Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis.

Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of CRAC channels has been proposed as a potential treatment and currently, a novel selective CRAC channel inhibitor CM4620 (AuxoraTM, CalciMedica), is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 nM, have been studied against necrosis induced by either bile acids, palmitoleic acid or L-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 nM, and palmitoleic acid starting from 1 nM. Combining CM4620 and galactose (1 mM) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acids-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced oedema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 mM) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.

Mechanistic study of the stabilization of dentin-bonded restorative interfaces via collagen reinforcement by multi-acrylamides.

Hydrolytically and enzymatically-stable multi-acrylamides have been proposed to increase the long-term durability of dental adhesive interfaces as alternatives to methacrylates. The aim of this study was to investigate the mechanical and biochemical properties of experimental adhesives containing multi-functional acrylamides concerning collagen reinforcement and metalloproteinases (MMP) activity. Multi-functional acrylamides, TMAAEA (Tris[(2-methylaminoacryl) ethylamine) and DEBAAP (N,N-Diethyl-1,3-bis(acrylamido) propane), along with the commercially available DMAM (N,N-dimethylacrylamide) (monofunctional acrylamide) and HEMA (2-Hydroxyethyl methacrylate) (monofunctional methacrylate - control) were tested for stability against enzymatic hydrolysis by cholesterol esterase/pseudocholinesterase (PC/PCE) solutions for up to 30 days. Collagen-derived substrate and gelatin zymography were performed to examine the effect of the compounds on the biological activity of human recombinant and dentin-extracted gelatinases MMP-2 and MMP-9. In situ zymography was carried out by fluorescent collagen degradation combined with confocal microscopy analysis. Hydroxyproline content was measured in collagen derived from dentin extracts though reaction with Ehrlich's reagent p-dimethylaminobenzaldehyde (DMAB), generating a stable chromophore measured at 550 nm. Storage shear modulus of demineralized dentin discs treated with the tested compounds was measured by oscillatory rheometry, in order to investigate potential collagen reinforcement. FT-IR was performed to determine qualitative differences in collagen based on observed changes in amide bands. The results were analyzed by ANOVA/Tukey's test (α = 0.05). Multi-acrylamides survived 30 days of incubation in cholinesterase/pseudo-cholinesterase (PC/PCE) solutions, while HEMA showed approximately 70 % overall degradation. Incubation with multi-acrylamides reduced collagen degradation as evidenced by the reduced hydroxyproline levels and by the 30 % increase inshear storage modulus. Biochemical and zymography assays showed no noticeable inhibition of recombinant and extracted MMPs enzymatic activity. The infra-red spectroscopy results for multi-functional acrylamides treated samples demonstrated shifts of the amide II bonds and marked increase in intensity of the bands 1200 cm-1, which may indicate partial collagen denaturation and some degree of cross-linking of the compounds with collagen, respectively. The multi-acrylamides exhibited not only comparable mechanical properties but also demonstrated significantly enhanced biochemical stability when compared to the widely used methacrylate control. Clinical relevance: These findings highlight the potential of multi-acrylamides to increase the bonding stability to tissues and, ultimately, contribute to the longevity of dental restorations.

The American Society of Addiction Medicine Clinical Practice Guideline Development Methodology.

ABSTRACT: The American Society of Addiction Medicine (ASAM) has published clinical practice guidelines (CPGs) since 2015. As ASAM's CPG work continues to develop, it maintains an organizational priority to establish rigorous standards for the trustworthy production of these important documents. In keeping with ASAM's mission to define and promote evidence-based best practices in addiction prevention, treatment, and recovery, ASAM has rigorously updated its CPG methodology to be in line with evolving international standards. The CPG Methodology and Oversight Subcommittee was formed to establish and publish a methodology for the development of ASAM CPGs and to develop an ASAM CPG strategic plan. This article provides a focused overview of the ASAM CPG methodology.

Estimating the size and scope of the academic emergency physician workforce.

