Proactive Therapeutic Drug Monitoring Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease Treated With Intravenous Vedolizumab.

BACKGROUND: There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to evaluate the efficacy of proactive TDM in IBD patients treated with intravenous (iv) vedolizumab (VDZ). METHODS: This single-center retrospective cohort study included consecutive IBD patients treated with maintenance iv VDZ therapy undergoing TDM from November 2016 to March 2023. Patients were followed through June 2023 and were divided in to 2 groups: those who had at least 1 proactive TDM vs those who underwent only reactive TDM. A survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event, or an IBD-related surgery. RESULTS: The study population consisted of 94 patients (proactive TDM, n = 72) with IBD (ulcerative colitis, n = 53). Patients undergoing at least 1 proactive TDM compared with patients having only reactive TDM demonstrated a higher cumulative probability of drug persistence (Log-rank P < .001). In multivariable Cox proportional hazard regression analysis, at least 1 proactive TDM was the only factor associated with drug persistence (hazard ratio, 14.3; 95% confidence interval [CI], 3.8-50; P < .001). A ROC analysis identified a VDZ concentration of 12.5 µg/mL as the optimal drug concentration threshold associated with drug persistence (area under the ROC curve: 0.691; 95% CI, 0.517-0.865; P = .049). CONCLUSION: In this single-center retrospective study reflecting real-life clinical practice, proactive TDM was associated with increased drug persistence in patients with IBD treated with iv VDZ.

There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). We found that proactive TDM was associated with drug persistence in patients with IBD treated with vedolizumab. Moreover, a vedolizumab concentration of 12.5 µg/mL was identified as the optimal drug concentration threshold associated with drug persistence.

Effects of ozone exposure on lung injury, inflammation, and oxidative stress in a murine model of non-pneumonic endotoxemia.

Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 hr) or air control followed 24 hr later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2, Arg1, Cxcl1, Cxcl2, Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence.

Time evolution of moduli of a polymer-induced liquid precursor (PILP) of calcium carbonate.

In situ AFM observations show that when PILP droplets contact a surface, their initial properties are either a liquid with a high interfacial tension (350 mJ m-2) or a soft gel-like material with a low modulus (less than 0.2 MPa). These findings suggest that PILP may initially be liquid-like to infiltrate collagen fibrils, enabling the production of interpenetrating composites, and/or become viscoelastic, to provide a means for moulding minerals.

Barriers and enablers in doping, anti-doping, and clean sport: A qualitative meta-synthesis informed by the theoretical domains framework and COM-B model.

To protect the integrity of sport, and the health of athletes, global anti-doping programmes seek to prevent doping, and elicit anti-doping and clean sport behaviours, through education, deterrence, detection, enforcement, and rules. To guide programme development, this meta-synthesis of qualitative research applied a behavioural science framework to identify barriers and enablers to doping, anti-doping, and clean sport. A systematic search of electronic databases up to May 2022, followed by critical appraisal, resulted in 73 included articles. Fifty-two articles reported the athlete perspective, thirteen included athletes, athlete support personnel (ASP), and other experts, and eight focused on ASP only. Rigorous methods of thematic synthesis were drawn upon to construct analytical themes in line with the theoretical domains framework (TDF) and the capability, opportunity, and motivation model of behaviour (COM-B). A wide range of barriers and enablers were identified which influenced capability, opportunity, and motivation to participate in a clean sport environment. The weight of evidence pointed to limitations in the current anti-doping education system in providing athletes and ASP with the knowledge and skills to protect against doping, as well as the significant influence of social and cultural norms in shaping doping and clean sport behaviours through a shared social identity, and risky contexts leading to moments of vulnerability to doping. We identified a need for anti-doping programmes to move beyond the current focus on athlete capability, and address the opportunity and motivation components of clean sport behaviours through a targeted and tailored focus on education, training, persuasion, modelling and environmental restructuring interventions.

Development of bioreactor scale-down model using orthogonal projections to latent structures method and CO2 supplementation.

Scale-down model qualification is an important step for developing a large-scale cell culture process to enhance process understanding and support process characterization studies. Traditionally, only harvest data are used to show consistency between small-scale and large-scale bioreactor performance, allowing attributes that are dynamic over the cell culture period to be overlooked. A novel statistical method, orthogonal projections to latent structures (OPLS) analysis, can be utilized to compare time-course cell culture data across scales. Here we describe an example where OPLS is used to identify gaps between small-scale and large-scale bioreactor performances. In this case, differences in the partial pressure of carbon dioxide (pCO2) and lactate profiles were observed between small- and large-scale bioreactors, which were linked to differences in the product-quality attributes fragments and galactosylation. An improved small-scale model was developed, leading to improved consistency in the process performance and product qualities across scales and qualification of the scale-down model for regulatory submissions. This new statistical approach can provide valuable insights into process understanding and process scale-up.

