38.2%, respectively). On a per-patient level, the false-negative rate of pFGS was 23.7% (9 of 38), and sensitivity was 76.3% (29 of 38). Among 32 patients who underwent excision of pFGS-guided shaves, pFGS averted the need for reexcision in 6 (19%). Conclusions and Relevance: In this pilot feasibility study, the safety profile of pegulicianine was consistent with other imaging agents used in BCS, and was associated with a reduced need for second surgery in patients who underwent intraoperative additional excision of pFGS-guided shaves. These findings support further development and clinical performance assessment of pFGS in a prospective randomized trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03321929.

INTRODUCTION: Conduction system pacing (CSP) has emerged as an ideal physiologic pacing strategy for patients with permanent pacing indications. We sought to evaluate the safety and feasibility of CSP in a consecutive series of unselected patients with congenital heart disease (CHD). METHODS: Consecutive patients with CHD in which CSP was attempted were included. Safety and feasibility, implant tools and electrical parameters at implant and at follow-up were evaluated. RESULTS: A total of 20 patients were included (10 with a previous device). A total of 10 patients had complex forms of CHD, 9 moderate defects and 1 a simple defect. CSP was achieved in 75% of cases (10 His bundle pacing, 5 left bundle branch pacing) with left ventricular septal pacing in the remaining 5 patients. Procedure times and fluoroscopy times were prolongued (126 ± 82 min and 27 ± 30 min, respectively). Ventricular lead implant times widely varied ranging from 4 to 115 min, (mean 31 ± 28 min) and the use of multiple delivery sheaths was frequent (50%). The QRS width was reduced from 145 ± 36 ms at baseline to 116 ± 18 ms with CSP. Implant electrical parameters included: CSP pacing threshold 0.95 ± 0.65 V; R wave amplitude 9.2 ± 8.8 mV and pacing impedance 632 ± 183 Ohms, and remained stable at a median follow-up of 478 days (interquartile range: 225-567). Systemic ventricle systolic function and NYHA class (1.50 ± 0.51 vs. 1.10 ± 0.31; p = .008) significantly improved at follow-up. Lead revision was required in one patient at Day 4. CONCLUSIONS: Permanent CSP is safe and feasible in patients with CHD although implant technique is complex.

BACKGROUND AND PURPOSE: Computer-based analysis of Dopamine transporter imaging (DaTscan) can aid in image interpretation. In this study, we examined the distribution of putamen-to-caudate ratios (PCRs) obtained by using a clinically available semiquantification method. METHODS: Medical records of 32 patients (M:16) with a diagnosis of Parkinson's disease (PD) (n = 22) or Parkinson's plus syndromes (PPS) (n = 10) based on clinical follow-up, were retrospectively reviewed. Single photon emission tomography (SPECT) imaging was performed 4 hours after intravenous injection of 3-5 mCi [I-123]-ioflupane. Semiquantitative evaluation using DaTQUANT software was performed. Utility of PCR with a cutoff of .7 and .8 in the diagnosis of nigrostriatal degeneration was assessed. PD and PPS groups based on clinical assessment and caudate-to-background ratio (CBR) were assessed separately. RESULTS: Minimum PCR for both hemispheres was .74 ± .09 (Mean ± SD, range: .58-.89), with 65.63% patients (21/32) having PCR > .7. Mean PCR in mild nigrostriatal degeneration was .77 ± .08 (range: .62-.89) and in advanced nigrostriatal degeneration was .73 ± .09 (range: .58-.89). Mean PCR in PD group was .73 ± .09 (range: .58-.89) and in PPS group was .75 ± .10 (range: .61-.88). CONCLUSIONS: Although PCR can intrinsically be a useful indication of disease, this ratio obtained in our analysis by using one of the clinically available automatic semiquantitative methods has large variability and might not be a reliable numeric marker in interpretation of [I-123]ioflupane studies. This may be due to difficulty in separating caudate from putamen on SPECT images, as well as the nonuniform decreased Ioflupane uptake in both putamen and caudate.

