Long-Term Survival and Induction of Operational Tolerance to Murine Islet Allografts by Co-Transplanting Cyclosporine A Microparticles and CTLA4-Ig.

One strategy to prevent islet rejection is to create a favorable immune-protective local environment at the transplant site. Herein, we utilize localized cyclosporine A (CsA) delivery to islet grafts via poly(lactic-co-glycolic acid) (PLGA) microparticles to attenuate allograft rejection. CsA-eluting PLGA microparticles were prepared using a single emulsion (oil-in-water) solvent evaporation technique. CsA microparticles alone significantly delayed islet allograft rejection compared to islets alone (p < 0.05). Over 50% (6/11) of recipients receiving CsA microparticles and short-term cytotoxic T lymphocyte-associated antigen 4-Ig (CTLA4-Ig) therapy displayed prolonged allograft survival for 214 days, compared to 25% (2/8) receiving CTLA4-Ig alone. CsA microparticles alone and CsA microparticles + CTLA4-Ig islet allografts exhibited reduced T-cell (CD4+ and CD8+ cells, p < 0.001) and macrophage (CD68+ cells, p < 0.001) infiltration compared to islets alone. We observed the reduced mRNA expression of proinflammatory cytokines (IL-6, IL-10, INF-γ, and TNF-α; p < 0.05) and chemokines (CCL2, CCL5, CCL22, and CXCL10; p < 0.05) in CsA microparticles + CTLA4-Ig allografts compared to islets alone. Long-term islet allografts contained insulin+ and intra-graft FoxP3+ T regulatory cells. The rapid rejection of third-party skin grafts (C3H) in islet allograft recipients suggests that CsA microparticles + CTLA4-Ig therapy induced operational tolerance. This study demonstrates that localized CsA drug delivery plus short-course systemic immunosuppression promotes an immune protective transplant niche for allogeneic islets.

Outpatient Parenteral Antibiotic Therapy for Diabetic Foot Osteomyelitis in an Uninsured and Underinsured Cohort.

Background: Diabetic foot osteomyelitis (DFO) is usually treated with prolonged outpatient parenteral antibiotic therapy (OPAT). Evaluation and treatment of non-antibiotic aspects of DFO (e.g., peripheral artery disease [PAD]) are also recommended. There is limited data regarding OPAT practice patterns and outcomes for DFO. Methods: Single-center observational study of patients receiving OPAT for DFO in a large United States public hospital between January 2017 and July 2019. We abstracted data regarding microbiology test, antibiotics, clinical outcomes, and non-antibiotic DFO management. Results: Ninety-six patients were included and some had >1 DFO-OPAT course during the study period (106 DFO-OPAT courses included). No culture was obtained in 40 (38%) of courses. Methicillin-resistant S. aureus (MRSA) was cultured in 15 (14%) and P. aeruginosa in 1 (1%) of DFO-OPAT courses. An antibiotic with MRSA activity (vancomycin or daptomycin) was used in 79 (75%) of courses and a parenteral antibiotic with anti-pseudomonal activity was used in 7 (6%) of courses. Acute kidney injury occurred in 19 (18%) DFO-OPAT courses. An ankle-brachial index measurement was obtained during or 6 months prior to the first DFO-OPAT course for 44 (49%) of patients. Forty-two (44%) patients died or had an amputation within 12 months of their initial hospital discharge. Conclusions: We found high rates of empiric antibiotic therapy for DFO and low uptake of the non-antibiotic aspects of DFO care. Better implementation of microbiological tests for DFO in addition to stronger integration of infectious disease and non-infectious diseases care could improve DFO outcomes.

Recent Developments in Islet Biology: A Review With Patient Perspectives.