A Microfabricated, Flow-Driven Grinding Mill for Mechanical Cell Lysing.

This paper presents the design, microfabrication, and demonstration of a novel microfluidic grinding mill for the lysis of the dinoflagellate, Alexandrium, a neurotoxin-producing genus of algae that is responsible for red tide and paralytic shellfish poisoning. The mill consists of a high-speed, hydrodynamically driven microrotor coupled to a micro grinding mill that lyses robust algal cells by mechanical abrasion with single-pass efficiencies as high as 97%. These efficiencies are comparable to, or better than, current mechanical and chemical lysing methods without adding complications associated with harsh chemical additives that can interfere with subsequent downstream bioanalysis. Release of cytoplasm from lysed algae was confirmed using polymerase chain reaction (PCR) amplification of Alexandrium DNA using dinoflagellate primers.

Patient-Centered Core Impacts Sets (PC-CIS): What They Are and What They Are Not.

Letter to the Editor We are writing regarding the Innovations in Pharmacy commentary entitled, "Evidentiary Standards for Patient-Centered Core Impact Value Claims."(1) We thank Dr. Langley for commenting on the National Health Council's work on patient-centered core impact sets (PC-CIS), an initiative spearheaded by the nonprofit organization and its membership with multi-stakeholder representation and input.(2-4) While we have tried to be clear and transparent about the intent of PC-CIS, the commentary made it apparent to us we need to (and will) do more to be explicit about what a PC-CIS is and is not, and its possible downstream uses. We believe the PC-CIS concept was misrepresented in the commentary and want to provide clarification for readers so they can consider the merits of the initiative for themselves.

Skin Models Used to Define Mechanisms of Action of Sulfur Mustard.

Sulfur mustard (SM) is a threat to both civilian and military populations. Human skin is highly sensitive to SM, causing delayed erythema, edema, and inflammatory cell infiltration, followed by the appearance of large fluid-filled blisters. Skin wound repair is prolonged following blistering, which can result in impaired barrier function. Key to understanding the action of SM in the skin is the development of animal models that have a pathophysiology comparable to humans such that quantitative assessments of therapeutic drugs efficacy can be assessed. Two animal models, hairless guinea pigs and swine, are preferred to evaluate dermal products because their skin is morphologically similar to human skin. In these animal models, SM induces degradation of epidermal and dermal tissues but does not induce overt blistering, only microblistering. Mechanisms of wound healing are distinct in these animal models. Whereas a guinea pig heals by contraction, swine skin, like humans, heals by re-epithelialization. Mice, rats, and rabbits are also used for SM mechanistic studies. However, healing is also mediated by contraction; moreover, only microblistering is observed. Improvements in animal models are essential for the development of therapeutics to mitigate toxicity resulting from dermal exposure to SM.

Perfectionism and doping willingness in athletes: The mediating role of moral disengagement.

Although trait perfectionism has been related to doping attitudes in athletes, research investigating variables that could account for relationships between perfectionism and doping outcomes has received scant attention. Consequently, the aim of the present study was to investigate whether perfectionism was related to doping willingness directly, and indirectly via moral disengagement. We recruited a sample of 204 student athletes (M age = 19.12 years, SD = 1.17, n = 81 females - 39.70%) who completed measures of perfectionistic strivings, perfectionistic concerns, doping moral disengagement, and doping willingness. Multiple regression analyses revealed a significant positive relationship between perfectionistic concerns and doping willingness (ß = .13, p < .05) and a nonsignificant relationship between perfectionistic strivings and doping willingness (ß = -.01, p > .05). Moreover, bias-corrected bootstrapped indirect effects revealed that doping moral disengagement mediated the relationship between perfectionistic concerns and doping willingness (ab = .12; 95% CI = 0.02 to 0.21). The findings suggest that the relationship between perfectionistic concerns and doping extends beyond attitudes - to doping willingness - and the propensity to morally disengage explains why this is the case.

Navigation of Prenatal Care With Sex Discordance Between Cell-free DNA and Ultrasound Findings.