BACKGROUND: Academic emergency medicine (EM) is foundational to the EM specialty through the development of new knowledge and clinical training of resident physicians. Despite recent increased attention to the future of the EM workforce, no evaluations have specifically characterized the U.S. academic EM workforce. We sought to estimate the national proportion of emergency physicians (EPs) identified as academic and the proportion of emergency department (ED) visits that take place at academic sites. METHODS: We performed a cross-sectional analysis of EPs and EDs using data from the American Hospital Association, the Centers for Medicare & Medicaid Services, and Doximity's Residency Navigator. EPs were identified as "academic" if they were affiliated with at least one facility determined to be academic, defined as EDs officially designated by the Accreditation Council for Graduate Medical Education (ACGME) as clinical training sites at accredited EM residency programs. Our primary outcomes were to estimate the national proportion of EPs identified as academic and the proportion of ED visits performed at academic sites. RESULTS: Our analytic sample included 26,937 EPs practicing clinically across 4920 EDs and providing care during 130,471,386 ED visits. Among EPs, 11,720 (43.5%) were identified as academic, and among EDs, 635 (12.9%) were identified as academic sites, including 585 adult/general sites, 45 pediatric-specific sites, and 10 sites affiliated with the Department of Veterans Affairs. In 2021, academic EDs provided care for 42,794,106 ED visits or 32.8% of all ED visits nationally. CONCLUSIONS: Approximately four in 10 EPs practice in at least one clinical training site affiliated with an ACGME-accredited EM residency program, and approximately one in three ED visits nationally occur in these academic EDs. We encourage further work using alternative definitions of an academic EPs and EDs, along with longitudinal research to identify trends in the workforce's composition.

Is prone positioning a valid intervention for ARDS in the deployed intensive care unit?

Prone positioning is an intervention used for patients with acute respiratory distress syndrome (ARDS) whose hypoxia is worsening despite conventional treatment. Previously used infrequently, it became an important treatment escalation strategy for hypoxia during the COVID-19 pandemic. Current evidence for prone positioning suggests increased survivability in intubated patients with moderate to severe ARDS who are prone for >12 hours a day. As a relatively low-cost, low-tech intervention with a growing evidence base, the viability of prone positioning in the deployed land environment is considered in this article. The practical technique of prone positioning is easy to teach to healthcare staff experienced in manual handling. However, it requires significant resources, in particular staff numbers, and time to execute and maintain, and necessitates a pressure-minimising mattress. Additionally, staff are placed at increased risk of musculoskeletal injuries and potential exposure to aerosolised microbes if there is a disconnection of the breathing system. We conclude that in the deployed 2/1/2/12 facility (or larger), with access to higher staff numbers and high-specification mattresses, prone positioning is a valid escalation technique for intubated hypoxic patients with ARDS. However, in smaller facilities where resources are constrained, its implementation is unlikely to be achievable.

Medical Costs Associated with High/Moderate/Low Likelihood of Adult Growth Hormone Deficiency: A Healthcare Claims Database Analysis.

Purpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level. Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on algorithmically determined likelihoods of AGHD. Likelihood groups were further stratified by age and sex. Trajectories of annual costs (USD) by likelihood level were also investigated. Results: The study cohort comprised 135 million US adults (aged ≥18 years). Individuals ranked as high-likelihood AGHD had a greater burden of comorbid illness, including cardiovascular disease and diabetes, than those ranked moderate- or low-likelihood. Those in the high-likelihood group had greater mean total direct medical monthly costs ($1844.51 [95% confidence interval (CI): 1841.24;1847.78]) than those in the moderate- ($945.65 [95% CI: 945.26;946.04]) and low-likelihood groups ($459.10 [95% CI: 458.95;459.25]). Outpatient visits accounted for the majority of costs overall, although cost per visit was substantially lower than for inpatient services. Costs tended to increase with age and peaked around the time that individuals were assigned a level of AGHD likelihood. Total direct medical costs in individuals with a high likelihood of AGHD exceeded those for individuals with moderate or low likelihood. Conclusion: Understanding the trajectory of healthcare costs in AGHD may help rationalize allocation of healthcare resources.

Growth hormone is an important substance found in the body. Adult growth hormone deficiency (AGHD) is the reduced production of growth hormone unrelated to the normal reduction seen with aging. Untreated AGHD can result in the development of other conditions, known as comorbidities, which can be expensive to manage. Previously, 135 million privately insured people in the US, aged 18­64 years, were categorized into groups by their likelihood (high, medium, or low) of having AGHD. This study compared the estimated direct medical costs (eg hospital care and medication) across the different likelihood levels. People with a high likelihood of AGHD had more comorbidities than people with a medium/low likelihood, and an average total direct medical monthly cost of $1844.51, nearly twice as much as those with a medium likelihood ($945.65), and four times as much as those with a low likelihood ($459.10). These costs tended to increase with age, with the highest costs associated with people aged 50­59 years and 60­64 years. Outpatient costs (for treatments not requiring an overnight hospital stay) accounted for the greatest proportion of total medical costs, ahead of inpatient costs (for treatments requiring an overnight hospital stay) and medication costs. These findings suggest that diagnosing and treating AGHD earlier may help to reduce medical costs over time. Increased testing and treatment will cause an initial increase in the use of healthcare resources, but could improve overall cost effectiveness by reducing the long-term impact of the disease and avoiding unnecessary healthcare use.