Navigating the coronavirus disease-2019 (COVID-19, now COVID) pandemic has required resilience and creativity worldwide. Despite early challenges to productivity, more than 2,000 peer-reviewed articles on islet biology were published in 2021. Herein, we highlight noteworthy advances in islet research between January 2021 and April 2022, focussing on 5 areas. First, we discuss new insights into the role of glucokinase, mitogen-activated protein kinase-kinase/extracellular signal-regulated kinase and mitochondrial function on insulin secretion from the pancreatic ß cell, provided by new genetically modified mouse models and live imaging. We then discuss a new connection between lipid handling and improved insulin secretion in the context of glucotoxicity, focussing on fatty acid-binding protein 4 and fetuin-A. Advances in high-throughput "omic" analysis evolved to where one can generate more finely tuned genetic and molecular profiles within broad classifications of type 1 diabetes and type 2 diabetes. Next, we highlight breakthroughs in diabetes treatment using stem cell-derived ß cells and innovative strategies to improve islet survival posttransplantation. Last, we update our understanding of the impact of severe acute respiratory syndrome-coronavirus-2 infection on pancreatic islet function and discuss current evidence regarding proposed links between COVID and new-onset diabetes. We address these breakthroughs in 2 settings: one for a scientific audience and the other for the public, particularly those living with or affected by diabetes. Bridging biomedical research in diabetes to the community living with or affected by diabetes, our partners living with type 1 diabetes or type 2 diabetes also provide their perspectives on these latest advances in islet biology.

Characteristics of and reasons for electronic cigarette use among adult smokers with schizophrenia/schizoaffective disorder.

BACKGROUND: The objective of our study was to determine lifetime and current e-cigarette use among adult cigarette smokers with schizophrenia or schizoaffective disorder, and to describe characteristics of these e-cigarette users. METHODS: Adult daily tobacco smokers with schizophrenia who were psychiatrically stable in outpatient treatment (n = 162) were enrolled in a motivational intervention study from 2013 to 2015 and followed for 6 months. Approximately 80% (n = 140) completed a 6-month follow-up, including the Population Assessment of Tobacco and Health survey. RESULTS: Among the 140 participants, 46% (n = 64) reported ever using e-cigarettes and 15% (n = 21) reported current use. Participants were significantly more likely to report ever-use if they were younger (Chi-square = 11.7, P < .01), lesbian/gay/bisexual (LGB) (Chi-square = 4.8, P = .03), or reported recent drug use (Chi-square = 6.5, P = .01). In a multivariate model, only age remained a significant predictor of ever-use (coefficient: 0.03; P = .02). The most common reasons for using e-cigarettes were "helps people quit cigarettes" and "less harmful to me or to people around me than cigarettes." Current e-cigarette users had significantly lower carbon monoxide levels than past e-cigarettes users (T = 2.08, P = .04). CONCLUSIONS: Almost one-half of smokers with schizophrenia or schizoaffective disorder reported ever using e-cigarettes. Interventions for tobacco use among this demographic should incorporate recognition of e-cigarette use, particularly among younger adults, illicit drug users, and LGB individuals.

Training and Validation of Deep Learning-Based Auto-Segmentation Models for Lung Stereotactic Ablative Radiotherapy Using Retrospective Radiotherapy Planning Contours.

PURPOSE: Deep learning-based auto-segmented contour (DC) models require high quality data for their development, and previous studies have typically used prospectively produced contours, which can be resource intensive and time consuming to obtain. The aim of this study was to investigate the feasibility of using retrospective peer-reviewed radiotherapy planning contours in the training and evaluation of DC models for lung stereotactic ablative radiotherapy (SABR). METHODS: Using commercial deep learning-based auto-segmentation software, DC models for lung SABR organs at risk (OAR) and gross tumor volume (GTV) were trained using a deep convolutional neural network and a median of 105 contours per structure model obtained from 160 publicly available CT scans and 50 peer-reviewed SABR planning 4D-CT scans from center A. DCs were generated for 50 additional planning CT scans from center A and 50 from center B, and compared with the clinical contours (CC) using the Dice Similarity Coefficient (DSC) and 95% Hausdorff distance (HD). RESULTS: Comparing DCs to CCs, the mean DSC and 95% HD were 0.93 and 2.85mm for aorta, 0.81 and 3.32mm for esophagus, 0.95 and 5.09mm for heart, 0.98 and 2.99mm for bilateral lung, 0.52 and 7.08mm for bilateral brachial plexus, 0.82 and 4.23mm for proximal bronchial tree, 0.90 and 1.62mm for spinal cord, 0.91 and 2.27mm for trachea, and 0.71 and 5.23mm for GTV. DC to CC comparisons of center A and center B were similar for all OAR structures. CONCLUSIONS: The DCs developed with retrospective peer-reviewed treatment contours approximated CCs for the majority of OARs, including on an external dataset. DCs for structures with more variability tended to be less accurate and likely require using a larger number of training cases or novel training approaches to improve performance. Developing DC models from existing radiotherapy planning contours appears feasible and warrants further clinical workflow testing.