The utilization of cell-free DNA (cfDNA) screening has expanded rapidly across the age spectrum of pregnant persons. With cfDNA's widespread adoption, genetic fetal sex is now often known before a phenotypic assessment on anatomic survey. CfDNA detects sex discordance in 1/1500 to 2000 pregnancies. Upon detection of sex discordance, lab error or other factors should first be assessed. Once other causes have been ruled out, this may indicate an underlying disorder/difference in sex development. A multidisciplinary team should coordinate diagnosis, treatment, and support for the family. This review discusses the diagnostic workup, emphasizing the multidisciplinary counseling and management of disorder/differences in sex development.

Doping in Paralympic sport: perceptions, responsibility and anti-doping education experiences from the perspective of Paralympic athletes and parasport coaches.

Introduction: Limited effort has been invested in understanding doping in Paralympic sport. The limited evidence that exists suggests that factors influencing doping in parasport are similar to Olympic sport. However, based on the design and nature of the previous studies, where methods have been mostly limited to qualitative data and prevalence numbers, further research is warranted to extend previous findings. Methods: Informed by current evidence from Paralympic and Olympic sport, we aimed to investigate (1) para-athletes' perceptions of Anti-Doping Rule Violations (ADRVs) and responsibility for them, (2) descriptive norms for doping in parasport (3) perceptions of anti-doping education and legitimacy of anti-doping authorities, and (4) coach engagement in doping prevention and levels of doping confrontation efficacy using a quantitative survey approach. Results: In total, valid survey responses from 126 Paralympic athletes and 35 coaches from four countries (Germany, Austria, Switzerland, UK) were analysed for experience with anti-doping, descriptive norms, anti-doping education, perceived legitimacy, knowledge, and doping confrontation efficacy (coaches only). Across both athletes and coaches, the level of education was generally good and doping willingness was low. Classification cheating was considered a form of doping and seems to be an important issue for athletes and coaches, especially within the UK sample. For 33.3% of the athletes, doping control was their first experience with anti-doping. Coaches' engagement with doping prevention activities and their perceived efficacy to confront doping-related matters appears to be higher compared to Olympic coaches' samples. Discussion: Sport organisations/NADOs in Paralympic sport could use synergies with those organisations in Olympic sport, adopting similar approaches to anti-doping education, also focusing on a balanced communication of doping prevalence numbers and testing figures. Efforts to ensure athletes are educated about anti-doping before they are tested should be upheld. It seems that in para sport, different compared to able-bodied coaches, anti-doping organizations do not have to convince the coaches about their roles (i.e., being responsible for anti-doping education) anymore but can directly build on these resources. Overall, it seems that there are few differences between parasport and able-bodied sports and thus responsible organisations could use the existing programmes in Olympic sport and only adapt special content (e.g., boosting) which is unique to Paralympic athletes.

A pilot randomized control trial of topical capsaicin as adjunctive therapy for nausea and vomiting of pregnancy.

BACKGROUND: Nausea and vomiting is one of the most common complications of pregnancy, affecting 50% to 80% of pregnant persons. Moreover, despite its prevalence, it remains a challenging condition to treat. Treatment often involves oral and intravenous medications with potential side effects, particularly when taken in combination. Capsaicin cream is proven to decrease nausea and vomiting in cyclic vomiting syndrome; however, its use has not been well studied among pregnant patients. OBJECTIVE: This study aimed to test the feasibility of the off-label use of capsaicin for the treatment of nausea and vomiting in pregnancy. STUDY DESIGN: This was a double-blinded randomized controlled trial of pregnant individuals in their first trimester of pregnancy seeking care at a tertiary care hospital for nausea and vomiting. Consenting participants were randomized to abdominal application of topical capsaicin vs placebo. All participants received intravenous hydration and metoclopramide. The primary outcome, total treatment time, was recorded for all participants. In addition, symptom severity was assessed every 30 minutes using a visual analog scale. Data were analyzed using the Wilcoxon rank-sum test for continuous variables and the Fisher exact test for binary variables. RESULTS: Of the 38 eligible individuals approached, 30 were randomized. There was a trend toward decreased mean treatment time in the capsaicin group compared with the placebo group (79.9 vs 97.3 minutes; P=.1). There was no significant difference in visual analog scale scores at any time point between groups. Furthermore, capsaicin was well tolerated, with only 1 individual requesting the medication be removed. CONCLUSION: This study demonstrated that capsaicin is an acceptable treatment of nausea and vomiting in pregnancy and additional explorations of its use as treatment are feasible. A larger randomized controlled trial is needed to determine the efficacy of capsaicin in this population.

Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) Collaboration.

