SIX1+PAX3+ identify a progenitor for myogenic lineage commitment from hPSCs.

The earliest skeletal muscle progenitor cells (SMPCs) derived from human pluripotent stem cells (hPSCs) are often identified by factors expressed by a diverse number of progenitors. An early transcriptional checkpoint that defines myogenic commitment could improve hPSC differentiation to skeletal muscle. Analysis of several myogenic factors in human embryos and early hPSC differentiations found SIX1+PAX3+ co-expression was most indictive of myogenesis. Using dCas9-KRAB hPSCs, we demonstrate that early inhibition of SIX1 alone significantly decreased PAX3 expression, reduced PAX7+ SMPCs, and myotubes later in differentiation. Emergence of SIX1+PAX3+ precursors can be improved by manipulating seeding density, monitoring metabolic secretion and altering the concentration of CHIR99021. These modifications resulted in the co-emergence of hPSC-derived sclerotome, cardiac and neural crest that we hypothesized enhanced hPSC myogenic differentiation. Inhibition of non-myogenic lineages modulated PAX3 independent of SIX1. To better understand SIX1 expression, we compared directed differentiations to fetal progenitors and adult satellite cells by RNA-seq. Although SIX1 continued to be expressed across human development, SIX1 co-factor expression was dependent on developmental timing. We provide a resource to enable efficient derivation of skeletal muscle from hPSCs.

Assessing the efficacy-effectiveness gap for cancer therapies: A comparison of overall survival and toxicity between clinical trial and population-based, real-world data for contemporary parenteral cancer therapeutics.

BACKGROUND: Although increasing evidence has suggested that an efficacy-effectiveness gap exists between clinical trial (CT) and real-world evidence (RWE), to the authors' knowledge, the magnitude of this difference remains undercharacterized. The objective of the current study was to quantify the magnitude of survival and toxicity differences between CT and RWE for contemporary cancer systemic therapies. METHODS: Patients receiving cancer therapies funded under Cancer Care Ontario's New Drug Funding Program (NDFP) were identified. Landmark CTs with data regarding survival and adverse events (AEs) for each drug indication were identified. RWE for survival and hospitalization rates during treatment were ascertained through Canadian population-based databases. The efficacy-effectiveness gap for each drug indication was calculated as the difference between RWE and CT data for median overall survival (OS), 1-year OS, and generated hazard ratios (HRs) with 95% CIs from Kaplan-Meier OS curves. Toxicity differences were calculated as the difference between RWE of hospitalization rates and CT serious AE rates. RESULTS: Twenty-nine indications from 20 systemic therapies were included. Twenty-eight of 29 indications (97%) demonstrated worse survival in RWE, with a median OS difference of 5.2 months (interquartile range, 3.0-12.1 months). Lower effectiveness in RWE also was demonstrated through a meta-analysis of an OS hazard ratio of 1.58 (95% CI, 1.39-1.80). The median difference between RWE for hospitalization rates and CT serious AEs was 14% (95% CI, 9%-22%). CONCLUSIONS: An efficacy-effectiveness gap exists for contemporary cancer systemic therapies, with a 5.2-month lower median OS observed in RWE compared with CT data. These data supports the use of RWE to better inform real-world decision making regarding the use of cancer systemic therapies.

Increase in Hospital-Acquired Carbapenem-Resistant Acinetobacter baumannii Infection and Colonization in an Acute Care Hospital During a Surge in COVID-19 Admissions - New Jersey, February-July 2020.