Implementation of deep learning-based auto-segmentation for radiotherapy planning structures: a workflow study at two cancer centers.

PURPOSE: We recently described the validation of deep learning-based auto-segmented contour (DC) models for organs at risk (OAR) and clinical target volumes (CTV). In this study, we evaluate the performance of implemented DC models in the clinical radiotherapy (RT) planning workflow and report on user experience. METHODS AND MATERIALS: DC models were implemented at two cancer centers and used to generate OAR and CTVs for all patients undergoing RT for a central nervous system (CNS), head and neck (H&N), or prostate cancer. Radiation Therapists/Dosimetrists and Radiation Oncologists completed post-contouring surveys rating the degree of edits required for DCs (1 = minimal, 5 = significant) and overall DC satisfaction (1 = poor, 5 = high). Unedited DCs were compared to the edited treatment approved contours using Dice similarity coefficient (DSC) and 95% Hausdorff distance (HD). RESULTS: Between September 19, 2019 and March 6, 2020, DCs were generated on approximately 551 eligible cases. 203 surveys were collected on 27 CNS, 54 H&N, and 93 prostate RT plans, resulting in an overall survey compliance rate of 32%. The majority of OAR DCs required minimal edits subjectively (mean editing score ≤ 2) and objectively (mean DSC and 95% HD was ≥ 0.90 and ≤ 2.0 mm). Mean OAR satisfaction score was 4.1 for CNS, 4.4 for H&N, and 4.6 for prostate structures. Overall CTV satisfaction score (n = 25), which encompassed the prostate, seminal vesicles, and neck lymph node volumes, was 4.1. CONCLUSIONS: Previously validated OAR DC models for CNS, H&N, and prostate RT planning required minimal subjective and objective edits and resulted in a positive user experience, although low survey compliance was a concern. CTV DC model evaluation was even more limited, but high user satisfaction suggests that they may have served as appropriate starting points for patient specific edits.

Delirious Mania: An Approach to Diagnosis and Treatment.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin.

BACKGROUND: SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-INa) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-INa. METHODS: Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question. RESULTS: The SGLT2 inhibitor empagliflozin reduced late-INa in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of H2O2-induced late-INa (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-INa activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia. CONCLUSIONS: Our results provide evidence that late-INa may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.

Impact of Clinical Decision Support on Azithromycin Prescribing in Primary Care Clinics.

BACKGROUND: Inappropriate use of antibiotics in the outpatient setting is a common problem, yet literature evaluating best practices for stewardship interventions in this setting is sparse. OBJECTIVE: To evaluate the impact of clinical decision support (CDS) order panels for azithromycin prescribing on the percentage of inappropriate azithromycin prescriptions in primary care clinics. DESIGN: Single-center, retrospective analysis of azithromycin prescribing within nine primary care clinics. Pre-intervention and post-intervention data included azithromycin prescriptions from November 2016 to April 2017 and February 2019 to July 2019, respectively. Key exclusion criteria included prescriptions for the treatment of a sexually transmitted infection or for prophylaxis against Mycobacterium avium complex. INTERVENTION: The azithromycin CDS panel was created to provide point-of-care information on appropriate use of azithromycin along with recommended alternatives based on indications. CDS panels were implemented on January 10, 2019. MAIN MEASURES: The primary composite outcome was the change in the percentage of inappropriate azithromycin prescribing before and after implementation of CDS panels. The composite outcome included prescriptions with inappropriate indications for azithromycin, unnecessary prescriptions, inappropriate treatment durations, and/or inappropriate dose. KEY RESULTS: There were 306 and 263 prescriptions for azithromycin prescriptions included for analysis in the pre- and post-intervention periods, respectively. Inappropriate prescriptions decreased by 12.6% from the pre- to post-intervention period (81.4% vs. 68.8%; P < 0.001). In both the pre- and post-intervention period, bronchitis and unspecified upper respiratory tract infections (URI) were the two most common indications where azithromycin was prescribed inappropriately. CONCLUSIONS: Implementation of CDS order panels resulted in a reduction in inappropriate azithromycin prescribing. However, additional improvement in azithromycin prescribing is needed especially for the indications of bronchitis and unspecified URI.

