Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

ScreenPlus: A comprehensive, multi-disorder newborn screening program.

The increasing availability of novel therapies highlights the importance of screening newborns for rare genetic disorders so that they may benefit from early therapy, when it is most likely to be effective. Pilot newborn screening (NBS) studies are a way to gather objective evidence about the feasibility and utility of screening, the accuracy of screening assays, and the incidence of disease. They are also an optimal way to evaluate the complex ethical, legal and social implications (ELSI) that accompany NBS expansion for disorders. ScreenPlus is a consented pilot NBS program that aims to enroll over 100,000 infants across New York City. The initial ScreenPlus panel includes 14 disorders and uses an analyte-based, multi-tiered screening platform in an effort to enhance screening accuracy. Infants who receive an abnormal result are referred to a ScreenPlus provider for confirmatory testing, management, and therapy as needed, along with longitudinal capture of outcome data. Participation in ScreenPlus requires parental consent, which is obtained in active and passive manners. Patient-facing documents are translated into the ten most common languages spoken at our nine pilot hospitals, all of which serve diverse communities. At the time of consent, parents are invited to receive a series of online surveys to capture their opinions about specific ELSI-related topics, such as NBS policy, residual dried blood spot retention, and the types of disorders that should be on NBS panels. ScreenPlus has developed a stakeholder-based, collective funding model that includes federal support in addition to funding from 14 advocacy and industry sponsors, all of which have a particular interest in NBS for at least one of the ScreenPlus disorders. Taken together, ScreenPlus is a model, multi-sponsored pilot NBS program that will provide critical data about NBS for a broad panel of disorders, while gathering key stakeholder opinions to help guide ethically sensitive decision-making about NBS expansion.

Effects of Nature-Based Multisensory Stimulation on Pain Mechanisms in Women with Fibromyalgia Syndrome: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: The term "nature-based sensory stimuli" refers to the sensory information produced by biotic and abiotic agents from natural environments. The literature has reported the beneficial effects of these agents on various pain dimensions in non-clinical populations. AIMS: To evaluate the potential analgesic effects of nature-based multisensory stimulation in women with fibromyalgia syndrome. METHODS: A randomized, double-blind, placebo-controlled, parallel-group trial with a 1:1 allocation ratio was conducted. Forty-two women with fibromyalgia syndrome interacted with either different plant species with flowers, stones, and soil organic matter or their synthetic imitations for 30 minutes. Outcome measurements were performed before and after the intervention, including clinical pain intensity using the Numeric Rating Scale, cold pain thresholds using the Cold Pressor Test, mechanical hyperalgesia and wind-up using a monofilament, and pressure pain thresholds using a pressure algometer. RESULTS: Analyses revealed group × time interactions for clinical pain intensity (F = 7.915, p = .008), cold-water immersion time (F = 7.271, p = .010), mechanical hyperalgesia (F = 4.701, p = .036), and pressure pain threshold (p ≤ .017). Between-group differences were found in clinical pain intensity (p = .012), cold pain thresholds (p = .002), and pressure pain thresholds (p < .05). The experimental group exhibited reduced clinical pain intensity (p = .001) and increased pressure pain thresholds (p ≤ .034). CONCLUSIONS: Women with fibromyalgia syndrome may benefit from multisensory stimulation using biotic and abiotic agents from natural environments for 30 minutes. Interacting with flowering plants and soil components appears to induce analgesic effects.

Intended and unintended consequences of strategies to meet performance benchmarks for rheumatologist referrals in a centralized intake system.

RATIONALE: Timely assessment of a chronic condition is critical to prevent long-term irreversible consequences. Patients with inflammatory arthritis (IA) symptoms require diagnosis by a rheumatologist and intervention initiation to minimize potential joint damage. With limited rheumatologist capacity, meeting urgency wait time benchmarks can be challenging. We investigate the impact of the maximum wait time guarantee (MWTG) policy and referral volume changes in a rheumatology central intake (CI) system on meeting this challenge. METHODS: We applied a system simulation approach to model a high-volume CI rheumatology clinic. Model parameters were based on the referral and triage data from the CI and clinic appointment data. We compare the wait time performance of the current distribution policy MWTG and when referral volumes change. RESULTS: The MWTG policy ensures 100% of new patients see a rheumatologist within their urgency wait time benchmark. However, the average wait time for new patients increased by 51% (178-269 days). A 10% decrease in referrals resulted in a 76% decrease on average wait times (178-43 days) for new patients and an increase in the number of patients seen by a rheumatologist within 1 year of the initial visit. CONCLUSION: An MWTG policy can result in intended and unintended consequences-ensuring that all patients meet the wait time benchmarks but increasing wait times overall. Relatively small changes in referral volume significantly impact wait times. These relationships can assist clinic managers and policymakers decide on the best approach to manage referrals for better system performance.

Longitudinal pathways of maltreated young children: Family stress processes and adverse childhood experiences.