Importance: Symptomatic intracranial hemorrhage (sICH) is a serious complication of stroke thrombolytic therapy. Many stroke centers have adopted 0.25-mg/kg tenecteplase instead of alteplase for stroke thrombolysis based on evidence from randomized comparisons to alteplase as well as for its practical advantages. There have been no significant differences in symptomatic intracranial hemorrhage (sICH) reported from randomized clinical trials or published case series for the 0.25-mg/Kg dose. Objective: To assess the risk of sICH following ischemic stroke in patients treated with tenecteplase compared to those treated with alteplase. Design, Setting, and Participants: This was a retrospective observational study using data from the large multicenter international Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) collaboration comprising deidentified data on patients with ischemic stroke treated with intravenous thrombolysis. Data from more than 100 hospitals in New Zealand, Australia, and the US that used alteplase or tenecteplase for patients treated between July 1, 2018, and June 30, 2021, were included for analysis. Participating centers included a mix of nonthrombectomy- and thrombectomy-capacity comprehensive stroke centers. Standardized data were abstracted and harmonized from local or regional clinical registries. Consecutive patients with acute ischemic stroke who were considered eligible and received thrombolysis at the participating stroke registries during the study period were included. All 9238 patients who received thrombolysis were included in this retrospective analysis. Main Outcomes and Measures: sICH was defined as clinical worsening of at least 4 points on the National Institutes of Health Stroke Scale (NIHSS), attributed to parenchymal hematoma, subarachnoid, or intraventricular hemorrhage. Differences between tenecteplase and alteplase in the risk of sICH were assessed using logistic regression, adjusted for age, sex, NIHSS score, and thrombectomy. Results: Of the 9238 patients included in the analysis, the median (IQR) age was 71 (59-80) years, and 4449 patients (48%) were female. Tenecteplase was administered to 1925 patients. The tenecteplase group was older (median [IQR], 73 [61-81] years vs 70 [58-80] years; P < .001), more likely to be male (1034 of 7313 [54%] vs 3755 of 1925 [51%]; P < .01), had higher NIHSS scores (median [IQR], 9 [5-17] vs 7 [4-14]; P < .001), and more frequently underwent endovascular thrombectomy (38% vs 20%; P < .001). The proportion of patients with sICH was 1.8% for tenecteplase and 3.6% for alteplase (P < .001), with an adjusted odds ratio (aOR) of 0.42 (95% CI, 0.30-0.58; P < .01). Similar results were observed in both thrombectomy and nonthrombectomy subgroups. Conclusions and Relevance: In this large study, ischemic stroke treatment with 0.25-mg/kg tenecteplase was associated with lower odds of sICH than treatment with alteplase. The results provide evidence supporting the safety of tenecteplase for stroke thrombolysis in real-world clinical practice.

Frequency, barriers, outcomes, and consequences of reporting sexual harassment in clinical oncology.

Sexual harassment is increasingly recognized as widely prevalent in medicine. Broad efforts at the organizational and society level are working to address this inequity, but many of these efforts rely on reporting to eradicate problematic behaviors and shift culture. We examined, among oncologists experiencing sexual harassment, the frequency of reporting, as well as barriers, outcomes, and consequences of reporting. Among 271 survey respondents, 217 reported sexual harassment from peers or superiors or from patients or families. Most harassed oncologists (n = 148, 68%) did not report the event to authority because of concerns about future negative consequences for themselves. Among the minority who reported harassment (n = 31, 14%), 52% felt their concerns were not taken seriously and 55% reported no action was taken as a result of their report. Furthermore, 52% experienced retaliatory behavior. Addressing these findings may help to inform the change necessary to create an antiharassment culture in oncology.

Prognostic value of longitudinal vasoreactivity in pediatric pulmonary hypertension.

Upon diagnosis of pulmonary hypertension in pediatrics, standard practice often involves acute vasoreactivity testing (AVT) in the cardiac catheterization laboratory. However, the importance of repeated AVT testing in a given patient thereafter remains unclear. This study sought to describe serial AVT results in pediatric patients and understand the prognostic significance of longitudinal AVT results in pediatric pulmonary hypertension. A retrospective chart review was performed for pediatric pulmonary hypertension patients diagnosed between 2008 and 2021. Patients were included if they had two or more catheterizations with AVT. The study cohorts were patients who were AVT negative upon initial catheterization then AVT positive at any subsequent catheterization (AVT-/+) compared to those were AVT negative upon initial and all subsequent catheterizations (AVT-/-). A positive AVT was defined by Sitbon criteria. The analyzed outcome was event-free survival. The relationship between study cohorts and event-free survival was analyzed by log-rank Kaplan-Meier survival as well as Cox proportional hazard regression to control for confounders. There were 35 patients who met inclusion criteria in this time period. Patients who were AVT(-/+) had statistically significantly better event-free survival than AVT(-/-) (p = 0.002). In univariate and multivariate Cox regressions, a subsequent AVT positive result amongst those who were initially AVT negative was a positive prognostic factor, hazard ratio 0.03 (95% confidence interval: 0.02-0.35). For patients with negative AVT upon initial cardiac catheterization, this data supports that continuing AVT should be performed as any subsequent AVT positive result may indicate improved expectations for event-free survival.