Novel method of calculating adjusted antibiotic use by microbiological burden.

OBJECTIVE: To determine the usefulness of adjusting antibiotic use (AU) by prevalence of bacterial isolates as an alternative method for risk adjustment beyond hospital characteristics. DESIGN: Retrospective, observational, cross-sectional study. SETTING: Hospitals in the southeastern United States. METHODS: AU in days of therapy per 1,000 patient days and microbiologic data from 2015 and 2016 were collected from 26 hospitals. The prevalences of Pseudomonas aeruginosa, extended-spectrum ß-lactamase (ESBL)-producing bacteria, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE) were calculated and compared to the average prevalence of all hospitals in the network. This proportion was used to calculate the adjusted AU (a-AU) for various categories of antimicrobials. For example, a-AU of antipseudomonal ß-lactams (APBL) was the AU of APBL divided by (prevalence of P. aeruginosa at that hospital divided by the average prevalence of P. aeruginosa). Hospitals were categorized by bed size and ranked by AU and a-AU, and the rankings were compared. RESULTS: Most hospitals in 2015 and 2016, respectively, moved ≥2 positions in the ranking using a-AU of APBL (15 of 24, 63%; 22 of 26, 85%), carbapenems (14 of 23, 61%; 22 of 25; 88%), anti-MRSA agents (13 of 23, 57%; 18 of 26, 69%), and anti-VRE agents (18 of 24, 75%; 15 of 26, 58%). Use of a-AU resulted in a shift in quartile of hospital ranking for 50% of APBL agents, 57% of carbapenems, 35% of anti-MRSA agents, and 75% of anti-VRE agents in 2015 and 50% of APBL agents, 28% of carbapenems, 50% of anti-MRSA agents, and 58% of anti-VRE agents in 2016. CONCLUSIONS: The a-AU considerably changes how hospitals compare among each other within a network. Adjusting AU by microbiological burden allows for a more balanced comparison among hospitals with variable baseline rates of resistant bacteria.

Effectiveness of an Automated Error Checking and Feedback System to Improve Text Message Reporting for Disease Surveillance in Viet Nam.

Purpose: Viet Nam currently relies on a manual paper-based system to track and monitor 28 major infectious diseases. This inefficient system takes 2 or more months to complete. Method: We designed and pilot tested the use of text messaging to report certain infectious disease symptoms in rural areas of northern Viet Nam. The project was divided into three 6-month phases carried out in two provinces. The current analysis focuses on the implementation of a two-way feedback system between Phases II and III, which aims at (1) evaluating whether this system improves efficiency by determining the number of correctly (vs. incorrectly) formatted text messages; (2) assessing this system's influence on accuracy by comparing text messages with their respective official paper-based documented forms; and (3) determining whether the amount of information required to report through text messages influences the efficiency and accuracy of the text messages. Results: Between Phases II and III, results revealed a significant improvement in correctly formatted texts in comparison to incorrectly formatted texts. As the number of fields required to report increased, the number of correctly formatted texts (efficiency) as well as the number of matched text messages (accuracy) decreased. Conclusion: Our research demonstrates that an automated error bidirectional feedback system can significantly improve both the efficiency and accuracy of a Short Message Service-based method for disease surveillance. Also, our data may suggest that two-way communication has better engaged health care staff to follow reporting protocols as well as to maintain accuracy from their clinic's own data.

Efficacy of Palliative Radiation Therapy (RT) for Chemotherapy Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Population-Based Retrospective Review.