Concept analysis of 'Facilitating a transformative radiation protection environment'.

INTRODUCTION: Suboptimal radiation protection evidenced in literature necessitated the development of a theory to optimise radiation protection. To develop a theory, concept analysis of the central concept guiding the theory is required to provide explicit theoretical and operational definitions. This article presents the concept analysis of the central concept of 'facilitating a transformative radiation protection environment' used to develop a theory to optimise radiation protection. METHODS: The study used Walker and Avant's concept analysis process of selecting a concept, determining the aims and purpose of analysis, identifying all uses of the concept, and determining the defining attributes by identifying a model case, a borderline case and a contrary case. RESULTS: The central concept was dissected into the individual concepts of facilitating, transformative, radiation, protection, and environment to enhance the definition and conceptual meaning of the central concept. The essential and related attributes of the individual concepts informed the summative definition of the central concept, and a model, borderline and contrary case contributed to the conceptual meaning. CONCLUSION: The summative definition of the central concept of "facilitating a transformative radiation protection environment" was determined to be through the essential attributes of help, process, change, X-rays, keeping safe considering the benefits versus risks of ionising radiation exposure and the total internal, external context within which persons exist and the related attributes. IMPLICATIONS FOR PRACTICE: Explored extensively in nursing literature, concept analyses in radiography are limited. Therefore, this article articulates the process of concept analysis and its use in radiography. Concept analysis provides a systematic process to analyse concepts often assumed to be understood, highlighting its importance in radiography literature and to educational praxis.

National Institute on Drug Abuse Clinical Trials Network Meeting Report: Managing Patients Exposed to Xylazine-Adulterated Opioids in Emergency, Hospital and Addiction Care Settings.

Used as a veterinary sedative and not approved for human use, xylazine has been increasingly linked with opioid overdose deaths in the United States. A growing number of people have been exposed to xylazine in the illicit opioid supply (especially fentanyl) or in other drugs, particularly in some areas of the Northeast. Xylazine is an α-2 adrenergic agonist that decreases sympathetic nervous system activity. When combined with fentanyl or heroin, it is purported to extend the duration of the opioid's sedative effect and to cause dependence and an associated withdrawal syndrome; however, data to support these concerns are limited. Despite the escalating frequency of detection of xylazine in people with nonfatal and fatal opioid overdose, direct links to these outcomes have not been identified. Because the strongest causal link is to fentanyl coexposure, ventilatory support and naloxone remain the cornerstones of overdose management. Xylazine is also associated with severe tissue injury, including skin ulcers and tissue loss, but little is known about the underlying mechanisms. Nonetheless, strategies for prevention and treatment are emerging. The significance and clinical effects of xylazine as an adulterant is focused on 4 domains that merit further evaluation: fentanyl-xylazine overdose, xylazine dependence and withdrawal, xylazine-associated dermal manifestations, and xylazine surveillance and detection in clinical and nonclinical settings. This report reflects the Proceedings of the National Institute on Drug Abuse Center for the Clinical Trials Network convening of clinical and scientific experts, federal staff, and other stakeholders to describe emerging best practices for treating people exposed to xylazine-adulterated opioids. Participants identified scientific gaps and opportunities for research to inform clinical practice in emergency departments, hospitals, and addiction medicine settings.

Time to blood pressure control and predictors among patients receiving integrated treatment for hypertension and HIV based on an adapted WHO HEARTS implementation strategy at a large urban HIV clinic in Uganda.

In this cohort study, we determined time to blood pressure (BP) control and its predictors among hypertensive PLHIV enrolled in integrated hypertension-HIV care based on the World Health Organization (WHO) HEARTS strategy at Mulago Immunosuppression Clinic in Uganda. From August 2019 to March 2020, we enrolled hypertensive PLHIV aged ≥ 18 years and initiated Amlodipine 5 mg mono-therapy for BP (140-159)/(90-99) mmHg or Amlodipine 5 mg/Valsartan 80 mg duo-therapy for BP ≥ 160/90 mmHg. Patients were followed with a treatment escalation plan until BP control, defined as BP < 140/90 mmHg. We used Cox proportional hazards models to identify predictors of time to BP control. Of 877 PLHIV enrolled (mean age 50.4 years, 62.1% female), 30% received mono-therapy and 70% received duo-therapy. In the monotherapy group, 66%, 88% and 96% attained BP control in the first, second and third months, respectively. For patients on duo-therapy, 56%, 83%, 88% and 90% achieved BP control in the first, second, third, and fourth months, respectively. In adjusted Cox proportional hazard analysis, higher systolic BP (aHR 0.995, 95% CI 0.989-0.999) and baseline ART tenofovir/lamivudine/efavirenz (aHR 0.764, 95% CI 0.637-0.917) were associated with longer time to BP control, while being on ART for >10 years was associated with a shorter time to BP control (aHR 1.456, 95% CI 1.126-1.883). The WHO HEARTS strategy was effective at achieving timely BP control among PLHIV. Additionally, monotherapy anti-hypertensive treatment for stage I hypertension is a viable option to achieve BP control and limit pill burden in resource limited HIV care settings.

