Mitigation of Nitrogen Mustard-Induced Skin Injury by the ß-Blocker Carvedilol and Its Enantiomers.

The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard (NM) cause severe vesicating skin injuries. The pathologic mechanisms for the skin injury following mustard exposure are poorly understood; therefore, no effective countermeasure is available. Previous reports demonstrated the protective activity of carvedilol, a US Food and Drug Administration (FDA)-approved ß-blocker, against UV radiation-induced skin damage. Thus, the current study evaluated the effects of carvedilol on NM-induced skin injuries in vitro and in vivo. In the murine epidermal cell line JB6 Cl 41-5a, ß-blockers with different receptor subtype selectivity were examined. Carvedilol and both of its enantiomers, R- and S-carvedilol, were the only tested ligands statistically reducing NM-induced cytotoxicity. Carvedilol also reduced NM-induced apoptosis and p53 expression. In SKH-1 mice, NM increased epidermal thickness, damaged skin architecture, and induced nuclear factor κB (NF-κB)-related proinflammatory genes as assessed by RT2 Profiler PCR (polymerase chain reaction) Arrays. To model chemical warfare scenario, 30 minutes after exposure to NM, 10 µM carvedilol was applied topically. Twenty-four hours after NM exposure, carvedilol attenuated NM-induced epidermal thickening, Ki-67 expression, a marker of cellular proliferation, and multiple proinflammatory genes. Supporting the in vitro data, the non-ß-blocking R-enantiomer of carvedilol had similar effects as racemic carvedilol, and there was no difference between carvedilol and R-carvedilol in the PCR array data, suggesting that the skin protective effects are independent of the ß-adrenergic receptors. These data suggest that the ß-blocker carvedilol and its enantiomers can be repurposed as countermeasures against mustard-induced skin injuries. SIGNIFICANCE STATEMENT: The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard cause severe vesicating skin injuries for which no effective countermeasure is available. This study evaluated the effects of US Food and Drug Administration (FDA)-approved ß-blocker carvedilol on nitrogen mustard-induced skin injuries to repurpose this cardiovascular drug as a medical countermeasure.

Impact of bariatric surgery on cytochrome P 450 enzyme activity.

Bariatric surgeries are becoming more prevalent as obesity rates continue to rise. Being that it is an effective weight-loss procedure, it can induce significant anatomical, physiological, and metabolic alterations, which affect the pharmacokinetics of various medications. Cytochrome (CYP) P450 is a group of enzymes that are primarily responsible for metabolizing most medications. Bariatric surgery may affect CYP activity and consequently alter metabolism of various medications, and the resulting weight loss may influence the metabolism of various drugs. This study investigates the impact of bariatric surgery on which CYP enzymes are affected and their effects medications. Authors of this study did an extensive literature review and research in databases including PubMed and EMBASE. The evidence was gathered for medication efficacy influenced by enzyme fluctuations to advocate for further studies for patients that undergo bariatric surgery. The search was limited to English-language results and is deemed up to date as of September 2023. There are numerous studies that indicated alterations of the CYP enzyme activity, which affects the pharmacokinetics of medications used to treat acute and chronic conditions after bariatric surgery. There are various mechanisms involved in CYP enzyme activity leading to fluctuations and the clearance of medications and subsequently compromising the efficacy and safety of these agents. It is imperative to conduct more prospective randomized control studies with longer duration to guide clinicians on how to manage medications with various CYP activity for patients' post-bariatric surgery.

Effects of bariatric surgery on drug pharmacokinetics-Preclinical studies.

With the rising worldwide obesity rates, bariatric surgeries are increasing. Although the surgery offers an effective treatment option for weight loss, the procedure causes dramatic physiological and metabolic changes. Animal models in rodents provide a valuable tool for studying the systemic effects of the surgery. Since the surgery may significantly influence the pharmacokinetic properties of medications, animal studies should provide essential insight into mechanisms underlying changes in how the body handles the drug. This review summarizes research work in rodents regarding the impact of standard bariatric procedures on pharmacokinetics. A qualitative literature search was conducted via PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE. Studies that examined bariatric surgery's effects on drug pharmacokinetics in rodent models were included. Clinical studies and studies not involving drug interventions were excluded. A total of 15 studies were identified and assessed in this review. These studies demonstrate the possible impact of bariatric surgery on drug absorption, distribution, metabolism, excretion, and potential mechanisms. Pharmacokinetic changes exhibited in the limited pre-clinical studies highlight a need for further investigation to fully understand the impact and mechanism of bariatric surgery on drug responses.

Caliber-persistent labial artery: report of 3 cases.

The caliber-persistent labial artery is a vascular anomaly in which a primary arterial branch penetrates into the submucosal tissue without reduction in diameter. Most lesions are benign and do not require treatment, except for complications and/or on patient demands. In this way, noninvasive diagnostic tools are preferred such as high-resolution and color Doppler ultrasonography which allow direct observation of the lesion, assessing its exact location and diameter at every axis, as well as the blood flow velocity. An excisional biopsy of these lesions or even their surgical extirpation could have a fatal outcome with profuse bleeding.

Circulating microRNAs in cellular and antibody-mediated heart transplant rejection.

BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection. METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use. RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively. CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

Effectiveness of a quality improvement intervention to increase adherence to key practices during female sterilization services in Chhattisgarh and Odisha states of India.