PURPOSE: The study objective was to investigate the effectiveness of palliative radiation therapy (RT) for patients with diffuse large B-cell lymphoma (DLBCL) and to identify factors, such as chemotherapy relapsed/refractory (R/R) disease, that may influence RT outcomes. METHODS AND MATERIALS: Patients with DLBCL who received palliative RT from 2001 to 2015 in British Columbia were reviewed for patient characteristics, treatment details, and outcomes. Univariable and multivariable analyses for response and local progression were performed. RESULTS: Three-hundred and seventy courses of palliative RT in 217 patients were identified. Median equivalent dose in 2 Gy fractions was 19 Gy (range, 2-42 Gy). Clinical and/or radiologic response occurred in 230 (83%) of the 276 courses with response data available. Local control following palliative RT at 6 months was 66.7%. On univariable analysis, R/R disease was not associated with lower clinical response rates but had higher risk of progression (hazard ratio [HR], 0.5; P = .040). On multivariable analyses, patients with R/R disease who did not require concurrent steroids had greater response compared with those who received upfront palliative RT (odds ratio, 3.5; P = .011). Response to first-line chemotherapy and smaller lesion size were associated with improved local progression rates (HR, 0.2; P < .001 and HR, 0.5; P = .020, respectively). RT dose fractionation factors were not significant on any analyses. CONCLUSIONS: Palliative RT for DLBCL is effective for symptom improvement, including in the chemotherapy R/R setting. Not requiring concurrent steroids, response to first-line chemotherapy, and smaller lesion size predicted better RT outcomes. There was no association between dose fractionation and response rates or local control to suggest that higher RT doses are more effective for palliation.

Long term toxicity of intracranial germ cell tumor treatment in adolescents and young adults.

PURPOSE: The purpose of this study is to describe the long-term toxicities of intracranial germ cell tumor (IGCT) in the adolescent and young adult (AYA) population. METHODS: We report late toxicities of a multi-center cohort of AYA patients treated for IGCT between 1975 and 2015. Charts were retrospectively reviewed for hormone deficiency, ototoxicity, seizure disorder, visual deterioration, cerebrovascular events, second neoplasm, psychiatric illness, and neurocognitive impairment. Statistical analysis was performed for late toxicities to evaluate the influence of select factors. RESULTS: Our patient cohort included 112 patients with IGCTs; 84% of patients had a germinoma as opposed to a non-germinomatous germ cell tumor (NGGCT), median age at radiotherapy (RT) was 19 years, and median follow-up was 8.3 years. Of the 94 patients with germinoma, 32 (34%) received both chemotherapy and RT as part of their upfront treatment, while 62 (66%) received RT alone. All 18 patients with NGGCT received chemotherapy and RT. The most common late toxicity following IGCT treatments was physician-reported neurocognitive impairment, with a 10-year cumulative incidence (CI) of 38.5%. Ten-year CI of treatment-induced ototoxicity was 39.2% for patients who received cisplatin, compared to 3.6% for those who received carboplatin but no cisplatin (p < 0.005). Suprasellar/hypothalamic tumor location was associated with 10-year CI of treatment-induced hormone deficiency (36.1 vs 6.2%, p < 0.005). CONCLUSIONS: A significant proportion of AYAs treated for IGCTs experience late effects from treatment, including neurocognitive impairment, ototoxicity, and hormone deficiency. Suprasellar/hypothalamic tumor location and cisplatin were associated with a higher risk of treatment-induced hormone deficiency and ototoxicity, respectively.

A Novel, Easy-to-Use Staple Line Reinforcement for Surgical Staplers.

BACKGROUND: Staple line reinforcement (SLR) is a popular tool used by surgeons to increase staple line strength and improve peri-operative hemostasis. However, currently marketed buttress materials require special attention in attachment to the staple anvil and cartridge and may come loose during typical maneuvering of stapling procedures. We have evaluated a new SLR that has an attachment material that affixes buttress across the entire anvil and cartridge face to prevent slipping, twisting, sliding and/or bunching. METHODS: In benchtop and preclinical testing, the new buttress material (ECHELON ENDOPATH™ Staple Line Reinforcement) was compared to a commercially available SLR for physical characteristics, including strength, absorption, security on the anvil and cartridge during stapler manipulation, impact on the tissue healing response and tissue abrasion. The two SLR's were also compared to a staple line without buttress for hemostasis. RESULTS: The new SLR was 180% stronger initially and maintained a greater strength for up to 14 days of exposure to an in vitro solution (p≤0.001), even though it was lighter and exhibited a faster rate of degradation. The new buttress material maintained complete adherence to the anvil and cartridge throughout tissue manipulation, whereas the commercial product lost substantial coverage in 72% of samples. Both SLR's provided superior hemostasis to the non-buttress control, with minimal impact on tissue healing or abrasion. CONCLUSION: Because the new buttress material comes with attachment material affixed across the entire anvil and cartridge face of the stapler and maintains coverage during manipulations, it should be much easier to use. The physical characteristics of the new SLR were as good as or better than current product that requires the buttress to be applied to the cartridge and anvil. In addition, the new SLR is similar in hemostasis to standard products and superior to stapling without the use of buttress. Further research is needed to determine whether these preclinical benefits carry over into a clinical setting.