Opioid and Benzodiazepine Co-Prescribing Trends from the Emergency Department from 2012 to 2019: A National Analysis.

BACKGROUND: In 2016, the U.S. Food and Drug Administration (FDA) issued its strongest safety warning ("Black Box Warning") for concomitant use of prescription opioids and benzodiazepines due to overdose deaths. OBJECTIVE: Our objective was to look at trends of opioid and benzodiazepine co-prescribing in the emergency department (ED) using national data, because recent data are sparse. METHODS: This is a retrospective review of data collected by the National Hospital Ambulatory Medical Care Survey between 2012 and 2019. Our primary outcome was to determine whether there was a trend in ED visits when opioids and benzodiazepines were co-prescribed at discharge. We also compared the rate of visits when co-prescribing occurred before (2012-2015) and after (2017-2019) the 2016 FDA warning. We identified commonly co-prescribed benzodiazepines and opioids, and the rate of naloxone co-prescribing. We used descriptive statistics and bivariate tests to describe data. RESULTS: Between 2012 and 2019, there were 4,489,613 ED visits (0.41% of ED visits) when benzodiazepines and opioids were co-prescribed. There was no trend in the rate of co-prescribing overall, but a decrease in visits after the 2016 FDA Black Box Warning (2012-2015: mean 0.49%; 2017-2019: mean 0.29%; p < 0.0001). There were 7980 ED visits (0.18%) when naloxone was co-prescribed for these visits within this time frame and an increase over time (p < 0.001). CONCLUSIONS: Our study found that between 2012 and 2019, there was no overall reduction in co-prescribing of opioids and benzodiazepines across EDs nationwide, but a decrease after the 2016 Black Box Warning.

Infection prevention and control in CT Part 1: An Australian study of roles, responsibilities and practices.

INTRODUCTION: The computed tomography (CT) suite presents Infection Prevention and Control (IPC) risks for staff and patients. This is the first of a two-part series on IPC in the CT setting and reports on Australian baseline data related to intravenous contrast media administration and the use of power injectors in the CT suite, including knowledge sources related to the delivery of contrast media. The second part provides insights into CT staff's perceptions of high-risk scenarios for non-adherence to standard or transmission-based precautions. METHODS: The study employed an online survey design, directed at radiographers and radiology nurses working in Australia. The survey included questions relating to CT workplace staffing and equipment, contrast media use and occupational roles, and knowledge sources used for infection control and contrast injectors. RESULTS: Overall, 160 study participants completed the survey (radiographers: n = 138, 86.3%; nurses: n = 22, 13.7%). Differences were identified between public and private practice. Public hospitals completed more contrast-enhanced scans, and with dual injecting systems, operated and cleaned by radiographers and nurses. Private clinics generally used single-system, power injectors. Radiographers and nurses relied heavily on their colleagues and product guidelines for IPC information. IPC teams were uncommon in private clinics, very common in public departments and 50% of respondents had undertaken IPC training in the last 12 months. CONCLUSION: Insights into use and duties of professionals delivering intravenous contrast media administration using power injectors in the CT suite will help to inform decision-making processes on IPC education strategies and map risk. IMPLICATION FOR PRACTICE: Future research should focus on how radiology workers in CT perceive IPC risk and/or might vary from best practice, which has direct clinical implications for safety if contamination, or incorrect information is routinely applied.

Infection prevention and control in CT Part 2: Radiographers' and radiology nurses' perceptions of high-risk scenarios contributing to non-adherence to IPC protocols.