Preoperative Management of Neonates With Congenital Heart Disease.

Clinicians caring for neonates with congenital heart disease encounter challenges in clinical care as these infants await surgery or are evaluated for further potential interventions. The newborn with heart disease can present with significant pathophysiologic heterogeneity and therefore requires a personalized therapeutic management plan. However, this complex field of neonatal-cardiac hemodynamics can be simplified. We explore some of these clinical quandaries and include specific sections reviewing the anatomic challenges in these patients. We propose this to serve as a primer focusing on the hemodynamics and therapeutic strategies for the preoperative neonate with systolic dysfunction, diastolic dysfunction, excessive pulmonary blood flow, obstructed pulmonary blood flow, obstructed systemic blood flow, transposition physiology, and single ventricle physiology.

Health effects associated with consumption of unprocessed red meat: a Burden of Proof study.

Characterizing the potential health effects of exposure to risk factors such as red meat consumption is essential to inform health policy and practice. Previous meta-analyses evaluating the effects of red meat intake have generated mixed findings and do not formally assess evidence strength. Here, we conducted a systematic review and implemented a meta-regression-relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity-to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes. We found weak evidence of association between unprocessed red meat consumption and colorectal cancer, breast cancer, type 2 diabetes and ischemic heart disease. Moreover, we found no evidence of an association between unprocessed red meat and ischemic stroke or hemorrhagic stroke. We also found that while risk for the six outcomes in our analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between-study heterogeneity was very wide: from 0-200 g d-1. While there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality, it is weak and insufficient to make stronger or more conclusive recommendations. More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.

Health effects associated with smoking: a Burden of Proof study.

As a leading behavioral risk factor for numerous health outcomes, smoking is a major ongoing public health challenge. Although evidence on the health effects of smoking has been widely reported, few attempts have evaluated the dose-response relationship between smoking and a diverse range of health outcomes systematically and comprehensively. In the present study, we re-estimated the dose-response relationships between current smoking and 36 health outcomes by conducting systematic reviews up to 31 May 2022, employing a meta-analytic method that incorporates between-study heterogeneity into estimates of uncertainty. Among the 36 selected outcomes, 8 had strong-to-very-strong evidence of an association with smoking, 21 had weak-to-moderate evidence of association and 7 had no evidence of association. By overcoming many of the limitations of traditional meta-analyses, our approach provides comprehensive, up-to-date and easy-to-use estimates of the evidence on the health effects of smoking. These estimates provide important information for tobacco control advocates, policy makers, researchers, physicians, smokers and the public.

A modified Delphi approach to determine current treatment advances for the development of a resuscitation program for maternal cardiac arrest.

OBJECTIVE: Maternal cardiac arrest is a rare and complex process requiring pregnancy-specific responses and techniques. The goals of this study were to (1) identify, evaluate, and determine the most current best practices to treat this patient population and (2) establish a standardized set of guidelines to serve as a foundation for a future educational simulation-based curriculum. STUDY DESIGN: We used a three-step modified Delphi process to achieve consensus. Twenty-two healthcare experts from across North America agreed to participate in the expert panel. In round 1, 12 pregnancy-specific best practice statements were distributed to the expert panel. Panelists anonymously ranked these using a 7-point Likert scale and provided feedback. Round 2 consisted of a face-to-face consensus meeting where statements that had not already achieved consensus were discussed and then subsequently voted upon by the panelists. RESULTS: Through two rounds, we achieved consensus on nine evidence-based pregnancy-specific techniques to optimize response to maternal cardiac arrest. Round one resulted in one of the 12 best practice statements achieving consensus. Round two resulted in six of the remaining 12 gaining consensus. Best practice techniques involved use of point-of care ultrasound, resuscitative cesarean delivery, cardiopulmonary resuscitation techniques, and the use of extracorporeal cardiopulmonary resuscitation. CONCLUSION: The results of this study provide the foundation to develop an optimal, long-term strategy to treat cardiac arrest in pregnancy. We propose these nine priorities for standard practice, curricula, and guidelines to treat maternal cardiac arrest and hope they serve as a foundation for a future educational curriculum.