The impact of an automated antibiotic stewardship intervention for the management of Staphylococcus aureus bacteraemia utilizing the electronic health record.

BACKGROUND: Staphylococcus aureus bacteraemia (SAB) management bundles have been shown to improve performance measures and clinical outcomes. SAB bundles often require direct intervention by infectious diseases (ID) physicians or antibiotic stewardship programme (ASP) members or pharmacists. The purpose of this study was to evaluate an automated, real-time ASP intervention utilizing clinical decision support (CDS) in the electronic health record (EHR) for the management of SAB. METHODS: A retrospective, single-centre quasi-experimental study of hospitalized patients with known SAB was conducted. The intervention was the implementation of a hard-stop best practice advisory (BPA) alert that would prompt physicians to use an electronic order set, on identification of SAB, with management recommendations, including ID consultation. The primary outcome was overall adherence to six institutional ASP SAB bundle elements. Secondary outcomes included both clinical and process outcomes. RESULTS: A total of 227 patients were included, 111 in the pre-intervention and 116 in the post-intervention period. Completion of all six bundle elements improved by 27.2% in the post-intervention group (29.7% versus 56.9%, P < 0.001). BPA activation and order-set utilization occurred in 95.7% and 57.8% in the post-intervention group, respectively. Composite outcome of 30 day mortality or 90 day readmission with SAB complication decreased in the post-intervention group by 9.6% (24.3% versus 14.7%, P = 0.092). CONCLUSIONS: Optimization of CDS within the EHR, using real-time BPA alert and order set, demonstrated an immediate, sustainable intervention that improved adherence to institutional performance measures for SAB management without direct prospective audit with intervention and feedback.

Comparing deep learning-based auto-segmentation of organs at risk and clinical target volumes to expert inter-observer variability in radiotherapy planning.

BACKGROUND: Deep learning-based auto-segmented contours (DC) aim to alleviate labour intensive contouring of organs at risk (OAR) and clinical target volumes (CTV). Most previous DC validation studies have a limited number of expert observers for comparison and/or use a validation dataset related to the training dataset. We determine if DC models are comparable to Radiation Oncologist (RO) inter-observer variability on an independent dataset. METHODS: Expert contours (EC) were created by multiple ROs for central nervous system (CNS), head and neck (H&N), and prostate radiotherapy (RT) OARs and CTVs. DCs were generated using deep learning-based auto-segmentation software trained by a single RO on publicly available data. Contours were compared using Dice Similarity Coefficient (DSC) and 95% Hausdorff distance (HD). RESULTS: Sixty planning CT scans had 2-4 ECs, for a total of 60 CNS, 53 H&N, and 50 prostate RT contour sets. The mean DC and EC contouring times were 0.4 vs 7.7 min for CNS, 0.6 vs 26.6 min for H&N, and 0.4 vs 21.3 min for prostate RT contours. There were minimal differences in DSC and 95% HD involving DCs for OAR comparisons, but more noticeable differences for CTV comparisons. CONCLUSIONS: The accuracy of DCs trained by a single RO is comparable to expert inter-observer variability for the RT planning contours in this study. Use of deep learning-based auto-segmentation in clinical practice will likely lead to significant benefits to RT planning workflow and resources.

Preclinical quantification of air leaks in a physiologic lung model: effects of ventilation modality and staple design.

