In vivo genotoxicity assessment of N-(-9 acridinyl)-b-alanine hydrochloride (S-300) using a validated Pig-a mutagenesis assay.

BACKGROUND: N-(-9 acridinyl)-b-alanine hydrochloride (S-300) is the main byproduct of red blood cell (RBC) amustaline/glutathione(GSH) pathogen reduction, currently undergoing phase III US clinical trials following successful European studies(1-3). Phosphatidylinositol glycan, class A (Pig-a) X-linked gene mutagenesis is a validated mammalian in vivo mutation assay for genotoxicity, assessed as clonal loss of glycosylphosphatidylinositol-linked CD59 cell-surface molecules on reticulocytes (RETs) and RBCs. METHODS: Male Sprague-Dawley rats received continuous infusion of S-300 up to the maximum feasible dose (240 mg/kg/day-limited by solubility and volume) for 28 days. Positive controls received a known mutagen by oral gavage on Days 1-3. Plasma levels of S-300 were assessed by HPLC before, during and after infusion. CD59-negative RBCs and RETs were enumerated in pre-dose and Day 28 samples, using a flow cytometric method. Outcome was evaluated by predetermined criteria using concurrent and historical controls. Toxicity was assessed by laboratory measures and necropsy. RESULTS: S-300 reached maximum, dose-dependent levels (3-15 µmol/L) within 2-8 h that were sustained for 672 h and undetectable 2 h after infusion. Circulating RET levels indicated a lack of hematopoietic toxicity. Necropsy revealed minimal-mild observations related to poor S-300 solubility at high concentrations. Pig-a assessment met the preset acceptability criteria and revealed no increase in mutant RBCs or RETs. CONCLUSIONS: Maximum feasible S-300 exposure of rats by continuous infusion for 28 days was not genotoxic as assessed by an Organization for Economic Cooperation and Development-compliant, mammalian, in vivo Pig-a gene mutation assay that meets the requirements of International Conference on Harmonization (ICH) S2(R1) and FDA guidances on genotoxicity testing.

The pharmacologic and toxicologic characterization of the potent and selective KRAS G12D inhibitors ERAS-4693 and ERAS-5024.

Two potent and selective KRASG12D inhibitors, ERAS-4693 and ERAS-5024, were generated as possible clinical candidates to treat patients harboring G12D mutations in solid tumors. Both molecules exhibited strong anti-tumor activity in the KRASG12D mutant PDAC xenograft mouse models while ERAS-5024 also showed tumor growth inhibition when administered on an intermittent dosing regimen. Acute dose-limiting toxicity consistent with an allergic reaction was observed for both molecules shortly after administration at doses just above those which demonstrated anti-tumor activity, indicative of a narrow therapeutic index. A series of studies were subsequently conducted to identify a common underlying mechanism for the observed toxicity, including CETSA® (Cellular Thermal Shift Assay) as well as several functional off-target screens. Both ERAS-4693 and ERAS-5024 were identified to agonize MRGPRX2 which has been linked to pseudo-allergic reactions. In vivo toxicologic characterization of both molecules included repeat-dose studies in the rat and dog. Dose-limiting toxicities were observed in both species with ERAS-4693 and ERAS-5024 and plasma exposure levels at the maximum tolerated doses were generally below that which caused strong anti-tumor activity, supporting the initial observation of a narrow therapeutic index. Additional overlapping toxicities included a reduction in reticulocytes and clinical pathological changes suggestive of an inflammatory response. Furthermore, increases in plasma histamine were observed in dogs administered ERAS-5024, supporting the hypothesis that MRGPRX2 agonism may be the cause of the pseudo-allergic reaction. This work highlights the importance of balancing both the safety and efficacy of KRASG12D inhibitors as this class of molecules begins to enter clinical development.

Development of a pilot interprofessional education workshop for healthcare students and assessment of interprofessional collaborative competency attainment.