Carbapenem-resistant Acinetobacter baumannii (CRAB), an opportunistic pathogen primarily associated with hospital-acquired infections, is an urgent public health threat (1). In health care facilities, CRAB readily contaminates the patient care environment and health care providers' hands, survives for extended periods on dry surfaces, and can be spread by asymptomatically colonized persons; these factors make CRAB outbreaks in acute care hospitals difficult to control (2,3). On May 28, 2020, a New Jersey hospital (hospital A) reported a cluster of CRAB infections during a surge in patients hospitalized with coronavirus disease 2019 (COVID-19). Hospital A and the New Jersey Department of Health (NJDOH) conducted an investigation, and identified 34 patients with hospital-acquired multidrug-resistant CRAB infection or colonization during February-July 2020, including 21 (62%) who were admitted to two intensive care units (ICUs) dedicated to caring for COVID-19 patients. In late March, increasing COVID-19-related hospitalizations led to shortages in personnel, personal protective equipment (PPE), and medical equipment, resulting in changes to conventional infection prevention and control (IPC) practices. In late May, hospital A resumed normal operations, including standard IPC measures, as COVID-19 hospitalizations decreased, lessening the impact of personnel and supply chain shortages on hospital functions. CRAB cases subsequently returned to a pre-COVID-19 baseline of none to two cases monthly. The occurrence of this cluster underscores the potential for multidrug-resistant organisms (MDROs) to spread during events when standard hospital practices might be disrupted; conventional IPC strategies should be reinstated as soon as capacity and resources allow.

Comparative Effectiveness and Safety of Trastuzumab Biosimilars to Herceptin for Adjuvant Treatment of HER2+ Breast Cancer.

Background: Ontario publicly funds reference trastuzumab (Herceptin) and four biosimilar trastuzumab products for adjuvant treatment of HER2+ breast cancer. We assessed the real-world safety and effectiveness of biosimilar trastuzumab compared to Herceptin for adjuvant treatment of patients with HER2+ breast cancer. Methods: This was a population-based, retrospective study comparing the safety and effectiveness of biosimilar trastuzumab and Herceptin for neoadjuvant/adjuvant treatment of HER2+ breast cancer from 2016 to 2021. Treatment patients started biosimilar trastuzumab from November 2019 to June 2021; historical comparator patients started Herceptin from June 2016 to October 2019. Safety outcomes death within 30 days of last dose of trastuzumab, direct hospitalization, emergency department visit leading to hospitalization, early treatment discontinuation, and in-patient admission for congestive heart failure were measured using logistic/negative binomial regression. Overall survival (OS) was measured using Kaplan-Meier methods and Cox proportional hazards regression. Propensity score matching was applied. Results: From June 2016 to 2021, 5071 patients with breast cancer were treated with neoadjuvant/adjuvant trastuzumab. The rate of direct hospitalization (RR: 0.85, 95% CI: 0.74-0.98, p-value: 0.032) was significantly lower in biosimilar compared to Herceptin patients. OS (log-rank test p = 0.98) and risk of mortality (HR: 1.29, 95% CI: 0.72-2.30, p-value = 0.39) did not significantly differ between treatment groups. Conclusions: Biosimilar trastuzumab demonstrated similar safety and effectiveness to Herceptin. The findings can help improve confidence in and use of biosimilars and demonstrate the value of real-world evidence generation for supporting biosimilar implementations and reassessments.

Conventional vs. Sutureless Aortic Valve Bioprosthesis: Is Faster Better?

Purpose: The benefits of sutureless compared to conventional aortic valve prosthesis replacement remain controversial. Supposed advantages of sutureless aortic valve replacement include shortened cross-clamp and implantation time, as well as improved overall safety and good post-operative performance. We aimed to compare the early outcomes and performance of sutureless aortic valve replacement (su-AVR) with the sutureless Perceval (Corcym, Milan, Italy) vs. the conventional AVR with a conventional counterpart, in this case, the Labcor Dokimos Plus (LDP) aortic bioprosthesis. Methods: We compared two types of aortic valve prostheses, the sutureless (Corcym, Milan, Italy) and the conventional valve Labcor Dokimos Plus (LDP), implanted between August 2014 and May 2019 in our Department of Cardiac Surgery at RWTH Aachen University Hospital. Data were collected from 141 patients who received the Perceval (Corcym, Milan, Italy) and 138 who received the Labcor Dokimos Plus (LDP) aortic bioprosthesis. After matching the two groups considering STS mortality risk and pre-operative LDH levels, 201 patients were included in our final study cohort. Seventy-one patients (17 from the Perceval group and 54 from the Dokimos group) were excluded due to the lack of complete data, particularly standardized echocardiographic data (n = 71). Primary endpoints were 30-day mortality, length of hospital stay, and pacemaker implantation. Secondary endpoints were echocardiographic parameters, major adverse cardiovascular events, and prosthesis failure (grade II aortic regurgitation, paravalvular leak with reintervention). Results: Bypass and cross-clamp time proved to be shorter in the Perceval group, while hospital stays were longer. The faster implantation had no effect on the 30-day mortality primary endpoint. Transvalvular gradients were significantly higher in the Perceval group, in addition to a smaller effective orifice area. The LDH values were remarkably higher post-operatively in the Perceval group. Conclusions: Regarding the clinical outcomes, Perceval was equivalent and not superior to the Dokimus bioprosthesis. The suitability of a Perceval prosthesis implantation must be determined on a case-by-case basis and reserved for elderly patients with increased comorbidity.