BACKGROUND: Absolute monocyte count (AMC) is often used to be assessed in cancer follow-up, which has regained interest as a potential prognostic indicator in many solid tumors, though not consistently or comprehensively. In the present study, we set out to perform a comprehensive meta-analysis of all available data regarding the prognostic significance of AMC in solid tumors. We also evaluated the association between AMC and clinical features in solid tumors. METHODS: A hazard ratio (HR) and corresponding 95% confidence interval (CI) or a p value (p) from eligible studies were extracted and subsequently pooled analyzed. Subgroup analyses and meta-regression analyses were conducted according to the confounders of included studies. In addition, the relationships between AMC and clinical characteristics were also explored in the meta-analysis. RESULTS: Overall, ninety-three articles comprising 104 studies with 32229 patients were finally included. The results showed that elevated AMC was associated with worse overall survival (OS) (HR = 1.615; 95% CI: 1.475-1.768; p < 0.001), disease-free survival (DFS) (HR:1.488; 95% CI: 1.357-1.633; p < 0.001), progressive-free survival (PFS) (HR: 1.533; 95% CI: 1.342-1.751; p < 0.001) and cancer-specific survival (CSS) (HR: 1.585; 95% CI: 1.253-2.006; p < 0.001) in non-hematological tumors. Subgroup analyses according to each confounder further proved the consistent prognostic value of AMC in solid tumor outcomes. Moreover, elevated AMC was more likely to be observed in male group and patients with smoking history, and associated with longer tumor length and advanced T stage. CONCLUSION: In short, the meta-analysis found that elevated AMC might indicate poor long-term outcomes in non-hematologic cancers, thus AMC may be a valuable marker in the prognosis for patients with solid tumors.

Currently, there is no specific treatment for COVID-19 proven by clinical trials. WHO and CDC guidelines therefore endorse supportive care only. However, frontline clinicians have been applying several virus-based and host-based therapeutics in order to combat SARS-CoV-2. Medications from COVID-19 case reports, observational studies and the COVID-19 Treatment Guideline issued by the China's National Health Commission (7th edition published March 3rd, 2020. Edited translation attached) are evaluated in this review. Key evidence from relevant in vitro researches, animal models and clinical studies in SARS-CoV-2, SARS-CoV and MERS-CoV are examined. Antiviral therapies remdesivir, lopinavir/ritonavir and umifenovir, if considered, could be initiated before the peak of viral replication for optimal outcomes. Ribavirin may be beneficial as an add-on therapy and is ineffective as a monotherapy. Corticosteroids use should be limited without indicating comorbidities. IVIG is not recommended due to lack of data in COVID-19. Xuebijing may benefit patients with complications of bacterial pneumonia or sepsis. The efficacy of interferon is unclear due to conflicting outcomes in SARS and MERS studies. Chloroquine and hydroxychloroquine have shown in vitro inhibition of SARS-CoV-2 and may be beneficial as both prophylactic and treatment therapy. For patients who developed cytokine release syndrome, interleukin-6 inhibitors may be beneficial. Given the rapid disease spread and increasing mortality, active treatment with readily available medications may be considered timely prior to disease progression.