We describe the development and student evaluation of a collaborative health service provider and higher education institution initiative designed to deliver an Interprofessional Education (IPE) pilot workshop program for healthcare students. The aim was to investigate whether an IPE workshop would result in improved student confidence in self-reported interprofessional competencies using the Interprofessional Collaborative Competency Attainment Scale (ICCAS) tool. The workshops involved interprofessional student groups working on a patient case followed by a facilitator-led discussion and patient representative interaction. There were three different voluntary, extra-curricular workshops. A total of 99 students registered, from 3rd to 5th year undergraduate and 2nd year graduate entry healthcare programs at a single Irish university in February 2022. Ninety-three post-workshop survey responses showed statistically significant improvements in the ICCAS subscales of Communication, Collaboration, Roles and Responsibilities, Collaborative Patient/Family-Centered Approach, and Team Functioning; Conflict Management showed less change. Students reported positively on the benefit of the patient representative, the workshop format, and the opportunity to collaborate with students from other professions. Our findings indicate that this was a beneficial and effective way to deliver IPE across a range of healthcare professions that led to improvements in self-reported interprofessional competencies.

Pleural Effusions Following Liver Transplantation: A Single-Center Experience.

INTRODUCTION: This was a single-center retrospective study to evaluate incidence, prognosis, and risk factors in patients with postoperative pleural effusions, a common pulmonary complication following liver transplantation. METHODS: A retrospective review was performed on 374 liver transplantation cases through a database within the timeframe of January 1, 2009 through December 31, 2015. Demographics, pulmonary and cardiac function testing, laboratory studies, intraoperative transfusion/infusion volumes, postoperative management, and outcomes were analyzed. RESULTS: In the immediate postoperative period, 189 (50.5%) developed pleural effusions following liver transplantation of which 145 (76.7%) resolved within 3 months. Those who developed pleural effusions demonstrated a lower fibrinogen (149.6 ± 66.3 mg/dL vs 178.4 ± 87.3 mg/dL; P = .009), total protein (5.8 ± 1.0 mg/dL vs 6.1 ± 1.2 mg/dL; P = .04), and hemoglobin (9.8 ± 1.8 mg/dL vs 10.3 ± 1.9 mg/dL; P = .004). There was not a statistically significant difference in 1-year all-cause mortality and in-hospital mortality between liver transplant recipients with and without pleural effusions. Liver transplant recipients who developed pleural effusions had a longer hospital length of stay (16.4 ± 10.9 days vs 14.0 ± 16.5 days; P = .1), but the differences were not statistically significant. However, there was a significant difference in tracheostomy rates (11.6% vs 5.4%; P = .03) in recipients who developed pleural effusions compared to recipients who did not. CONCLUSIONS: In summary, pleural effusions are common after liver transplantation and are associated with increased morbidity. Pre- and intraoperative risk factors can offer both predictive and prognostic value for post-transplantation pleural effusions. Further prospective studies will be needed to further evaluate the relevance of these findings to limit instances of postoperative pleural effusions.

Candida auris outbreak involving liver transplant recipients in a surgical intensive care unit.

Candida auris is a yeast that is difficult to eradicate and has caused outbreaks in health care facilities. We report a cluster of 5 patients in 1 intensive care unit who were colonized or infected in 2017. The initial 2 patients were recipients of liver transplants who had cultures that grew C auris within 3 days of each other in June 2017 (days 43 and 30 posttransplant). Subsequent screening cultures identified 2 additional patients with C auris colonization. Respiratory and urine cultures from a fifth patient yielded C auris. All isolates were fluconazole resistant but susceptible to echinocandins. Whole genome sequencing showed the strains were clonal, suggesting in-hospital transmission, and related but distinct from New York/New Jersey strains, consistent with a separate introduction. However, no source or contact was found. Two of the 5 patients died. C auris infection likely contributed to 1 patient death by infecting a vascular aneurysm at the graft anastomosis. Strict infection control precautions were initiated to control the outbreak. Our experience reveals that although severe disease from C auris can occur in transplant recipients, outbreaks can be controlled using recommended infection control practices. We have had no further patients infected with C auris to date.

Management of infections due to nontuberculous mycobacteria in solid organ transplant recipients-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the epidemiology, diagnosis, prevention, and management of nontuberculous mycobacterial infections in the pre- and post-transplant period. NTM commonly cause one of five different clinical syndromes: pleuropulmonary disease, skin and soft tissue infection, osteoarticular infection, disseminated disease, including that caused by catheter-associated infection, and lymphadenitis. Diagnosis of these infections can be challenging, particularly when they are isolated from nonsterile spaces, owing to their ubiquity in nature. Consequently, diagnosis of pulmonary infections with these pathogens requires fulfillment of microbiologic, radiographic, and clinical criteria to address this concern. A combination of culture and molecular diagnostic techniques is often required to make a species-level identification. Treatment varies depending on the species isolated and is complex, owing to drug toxicities, need for long-term multidrug regimens, and consideration of complex drug-drug interactions between antimicrobials and immunosuppressive agents. Given these treatment challenges, efforts should be made in both the hospital and community settings to limit exposure to these pathogens to the extent feasible.