BACKGROUND: In response to longstanding concerns around the quality of female sterilization services provided at public health facilities in India, the Government of India issued standards and quality assurance guidelines for female sterilization services in 2014. However, implementation remains a challenge. The Maternal and Child Survival Program rolled out a package of competency-based trainings, periodic mentoring, and easy-to-use job aids in parts of five states to increase service providers' adherence to key practices identified in the guidelines. METHODS: The study employed a before-and-after quasi-experimental design with a matched comparison arm to examine the effect of the intervention on provider practices in two states: Odisha and Chhattisgarh. Direct observations of female sterilization services were conducted in selected public health facilities, using a checklist of 30 key practices, at two points in time. Changes in adherence to key practices from baseline to endline were compared at 12 intervention and 12 comparison facilities using a difference in difference analysis. RESULTS: Several key practices were well-established prior to the intervention, with adherence levels over 90% at baseline, including hemoglobin and urine testing, use of sterile surgical gloves and instruments, and recommended surgical technique. However, adherence to many other practices was extremely low at baseline. The program significantly increased adherence to nine practices, including those related to ascertaining client's medical eligibility, client-provider interaction, the consent process, and post-operative care. The greatest improvement was observed in the provision of written instructions for clients prior to discharge. At endline, however, adherence remained below 50% for 14 practices. CONCLUSION: Low adherence to key practices at baseline confirmed the need for quality improvement interventions in female sterilization services. While the intervention improved adherence to certain practices around admission and post-operative care, inadequate human resources and infrastructure, among other factors, may have blunted the impact of the intervention.

One-year continuation of postpartum intrauterine contraceptive device: findings from a retrospective cohort study in India.

OBJECTIVE: To evaluate outcomes of a national postpartum (within 48 h of delivery) copper intrauterine device placement (PPCuIUD) program in six "high-focus states" with high unmet family planning need in India. STUDY DESIGN: We identified high-volume district hospitals that provided PPCuIUD in six (Bihar, Jharkhand, Uttar Pradesh, Uttarakhand, Madhya Pradesh and Chhattisgarh) Indian states (two per state). Each selected hospital maintained a list of PPCuIUD acceptors with contact phone numbers. We randomly selected 100 women at each site for inclusion in a telephone survey of IUD outcomes at 1 year. Questions regarded IUD expulsion, discontinuation because of symptoms (e.g., pain, bleeding, discharge), discontinuation for other reasons and use of alternative contraception if discontinuation reported. RESULTS: We could contact 844 of the 1200 randomly selected women, of whom 673 (79.7%) had postplacental insertion (within 10 min of delivery), while 171 (20.3%) had an early postpartum insertion (between 10 min to 48 h after delivery). Of those contacted, 530 women (62.8%) reported continuing with the method beyond 1 year, 63 (7.5%) reported having an expulsion, 163 (19.3%) reported having removals for associated side effects (bleeding, pain and discharge), and 88 (10.4%) reported having removals for other reasons. After removal or expulsion, almost half of the women (46.5%) did not switch to any other modern contraceptive method. CONCLUSION: PPCuIUD continuation rate at 1 year was 62.8%. Most removals within 1 year were due to associated side effects. Almost half of the women discontinuing PPCuIUD did not switch to an alternative modern contraceptive method. IMPLICATIONS: The 1-year continuation rate of PPCuIUD achieved through a large-scale national program in India is satisfactory. The program though needs to address the low uptake of other modern contraceptive methods after discontinuation.

Caliber-persistent labial artery: report of 3 cases

Abstract The caliber-persistent labial artery is a vascular anomaly in which a primary arterial branch penetrates into the submucosal tissue without reduction in diameter. Most lesions are benign and do not require treatment, except for complications and/or on patient demands. In this way, noninvasive diagnostic tools are preferred such as high-resolution and color Doppler ultrasonography which allow direct observation of the lesion, assessing its exact location and diameter at every axis, as well as the blood flow velocity. An excisional biopsy of these lesions or even their surgical extirpation could have a fatal outcome with profuse bleeding.

Transition from the Lactational Amenorrhea Method to other modern family planning methods in rural Bangladesh: barrier analysis and implications for behavior change communication program intervention design.

The timely transition from Lactational Amenorrhea Method (LAM)(2) to another modern family planning method contributes to healthy spacing of pregnancies by increasing the adoption of family planning during the first year postpartum. Yet, literature suggests challenges in completing a timely LAM transition. To guide program implementation in Bangladesh, this study identified factors influencing women's transition decisions. Eighty postpartum women, comprising 40 who transitioned from LAM(3) and 40 who did not,(4) participated. Half of each group participated in in-depth interviews to explore the decision-making process. All participants responded to a "Barrier Analysis" questionnaire to identify differences in eight behavioral determinants. More than half of transitioners switched to another modern method before or within the same month that LAM ended. Of the 18 transitioners who delayed,(5) 15 waited for menses to return. For non-transitioners, key barriers included waiting for menses to return, misconceptions on return to fertility, and perceived lack of familial support. The LAM transition can help women prevent unintended pregnancy during the first year postpartum. Increased emphasis on counseling women about the risk of pregnancy, and misconceptions about personal fertility patterns are critical for facilitating the transition. Strategies should also include interventions that train health workers and improve social support.