Chemorefractory diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes. Recent clinical trials testing chimeric antigen receptor T-cell (CAR T-cell) therapy, including ZUMA-1 leading to the first regulatory approval in DLBCL, demonstrate sustained complete remission, disease control, and long-term survival in a proportion of patients.1, 2 Despite the success of CAR T-cell therapies, trial outcomes must be interpreted in context of study definitions and eligibility parameters. A recent analysis of demonstrated poor outcomes in chemorefractory DLBCL, including a 2-year survival of 20%, but lacked detail on comorbidities which could impact clinical trial eligibility and survival expectations.3 Without understanding patient selection and comorbidities, interpretation of results—and optimal design of future trials—in chemorefractory DLBCL remains challenging. We postulated that clinical trial eligibility requirements could independently correlate with outcomes for patients with relapsed/refractory DLBCL. To evaluate this hypothesis, we examined chemorefractory DLBCL patients seen in the modern era from our center, applying key eligibility criteria from ZUMA-1 and describing the proportion likely to be excluded from trials, along with reasons for exclusion and survival outcomes. Patients with DLBCL seen at our institution from 2011 to 2015 were reviewed under IRB approval to determine chemorefractory status based on ZUMA-1 definition, and evaluate whether they would meet eligibility criteria.1 Chemorefractory status per ZUMA-1 was defined as stable disease (lasting 6 months or less) or progressive disease as best response to most recent chemotherapy, or disease progression within 12 months of autologous stem cell transplant. “Chemorefractory date” was identified by clinical assessment, biopsy, or imaging showing failure of DLBCL treatment (lack of response/progression), and served as the reference date for reviewing potential ZUMA-1 eligibility in detail, as well as the baseline date for survival estimates. Specifically, clinical data (ECOG, labs, organ function) within 8 weeks of chemorefractory date were examined to estimate potential ZUMA-1 eligibility. On occasion, more remote studies (eg, an echocardiogram >8 weeks prior) were included when relevant. Descriptive statistics and Kaplan-Meier overall survival (OS) estimates were performed, comparing patients potentially ZUMA-1 eligible with others. No attempt was made to compare outcomes among pts receiving specific therapies for chemorefractory DLBCL. The specific eligibility factors examined were: histology (DLBCL, PMBCL and tFL); prior therapy including history of allogeneic SCT; CNS involvement, performance status (ECOG 01- vs 2 or higher), laboratory parameters, cardiac disease, infectious comorbidities; history of second malignancy other than nonmelanoma skin cancer/in situ cancer or FL; need for urgent therapy due to tumor mass effect or rapid progression (a need for “bridging therapy”). Of 404 in our DLBCL database from 2011 to 2015, 163 had received at least two therapies and were examined. Thirty six had inadequate follow up, leaving 127 for detailed analysis. Of these, 78 were determined chemorefractory as per ZUMA-1 but an additional 12 patients who received CAR T-cell therapy on institutional trials were excluded. Thus, 66 chemorefractory DLBCL patients not treated with CAR T-cells were examined in depth. Median age was 63 (range, 19-77), 17 had transformed lymphoma. All had received and failed therapy with an anthracycline and a CD20-directed antibody. Fourteen relapsed within 1 year of autologous transplant, and 22 had primary refractory disease. A total of 39 patients (58%) were deemed ineligible for ZUMA-1 by retrospective review, with the most common exclusionary factors being need for urgent therapy, transformation from histology other than follicular lymphoma, and poor performance status (Table S1, Supplementary online materials). The median age of our ZUMA-1 “eligible” cohort was 59 years, and 64 years for “ineligible” patients. Figure 1 shows survival. Among eligible pts vs not: Median OS was 19 vs 7 months (eligible vs not, P = 0.06). 1-year OS was 55% vs 27%, 2-year OS 40% vs 23%. Univariate analysis of ZUMA-1 eligibility criteria indicated that only ECOG status 2 or higher (=0.05) predicted inferior OS. When applied to a historical cohort, fewer than half of chemorefractory DLBCL pts at our center met eligibility criteria for ZUMA-1. This finding resembles two recent studies describing use of axicabtagene ciloleucel in accordance with US Food and Drug Administration labeling (“real-world” use), projecting 49% to 60% of chemorefractory DLBCL patients to be ineligible for ZUMA-1. 4, 5 Our data, excluding patients treated with CAR T-cells but otherwise treated heterogeneously, found a trend toward improved survival patients meeting main inclusion criteria for the ZUMA-1 trial. The two compared groups (ZUMA-1 eligible/ineligible) could be imbalanced for additional factors impacting outcomes, including first remission duration and MYC gene dysregulation, so the comparison of outcomes based on eligibility for ZUMA-1 is exploratory. Nonetheless, the median and 2-year OS rates in each group (40% in eligible, vs 23%)—neither receiving CAR T-cell therapy—are thought-provoking. The eligible patients in our cohort experience comparable OS to that achieved among CAR T-cell study recipients in prospective trials, whereas ZUMA-1 ineligible patients face outcomes resembling those described in Scholar-1.3 Our data, suggesting a significant role of patient selection in the Zuma-1 trial, are supported by recent real-world data using axicabtagene ciloleucel. In those reports, treated patients who failed to meet eligibility criteria for ZUMA-1 had a lower complete response rate4 and nonsignificantly inferior OS.5 The most common exclusionary feature in our cohort was a need for urgent therapy (“bridging” therapy). Bridging therapy between leukoplasias and CAR T-cell administration was prohibited in ZUMA-1, but commonly reported (30%-56% of patients) in the real-world datasets.4, 5 Notably, of seven patients requiring urgent therapy in our series, five had additional features which would rendered them ineligible for ZUMA-1. Permitting bridging therapy, and intention-to-treat survival analysis, in the study of tisagenleceucel2 results in numerically inferior response and survival rates. An exclusionary performance status (ECOG 2 or higher) was present in 15% of our chemorefractory DLBCL cohort, a similar frequency to recent real-world datasets.4, 5 Advanced performance status was historically associated with chemotherapy toxicity and mortality in solid tumors (eg, colorectal cancer), but interobserver agreement at a cutoff of 2 is relatively poor, and data suggesting relevance in hematologic malignancies is limited.6, 7 While ECOG 2 or higher predicted inferior OS in our data and SCHOLAR-1,3 a recent study of real-world use of axicabtagene ciloleucel found these patients did not experience excess toxicity.5 Other major reasons for exclusion in our cohort—non-FL transformation and CNS involvement—may portend higher-risk disease, but without any anticipated impact on the safety of CAR T-cell therapy. Notably, CAR T-cells can cross the blood-brain barrier, and a case report of activity and safety in DLBCL involving CNS has been reported.8 This dataset has several limitations. First, clinical data were often incomplete around the chemorefractory date, resulting in small subsets evaluable for each ZUMA-1 eligibility factor. Patients received heterogenous therapies for chemorefractory DLBCL, including investigational therapies and allogeneic transplant, making generalization of results (and relevance outside of a tertiary care setting) less certain. Data regarding cause of death was unavailable for many patients, critical to distinguishing the impact of patient comorbidities and disease behavior. In conclusion, we found that a minority of patients with chemorefractory DLBCL appear to meet eligibility criteria for the pivotal ZUMA-1 trial. In addition, these criteria appear to select for lower-risk chemorefractory DLBCL risk patients and interpretation of survival outcomes is a challenge. A need for urgent or “bridging” therapy, non-FL transformation, ECOG performance status of 2, and CNS involvement are common exclusionary criteria, but may relate more to high-risk disease than safety of CAR T-cell therapy. In future clinical trials, eligibility criteria should be modified to permit evaluation of promising therapies among chemorefractory DLBCL patients with the greatest need. This work was supported by 5K24CA184039, STTR, The Seattle Cancer Care Alliance, donations from Frank and Betty Vandermeer and Sonya and Tom Campion. Stephen Smith has served as a consultant for Merck & Company; served on the Advisory board for AstraZeneca; and has received Research Funding from Acerta Pharma BV, AstraZeneca, De Novo Biopharma, Genentech, Incyte, Merck & Company, Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics; and his spouse receives Research Funding from Ayala Pharma, Bristol-Meyers Squibb, and Ignyta. Ryan Lynch has received Research Funding from Juno Therapeutics, Incyte, Rhizen Pharmaceuticals, Takeda, TG Therapeutics. Mazyar Shadman has served as a Consultant for AbbVie Pharmaceutical, Genentech, and Sound Biologics; served on the Advisory Board for AbbVie Pharmaceutical, ADC Therapeutics, Atari Therapeutics, Genentech, and Verastem Oncology; and has received Research Funding from Acerta Pharma BV, Beigene, Celgene, Emergent Biosolutions, Genentech, Gilead Sciences, Merck & Company, Mustang Biopharma, Pharmacyclics, and TG therapeutics. Ajay Gopal has served on the Advisory Board for Gilead Sciences and has received Research Funding from them. All other authors have no relevant conflicts of interest. Specific contributions include: Smith SD performed the research, designed the research study, and wrote the article. Reddy P performed the research. Sokolova A performed the research. Gopal AK designed the research study and wrote the article. All other authors assisted with critical review and writing of the article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