Intensive Care of Pulmonary Complications Following Liver Transplantation.

Chronic liver disease has been associated with pulmonary dysfunction both before and after liver transplantation. Post-liver transplantation pulmonary complications can affect both morbidity and mortality often necessitating intensive care during the immediate postoperative period. The major pulmonary complications include pneumonia, pleural effusions, pulmonary edema, and atelectasis. Poor clinical outcomes have been known to be associated with age, severity of liver dysfunction, and preexisting lung disease as well as perioperative events related to fluid balance, particularly transfusion and fluid volumes. Delineating each and every one of these pulmonary complications and their associated risk factors becomes paramount in guiding specific therapeutic strategies.

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840.

Mycobacterium haemophilum infection in a renal transplant patient with inflammatory bowel disease.

A 61-year-old immunosuppressed renal transplant patient with inflammatory bowel disease presented with tender pink nodules on the trunk and extremities. An initial biopsy was suggestive of metastatic Crohn disease, but after disease persistence, a second biopsy revealed disseminated Mycobacterium haemophilum. Atypical mycobacterial infections should be considered in immunosuppressed patients. This case highlights the complexities of diagnosing such infections in patients with an underlying granulomatous condition and the particular growth requirements of M. haemophilum.

Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility.

Formulation of nonclinical evaluations is a challenge, with the fundamental need to achieve multiples of the clinical exposure complicated by differences in species and routes of administration-specific tolerances, depending on concentrations, volumes, dosing regimen, duration of each administration, and study duration. Current practice to approach these differences is based on individual experience and scattered literature with no comprehensive data source (the most notable exception being our 2006 publication on this same subject). Lack of formulation tolerance data results in excessive animal use, unplanned delays in the evaluation and development of drugs, and vehicle-dependent results. A consulting firm, a chemical company, and 4 contract research organizations conducted a rigorous data mining operation of vehicle data from studies dating from 1991 to 2015, enhancing the data from this author's 2006 publication (3 of the six 2015 contributors were also 2006 contributors). Additional data were found in the published literature. The results identified 108 single-component vehicles (and 305 combination formulations) used in more than 1,040 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, pig, chick embryo, and cat) by multiple routes for a wide range of study durations. The tabulated data include maximum tolerated use levels by species, route, duration of study, dose-limiting toxicity where reported, review of the available literature on each vehicle, guidance on syringe selection, volume and pH limits by route with basic guidance on nonclinical formulation development, and guidance on factors to be considered in nonclinical route selection.

Phomopsis bougainvilleicola prepatellar bursitis in a renal transplant recipient.

Prepatellar bursitis is typically a monomicrobial bacterial infection. A fungal cause is rarely identified. We describe a 61-year-old man who had received a renal transplant 21 months prior to presentation whose synovial fluid and surgical specimens grew Phomopsis bougainvilleicola, a pycnidial coelomycete.

High-flow nasal cannula improves hypoxemia in dogs failing conventional oxygen therapy.

OBJECTIVE: A prospective clinical trial was performed to evaluate the efficacy and tolerance of high-flow nasal cannula (HFNC) in dogs with hypoxemia. ANIMALS: 20 client-owned dogs failing conventional oxygen therapy (COT). PROCEDURES: Patients admitted to the ICU for treatment of hypoxemic respiratory failure were enrolled in the study. PaO2, SPO2, respiratory rate (RR), and acute patient physiologic and laboratory evaluation scores were obtained at the time of COT failure and after initiation of HFNC. Complications and patient tolerance while receiving HFNC were also recorded. RESULTS: Compared to COT, the median PaO2 and SO2 were significantly higher when dogs were receiving HFNC (60.8 vs 135.6 mm Hg and 90.7% vs 99.25%, respectively). Dogs receiving HFNC had a significant reduction in median RR as compared to dogs undergoing COT (52 vs 36 breaths per minute). After the initiation of HFNC, all dogs showed clinical improvement as measured by PaO2, SO2, and RR. Of 20 dogs, 6 ultimately failed HFNC and mechanical ventilation was recommended. Nine dogs undergoing HFNC survived to discharge, and acute patient physiologic and laboratory evaluation scores had a significant positive severity correlation with death. Complications included pneumothorax in 1 dog. CLINICAL RELEVANCE: COT has limited flow rates due to airway irritation caused by room temperature, nonhumidified oxygen. HFNC uses vapor humidification and heated oxygen, allowing for higher flow rates. In people, HFNC is used as escalation of oxygen therapy when COT fails. Dogs treated with HFNC had significant improvements in PaO2, SO2, and RR as compared to COT. HFNC is well tolerated and effective in treating hypoxemia in dogs.