INTRODUCTION: Adherence to standard and transmission-based precautions in the computed tomography (CT) setting is central to effective infection prevention and control (IPC), yet there is limited evidence about medical imaging (MI) professionals' self-reported predictors of IPC breaches. This is the second of a two-part series on IPC in the CT setting. Part 1 reported on Australian baseline data relating to intravenous contrast media administration and power injectors. Part 2 presents Australian radiographers' and radiology nurses' perceptions of clinical situations that reduce adherence to standard and transmission-based precautions in CT. METHODS: A self-administered survey was distributed to Australian radiographers and radiology nurses working in CT. Responses to an open-ended question "If I was to not adhere to the standard and transmission-based precautions in the CT department, it is most likely when …" was analysed using inductive coding for themes, followed by deductive analysis mapped to the Systems Engineering Initiative for Patient Safety (SEIPS) model. RESULTS: Study participants (n = 136) were radiographers (n = 119; 87.5%) and nurses (n = 17; 12.5%). 'Four themes were derived from the inductive analysis: (1) high-risk working conditions, (2) compliance with good practice, (3) attitudes and practice, and (4) quality of communication. Deductive analysis, using the SEIPS domains revealed that predominant issues related to 'Tasks' (43.7%) and 'Organisation' (30.6%) followed by issues related to 'Person' (16.9%), 'Tools and technology' (6.9%) and 'Environment' (1.9%). CONCLUSION: Multi-faceted pressures on radiology staff may compromise adherence to standard and transmission-based precautions in CT. Task difficulty, time pressures whilst undertaking tasks, and reduced staffing could lead to lower adherence to standard and transmission-based precautions. IMPLICATIONS FOR PRACTICE: Future studies that focus on evaluation of 'Tasks' and 'Organisation' domains of the SEIPS model may provide further insights to non-adherence behaviours in MI.

Socioeconomic differences between medically and surgically treated prolactinomas: a retrospective review of 598 patients.

OBJECTIVE: Socioeconomic status (SES) is known to affect presentations and outcomes in pituitary neuroendocrine tumor resections, but there is a paucity of literature examining its impact specifically on patients with prolactinomas, who may be treated medically or surgically. The authors sought to determine whether SES was associated with differences in treatment choice or outcomes for prolactinoma patients. METHODS: The authors retrospectively reviewed patient records at a high-volume academic pituitary center for prolactinoma diagnoses. Patients were split into medically and surgically treated cohorts. Race, ethnicity, insurance status, primary care physician (PCP) status, and zip code-based income data were collected and examined as socioeconomic covariates. Outcomes of interest included pretreatment likelihood of surgical cure, medical versus surgical treatment allocation, and posttreatment remission rates. RESULTS: The authors analyzed 568 prolactinoma patients (351 medically treated and 217 surgically treated). Patients receiving surgery were more likely to have Medicaid or private insurance (p < 0.001) and have lower incomes (p < 0.001) than medically treated patients. Lower-income surgical patients were more likely to require surgical intervention for an indication such as tumor decompression than higher-income patients (p = 0.023). Surgical patients with a PCP had a higher estimated likelihood of surgical cure (p = 0.008), while no SES-based differences in surgical remission likelihood existed in the medical cohort. After surgery, surgical patients who achieved remission had significantly higher income than those who did not (p < 0.001). Other SES factors were not associated with surgical remission, and among medically treated patients, remission rates were not affected by any SES factor. Income was inversely related to prolactinoma size in both cohorts (surgical, p < 0.001; medical, p = 0.005) but was associated more prominently in surgical patients (surgical, -0.65 mm per $10,000; medical, -0.37 mm per $10,000). CONCLUSIONS: While surgical prolactinoma patients were prone to income and PCP-related disparities, no SES disparities were found among medically treated patients. Income had a more pronounced association with tumor size in the surgical cohort and likely contributed to the increased need for surgical intervention seen in low-income surgical patients. Addressing socioeconomic healthcare disparities is needed among surgical prolactinoma patients to increase rates of early presentation and improve the outcomes of low-SES populations.

Multiscale effects in tandem CO2 electrolysis to C2+ products.

CO2 electrolysis is a sustainable technology capable of accelerating global decarbonisation through the production of high-value alternatives to fossil-derived products. CO2 conversion can generate critical multicarbon (C2+) products such as drop-in chemicals ethylene and ethanol, however achieving high selectivity from single-component catalysts is often limited by the competitive formation of C1 products. Tandem catalysis can overcome C2+ selectivity limitations through the incorporation of a component that generates a high concentration of CO, the primary reactant involved in the C-C coupling step to form C2+ products. A wide range of approaches to promote tandem CO2 electrolysis have been presented in recent literature that span atomic-scale manipulation to device-scale engineering. Therefore, an understanding of multiscale effects that contribute to selectivity alterations are required to develop effective tandem systems. In this review, we use relevant examples to highlight the complex and interlinked contributions to selectivity and provide an outlook for future development of tandem CO2 electrolysis systems.