OBJECTIVE: To test the hypothesis that infants born <30 weeks' gestation supported by Seattle-PAP will have lower rates of continuous positive airway pressure (CPAP) failure than infants supported with conventional, Fisher&Paykel-CPAP (FP-CPAP). STUDY DESIGN: Randomized trial (3/2017-01/2019) at 5 NICUs. The primary outcome was CPAP failure; subgroup analyses (gestational age, receipt antenatal corticosteroids) were performed. RESULTS: A total of 232 infants were randomized. Infants in the Seattle-PAP and FP-CPAP groups had mean gestational ages of 27.0 and 27.2 weeks, respectively. We observed no differences in rates of treatment failure between Seattle-PAP (40/112, 35.7%) and FP-CPAP (38/120, 31.7%; risk difference, 4.1%; 95% CI, -8.1-16.2; P = 0.51). Subgroup analysis indicated no differences in rates of CPAP failure. We observed no differences between the two groups in frequencies of adverse events or duration of respiratory support. CONCLUSIONS: Among infants born <30 weeks' gestation, rates of CPAP failure did not differ between Seattle-PAP and FP-CPAP.

BACKGROUND: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging regarding the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher & Paykel CPAP or FP-CPAP). METHODS/DESIGN: weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short- and long-term respiratory morbidity and cost-effectiveness. DISCUSSION: This trial will assess whether Seattle-PAP is more efficacious and cost-effective than FP-CPAP in real-world practice among premature neonates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03085329 . Registered on 21 March 2017.