How does moving public engagement with research online change audience diversity? Comparing inclusion indicators for 2019 & 2020 European Researchers' night events.

Taking place annually in more than 400 cities, European Researchers' Night is a pan- European synchronized event that aims to bring researchers closer to the public. In this paper audience profiles are compared from events in 2019 and 2020. In 2019, face-to-face events reached an estimated 1.6 million attendees, while in 2020, events shifted online due to the COVID-19 pandemic and reached an estimated 2.3 million attendees. Focusing on social inclusion metrics, survey data is analyzed across two national contexts (Ireland and Malta) in 2019 (n = 656) and 2020 (n = 506). The results from this exploratory, descriptive study shed light on how moving public engagement with research online shifted audience profiles. Based on prior research about the digital divide in access and use of online media, hypotheses were proposed that online European Researchers' Night events would attract audiences with higher educational attainment levels and greater self-reported, subjective economic well-being. While changes were observed from 2019 to 2020, results for each hypothesis show a mixed picture. The first hypothesis was upheld for the highest education levels but failed for the lowest levels suggesting that the pivot to online events simultaneously attracted participants with no formal education and those with postgraduate qualifications, while attracting less of those with undergraduate or lower levels of education. The second hypothesis was not upheld, with online European Researchers' Night events attracting audiences with slightly higher levels of economic well-being compared to face-to-face events. The findings of this study indicate that European Researchers' Night events present a clear opportunity to measure the effects of the digital divide in relation to public engagement with research across Europe.

Modernization of a Large Spinal Cord Injuries and Disorders Registry: The Veterans Administration Experience.

Since the 1990s, Veterans Health Administration (VHA) has maintained a registry of Veterans with Spinal Cord Injuries and Disorders (SCI/Ds) to guide clinical care, policy, and research. Historically, methods for collecting and recording data for the VHA SCI/D Registry (VSR) have required significant time, cost, and staffing to maintain, were susceptible to missing data, and caused delays in aggregation and reporting. Each subsequent data collection method was aimed at improving these issues over the last several decades. This paper describes the development and validation of a case-finding and data-capture algorithm that uses primary clinical data, including diagnoses and utilization across 9 million VHA electronic medical records, to create a comprehensive registry of living and deceased Veterans seen for SCI/D services since 2012. A multi-step process was used to develop and validate a computer algorithm to create a comprehensive registry of Veterans with SCI/D whose records are maintained in the enterprise wide VHA Corporate Data Warehouse. Chart reviews and validity checks were used to validate the accuracy of cases that were identified using the new algorithm. An initial cohort of 28,202 living and deceased Veterans with SCI/D who were enrolled in VHA care from 10/1/2012 through 9/30/2017 was validated. Tables, reports, and charts using VSR data were developed to provide operational tools to study, predict, and improve targeted management and care for Veterans with SCI/Ds. The modernized VSR includes data on diagnoses, qualifying fiscal year, recent utilization, demographics, injury, and impairment for 38,022 Veterans as of 11/2/2022. This establishes the VSR as one of the largest ongoing longitudinal SCI/D datasets in North America and provides operational reports for VHA population health management and evidence-based rehabilitation. The VSR also comprises one of the only registries for individuals with non-traumatic SCI/Ds and holds potential to advance research and treatment for multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other motor neuron disorders with spinal cord involvement. Selected trends in VSR data indicate possible differences in the future lifelong care needs of Veterans with SCI/Ds. Future collaborative research using the VSR offers opportunities to contribute to knowledge and improve health care for people living with SCI/Ds.