Conventional Prostheses versus Sutureless Perceval for Aortic Valve Replacement: A Meta-Analysis.

PURPOSE: Perceval sutureless valves have gained popularity. Whether this implant performs superior to the traditional sutured prosthesis remains unclear. This meta- analysis compared the Perceval implants versus the sutured conventional valves for aortic valve replacement (AVR). METHODS: This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following databases were accessed: PubMed, Google Scholar, Web of Science, Scopus, and EMBASE. All clinical investigations comparing Perceval versus the conventional prostheses for AVR were considered. RESULTS: The Perceval group demonstrated higher rate of pacemaker implantation (P <0.00001). Aortic cross-clamp (ACC) time (P <0.00001) and cardiopulmonary bypass (CPB) time (P <0.00001) were shorter in the Perceval group. Similarity was found in mean and peak pressure gradient (P = 0.8 and P = 0.2, respectively), mean aortic valve area (P = 0.3), length of intensive care unit (P = 0.4) and hospital stay (P = 0.2), rate of revision (P = 0.11), hemorrhages (P = 0.05), paravalvular leak (P = 0.3), cerebrovascular complication (P = 0.7), and early mortality (P = 0.06). CONCLUSION: Given the shorter ACC time and CPB time, Perceval AVR can be an alternative in high-risk patients. The higher rate of pacemaker implantation following Perceval may limit its routine implantation.

Vocalizations of wild West Indian manatee vary across subspecies and geographic location.

Geographic variation in the vocal behavior of manatees has been reported but is largely unexplored. Vocalizations of wild West Indian manatees (Trichechus manatus) were recorded with hydrophones in Florida from Florida manatees (Trichechus manatus latirostris), and in Belize and Panama from Antillean manatees (Trichechus manatus manatus) to determine if calls varied between subspecies and geographic regions. Calls were visually classified into five categories: squeaks, high squeaks, squeals, squeak-squeals, and chirps. From these five categories, only three call types (squeaks, high squeaks and squeals) were observed in all three populations. Six parameters from the temporal and frequency domains were measured from the fundamental frequency of 2878 manatee vocalizations. A repeated measures PERMANOVA found significant differences for squeaks and high squeaks between each geographic location and for squeals between Belize and Florida. Almost all measured frequency and temporal parameters of manatee vocalizations differed between and within subspecies. Variables that may have influenced the variation observed may be related to sex, body size, habitat and/or other factors. Our findings provide critical information of manatee calls for wildlife monitoring and highlight the need for further study of the vocal behavior of manatees throughout their range.

Connectivity conservation at the crossroads: protected areas versus payments for ecosystem services in conserving connectivity for Colombian carnivores.