Background: Sepsis and septic shock are associated with enormous mortality and health care burden. Since the study of Marik et al suggested mortality benefit, there has been great interest in evaluating the role of hydrocortisone, ascorbic acid and thiamine (HAT therapy) in sepsis and septic shock. Purpose: The objective of this article is to review current literature of using HAT therapy in sepsis and septic shock, and discuss the findings in hospital mortality, change in 72 hr SOFA score, other outcomes, and the study limitations. Research Design: Three databases (PubMed, Embase, and Cochrane) were screened using predefined search terms ascorbic acid, vitamin C, thiamine, vitamin B1, hydrocortisone, sepsis, septic shock. Study Sample: Data extracted from eligible studies include authors, publication year, sample size, study design, intervention, outcome measures and study results. Each study was reviewed critically. Results: Among 11 studies included in this literature review, 3 studies reported HAT therapy was associated with mortality benefit, 1 reported hospital mortality was significantly higher in HAT group and the rest of studies didn’t reach statistical significance in mortality analysis. Significant improvement of secondary outcomes, although not consistently, were reported. Conclusions: In conclusion, HAT therapy has demonstrated a good safety profile and potential benefits in management of sepsis and septic shock. Further research is required to confirm these findings.

Despite numerous treatment modalities, there remains no clear consensus on the optimal surgical approach to mid-substance acute Achilles tendon ruptures (AATR). The purpose of this study is to present two novel minimally invasive surgery (MIS) approaches for AATR and compare their outcomes. Retrospective analysis of two surgeons's AATR patients (N=18) who underwent one of two modified minimally invasive repairs (MMIR). Group A received a modified Krackow suture repair via mini-open incision with percutaneous calcaneal anchors. Group B received a modified Kessler suture repair percutaneously. The mean follow-up period was 23.9 +/- 5.1 and 14.7 +/- 1.9 months respectively. Surgical outcomes were measured using Maryland Foot Score (MFS) and The Self-Reported Foot and Ankle Score (SEFAS). There was no statistically significant difference in patient outcomes between the two MMIR techniques. Overall, patient satisfaction with Maryland score was 95.7 +/- 9.0 in Group A and 89.6 +/- 19.0 in Group B (p=0.41). Overall SEFAS score was 43 +/- 4.73 in Group A and 39 +/- 11.6 in Group B (p=0.15). Sural nerve injury occurred in two of the eight patients in Group B (25%), with only one of the patients seeking further treatment for neuritic pain. There were no other complications in terms of wound dehiscence, infection, rerupture or functionality in either of the two surgical groups. These findings suggest that the reported MIS techniques may be an acceptable consideration for surgical treatment of acute Achilles tendon ruptures.

Purpose: This report describes a case of metronidazole injection infiltration which contrasts the sole other case report in the literature at this time, as the patient described herein experienced mild signs and symptoms with prompt resolution and no significant sequelae. Summary: The patient experienced metronidazole injection infiltration during administration open to gravity via an 18-gauge peripheral catheter in the left brachial vein. The site was examined at bedside within approximately 30 minutes of the incident and was noted to be slightly edematous, erythemic, and painful in terms of a 5.5 × 6.6-cm area. No blanching, blister formation, induration, skin discoloration, or diminished capillary refill were observed. The event was conservatively managed in the form of catheter discontinuation and marking of the affected area with a patient skin marker, as hyaluronidase was not administered due to a product osmolarity of ~314 mOsM/L and pH of 5.8. A bedside evaluation the next morning revealed full resolution of the previously described symptoms. The patient was discharged from the facility 11 days later without further complications from the infiltration event. Conclusion: We describe a case of metronidazole injection infiltration which did not require pharmacologic or nonpharmacologic interventions and resulted in complete resolution. This case supplements the current literature by contrasting the sole other case report which resulted in profound necrosis near the intravenous access site. This case suggests metronidazole infiltrations may not require clinician alarm or treatment if events occur under circumstances similar to that which is presented.

Mavrelis, Peter G. MD; Georgis, Peter MD; Todd, Michael DO; Gabrys, Stephen Author Information

During the coronavirus disease 2019 (COVID-19) pandemic, numerous existing chemicals have been screened for antiviral potential against the emerging coronavirus severe acute respiratory syndrome coronavirus 2. Chloroquine and hydroxychloroquine, after exhibiting potent in vitro efficacy, have gained tremendous attention. Both therapeutics are derivatives of natural alkaloid quinine and were first synthesized to treat malaria. Thereafter, the pharmaceutical applications of the agents have expanded to many new areas. In this article, the medicinal history and pharmacological activities of chloroquine and hydroxychloroquine are summarized. Antimalarial, anti-inflammatory, antitumor, antiviral properties, and therapeutic potential in the emerging viral infection COVID-19 are discussed. Pharmacokinetics, adverse effects, and toxicities are reviewed.