PURPOSE: Thoracic air leaks are a common complication following pulmonary resections. Limitations in clinical studies and preclinical models have hindered efforts to understand the pathophysiology of air leaks. With an emphasis on staple-line specific air leaks, we hypothesize that ventilation modality - intraoperative positive pressure vs postoperative negative pressure - and stapler design may play a role in air leaks. METHODS: Using a novel physiologic lung model, air leaks associated with graduated and uniform staple designs were evaluated under positive and negative pressure ventilation, simulating perioperative breathing in porcine lungs. Air leak incidence, air leak volume, and air leak rate were captured along with ventilation pressure and tidal volume. RESULTS: In all cases, negative pressure ventilation was associated with a higher occurrence of leaks when compared to positive pressure ventilation. Lungs leaked more air and at a faster rate under negative pressure ventilation compared to positive pressure ventilation. Graduated staple designs were associated with higher occurrence of leaks as well as larger leak rates when compared to uniform staples. Tissue thickness was not associated with differences in air leaks when tested with appropriate staple heights. CONCLUSION: Using a novel lung model to investigate the pathophysiology of air leaks, we have identified breathing modality and staple design as two important variables that may impact air leaks. This work will help guide device design and drive future studies in human tissue, and it may help inform clinical practice to ultimately improve patient outcomes.

Implementation and optimization of molecular rapid diagnostic tests for bloodstream infections.

PURPOSE: The implementation and optimization of molecular rapid diagnostic tests (mRDTs) as an antimicrobial stewardship intervention for patients with bloodstream infections (BSIs) are reviewed. SUMMARY: All U.S. acute care hospitals accredited by the Joint Commission are required to implement an antimicrobial stewardship program (ASP). Of the many interventions available to ASPs, mRDTs have demonstrated consistent, meaningful results on antimicrobial optimization and patient outcomes. Even among infectious diseases and antimicrobial stewardship-trained pharmacists, significant knowledge and familiarity gaps exist regarding available mRDTs and how best to implement and optimize them. Given the paucity of infectious diseases and/or antimicrobial stewardship-trained pharmacists, the mandates for establishing ASPs will require non-infectious diseases/antimicrobial stewardship-trained pharmacists to implement stewardship interventions, which may include mRDTs, within their institution. Optimization of mRDTs requires adequate diagnostic stewardship, specifically evaluating how mRDT implementation may decrease costs and assist in meeting antimicrobial stewardship regulatory requirements. Knowledge of how these technologies will augment existing microbiology and antimicrobial stewardship workflow is essential. Finally, selecting the right mRDT necessitates familiarity with the instrument's capabilities and with the institutional antibiogram. CONCLUSION: mRDTs have demonstrated the ability to be one of the most powerful antimicrobial stewardship interventions. Pharmacists required to implement an ASP in their institution should consider mRDTs as standard of care for patients with BSIs.

Ex Vivo Modeling of Perioperative Air Leaks in Porcine Lungs.

OBJECTIVE: A novel ex vivo model is described to advance the understanding of prolonged air leaks, one of the most common postoperative complications following thoracic resection procedures. METHODS: As an alternative to in vivo testing, an ex vivo model simulating the various physiologic environments experienced by an isolated lung during the perioperative period was designed and built. Isolated porcine lungs were perfused and ventilated during open chest and closed chest simulations, mimicking intra and postoperative ventilation conditions. To assess and validate system capabilities, nine porcine lungs were tested by creating a standardized injury to create an approximately 250 cc/min air leak. Air leak rates, physiologic ventilation, and perfusion parameters were continuously monitored, while gas transfer analysis was performed on selected lungs. Segmental ventilation was monitored using electrical impedance tomography. RESULTS: The evaluated lungs produced flow-volume and pressure-volume loops that approximated standard clinical representations under positive (mechanical) and negative (physiological) pressure ventilation modalities. Leak rate was averaged across the ventilation phases, and sharp increases in leak rate were observed between positive and negative pressure phases, suggesting that differences or changes in ventilation mechanics may strongly influence leak development. CONCLUSION: The successful design and validation of a novel ex vivo lung model was achieved. Model output paralleled clinical observations. Pressure modality may also play a significant role in air leak severity. SIGNIFICANCE: This work provides a foundation for future studies aimed at increasing the understanding of air leaks to better inform means of mitigating the risk of air leaks under clinically relevant conditions.