Protected areas (PAs) constitute one of the main tools for global landscape conservation. Recently, payments for environmental services (PES) have attracted interest from national and regional governments and are becoming one of the leading conservation policy instruments in tropical countries. However, the degree to which areas designated for PES overlap with areas that are critical for maintaining species' landscape connectivity is rarely evaluated. We estimated habitat distributions and connectivity for 16 of the 22 mammalian carnivores occurring in the Caribbean region of Colombia, and identified the overlap between existing PAs and areas identified as being important for connectivity for these species. We also evaluated the potential impact of creation of new PAs versus new PES areas on conserving connectivity for carnivores. Our results show that PAs cover only a minor percentage of the total area that is important for maintaining connectivity ( x = 26.8 % ± 20.2 s . d . ). On the other hand, PES, if implemented extensively, could contribute substantially to mammalian carnivores' connectivity ( x = 45.4 % ± 12.8 s . d . ). However, in a more realistic scenario with limited conservation investment in which fewer areas are set aside, a strategy based on implementing new PAs seems superior to PES. We argue that prioritizing designation of new PAs will be the most efficient means through which to maintain connectivity.

Who Can Debriefing Assessment for Simulation in Healthcare? Different Perspectives on Teledebriefing Assessments.

INTRODUCTION: Virtual debriefing is a cardinal element to achieve the effectiveness of telesimulation. There are different instruments to assess face-to-face debriefing to determine the degree of effectiveness of debriefing; Debriefing Assessment for Simulation in Healthcare (DASH) instrument is one of them. This study aims to describe and compare the evaluation of raters, instructors, and students during a virtual debriefing using the DASH. METHODS: A cross-sectional study was performed evaluating the virtual debriefing of 30 instructors after a heart failure telesimulation scenario. The evaluation was conducted by 30 instructors, 338 undergraduate students in the seventh semester, and 7 simulation raters. The 3 versions of the DASH instrument in Spanish were applied, respectively. RESULTS: Two comparisons were made, student versus instructor and rater versus instructor. Cronbach α was 0.97 for each version. The averages of the results on the DASH instrument were: 6.61 (3.34-7.0), 5.95 (4.65-7.0), and 4.84 (2.68-6.02) for student, rater, and instructor versions, respectively. The size effect between student and debriefer perspectives was 0.42. In contrast, the size effect between instructor and rater was 0.72. All differences were significant. CONCLUSIONS: There are different rates between the persons who use the DASH. In this study, from the perspective of the instructor and rater, the difference was 1 point with a wide range, in contrast with the difference between instructor and student, which is relatively minor. It is necessary to consider the perspectives of experts in the subject to achieve a virtual debriefing of high quality and improve a debriefing by using the DASH.

Real-World Cost-Effectiveness of First-Line Gemcitabine Plus Nab-Paclitaxel vs FOLFIRINOX in Patients With Advanced Pancreatic Cancer.

BACKGROUND: There are no randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and fluorouracil, folinic acid, irinotecan, oxaliplatin (FOLFIRINOX) for advanced pancreatic cancer (APC). Although it is well known that RCT-based efficacy often does not translate to real-world effectiveness, there is limited literature investigating comparative cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC. We aimed to examine the real-world cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC in Ontario, Canada. METHODS: This study compared patients treated with first-line Gem-Nab or FOLFIRINOX for APC in Ontario from April 2015 to March 2019. Patients were linked to administrative databases. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring, and discounted at 1.5%. Incremental cost-effectiveness ratio and net monetary benefit were computed to estimate cost-effectiveness from the public health-care payer's perspective. Sensitivity analysis was conducted using the propensity score matching method. RESULTS: A total of 1988 patients were identified (Gem-Nab: n = 928; FOLFIRINOX: n = 1060). Mean survival was lower for patients in the Gem-Nab than the FOLFIRINOX group (0.98 vs 1.26 life-years; incremental effectiveness = -0.28 life-years [95% confidence interval = -0.47 to -0.13]). Patients in the Gem-Nab group incurred greater mean 5-year total costs (Gem-Nab: $103 884; FOLFIRINOX: $101 518). Key cost contributors include ambulatory cancer care, acute inpatient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it was less effective and more costly. Results from the sensitivity analysis were similar. CONCLUSIONS: Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore not considered cost-effective at commonly accepted willingness-to-pay thresholds.