Lifestyle Interventions to Improve Glycemic Control in Adults with Type 2 Diabetes Living in Low-and-Middle Income Countries: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs).

Alongside glucose lowering therapy, clinical guidelines recommend lifestyle interventions as cornerstone in the care of people living with type 2 diabetes (T2DM). There is a specific need for an up-to-date review assessing the effectiveness of lifestyle interventions for people with T2DM living in low-and-middle income countries (MICs). Four electronic databases were searched for RCTs published between 1990 and 2020. T2DM, lifestyle interventions, LMICs and their synonyms were used as search terms. Data codebooks were developed and data were extracted. Narrative synthesis and meta-analysis were conducted using random effects models to calculate mean differences (MD) and standardized mean differences (SMD) and 95% confidence intervals (CI). Of 1284 articles identified, 30 RCTs (n = 16,670 participants) met the inclusion criteria. Pooled analysis revealed significant improvement in HBA1c (MD -0.63; CI: -0.86, -0.40), FBG (SMD -0.35; CI: -0.54, -0.16) and BMI (MD -0.5; CI: -0.8, -0.2). In terms of intervention characteristics, those that included promoted self-management using multiple education components (e.g., diet, physical activity, medication adherence, smoking cessation) and were delivered by healthcare professionals in a hospital/clinic setting were deemed most effective. However, when interpreting these results, it is important to consider that most included studies were evaluated as being of low quality and there was a significant amount of intervention characteristics heterogeneity. There is a need for further well-designed studies to inform the evidence base on which lifestyle interventions are most effective for glycemic control in adults with T2DM living in LMICs.

Treatment of Acute Graft-versus-Host Disease in Liver Transplant Recipients.

Acute graft-versus-host disease (aGvHD) is a rare complication of liver transplantation associated with high morbidity and mortality. Death typically occurs due to complications related to severe infection, shock, and multiorgan failure. The clinical presentation involves dysfunction of multiple organ systems with overlapping symptoms that often results in a diagnostic delay. As there are a limited number of cases reported in the literature, there are no clear guidelines for treatment. Many different therapeutic measures have been utilized that target various immune system pathways, but steroids remain the first line of therapy. We report on two patients who developed aGvHD after liver transplantation who were treated with ruxolitinib, a novel Janus kinase 1/2 (JAK) inhibitor that has been shown to improve outcomes in steroid refractory cases of aGvHD after allogenic hematopoietic stem cell transplantation. We reviewed the literature to discuss various therapeutic options currently available for aGvHD after liver transplantation.

A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central massachusetts.

Completion rates, total cost, and adverse effects were compared for patients in central Massachusetts treated for latent tuberculosis infection with 9 months of isoniazid or 4 months of rifampin. Although the adverse effects were similar between the 2 groups, 4 months of rifampin was associated with significantly better completion rates and less hepatotoxicity yet higher total cost.

Co-designed PICU Family Stress Screening and Response System to Improve Experience, Quality, and Safety.

OBJECTIVE: Evidence for successful and sustainable models that systematically identify and address family stress in the pediatric intensive care unit (PICU) remains scarce. Using an integrated improvement science and family engagement framework, we implemented a standardized family stress screening tool and response protocol to improve family experience and reduce family crises through the timely coordination of parent support interventions. METHODS: We conducted this improvement initiative in the 12-bed PICU of a children's hospital within a large, urban academic medical center. Our team, which included 2 family advisors, adapted a validated Distress Thermometer for use in pediatric intensive care. A co-designed family stress screening tool and response protocol were iteratively tested, refined, and implemented in 2015-2017. Process and outcome measures included screening and response reliability, parent satisfaction, and security calls for distressed families. RESULTS: Over the 18 months, the percentage of families screened for stress increased from 0% to 100%. Among families who rated stress levels ≥5, 100% received the recommended response protocol, including family support referrals made and completed within 24 hours of an elevated stress rating. From 2015 to 2017, PICU parent satisfaction scores regarding emotional support increased from a mean score of 81.7-87.0 (P < 0.01; 95% CI). The number of security calls for distressed families decreased by 50%. CONCLUSIONS: The successful implementation of a co-designed family stress screening tool and response protocol led to the timely coordination of parent support interventions, the improved family perception of emotional support, and reduced family crises in the PICU.