An important issue associated with at-risk families in the child welfare system is the impact of familial stress processes on child developmental outcomes. The present study used the family stress model (FSM) to examine the impact of economic hardship, economic pressure, caregiver emotional distress, caregiver/partner conflict, caregiver harsh parenting, and adverse childhood experiences (ACEs) on child's cognitive, behavioral, and social outcomes. Data from the National Survey on Child and Adolescent Well-Being II were utilized, and 1,363 children (709 male, 654 female) ages 2-18 months (at Wave 1) were included in the present study. Three waves of data were analyzed in the longitudinal structural equation model, with economic hardship and economic pressure at Wave 1, caregiver emotional distress, caregiver/partner conflict, and caregiver harsh parenting at Wave 2 predicting ACEs and child outcomes at Wave 3. Results were overall consistent with the FSM in that economic hardship led to economic pressure, and caregiver emotional distress and caregiver/partner conflict led to harsh parenting, which subsequently led to ACEs. ACEs led to negative child cognitive outcomes, and for female children only, ACEs led to internalizing/externalizing behaviors. The results demonstrate that over time, familial stress processes led to negative child developmental outcomes in this sample. Study results also highlight the inextricable connection between mild harsh parenting behaviors and more severe forms of maltreatment on child outcomes. The prevention of child maltreatment is emphasized, with a specific focus on increasing positive parenting behaviors and decreasing caregiver emotional distress and caregiver/partner conflict. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comparison of Tricaine Methanesulfonate (MS-222) and Alfaxalone Anesthesia in Zebrafish (Danio rerio).

The research use of zebrafish has risen exponentially over the past decade while anesthetic options have remained largely unchanged.6 ricaine methanesulfonate (MS-222) is widely accepted as an anesthetic for routine husbandry procedures, however it has limitations and safety concerns. 11 A greater variety of effective anesthetic options for surgical procedures would be advantageous for the research community. Adult zebrafish were randomly assigned to one of the following groups (n = 10, 5 males and 5 females): 200 mg/L MS-222; 6-, 10-, 13-, and 16-mg/L alfaxalone, and control. All zebrafish in the MS-222 group reached a surgical plane of anesthesia within 95 ± 32 s. By contrast, only 2 of 10, 1 of 10, 0 of 10, and 0 of 4 of the 6, 10, 13, and 16 mg/L alfaxalone groups, respectively, reached a surgical plane of anesthesia within the allotted 10-min period. Recovery time was also significantly slower in the alfaxalone groups as compared with MS-222, with some fish taking greater than 10 min to recover. In addition, 33 of 34 zebrafish (the 16 mg/L group was not completed due to safety concerns) in the alfaxalone groups lost opercular movements for greater than one minute during their anesthetic event and had to be removed to the recovery tank. The results demonstrated that alfaxalone was unable to provide a reliable and safe surgical plane of anesthesia at any of the drug doses tested. Therefore, we recommend alfaxalone not be used as an anesthetic for painful procedures on zebrafish and conclude that MS-222 remains a more viable anesthetic for immersion anesthesia in zebrafish.

A Case Series of Pregnant Women With Mitral Stenosis.

Pregnant women with mitral stenosis have a high cardiovascular risk, and their outcomes vary greatly. The management of these patients should be individualized and carried out by a multidisciplinary team. This case series presents 3 cases of pregnant women with severe mitral stenosis, describing their progression and therapeutic strategies.

Induction of antigen specific intrahepatic CD8+ T cell responses by a secreted heat shock protein based gp96-Ig-PfCA malaria vaccine.

Introduction: A highly efficacious and durable vaccine against malaria is an essential tool for global malaria eradication. One of the promising strategies to develop such a vaccine is to induce robust CD8+ T cell mediated immunity against malaria liver-stage parasites. Methods: Here we describe a novel malaria vaccine platform based on a secreted form of the heat shock protein, gp96-immunoglobulin, (gp96-Ig) to induce malaria antigen specific, memory CD8+ T cells. Gp96-Ig acts as an adjuvant to activate antigen presenting cells (APCs) and chaperone peptides/antigens to APCs for cross presentation to CD8+ T cells. Results: Our study shows that vaccination of mice and rhesus monkeys with HEK-293 cells transfected with gp96-Ig and two well-known Plasmodium falciparum CSP and AMA1 (PfCA) vaccine candidate antigens, induces liver-infiltrating, antigen specific, memory CD8+ T cell responses. The majority of the intrahepatic CSP and AMA1 specific CD8+ T cells expressed CD69 and CXCR3, the hallmark of tissue resident memory T cells (Trm). Also, we found intrahepatic, antigen-specific memory CD8+ T cells secreting IL-2, which is relevant for maintenance of effective memory responses in the liver. Discussion: Our novel gp96-Ig malaria vaccine strategy represents a unique approach to induce liver-homing, antigen-specific CD8+ T cells critical for Plasmodium liver-stage protection.

Incidence of ultrasonographic signs of pneumothorax in asymptomatic neonates.

INTRODUCTION: Pneumothorax in neonates can be life-threatening. In neonates without respiratory distress, spontaneous pneumothorax can also develop under certain conditions. OBJECTIVES: To determine the incidence of ultrasonographic signs of pneumothorax in asymptomatic neonates using lung ultrasound as the diagnostic tool. METHODS: This was an observational prospective study conducted at the Basurto University Hospital (Bilbao, Spain) between January 2018 and December 2020. Lung ultrasound was performed during routine examination of asymptomatic neonates admitted to the maternity ward. RESULTS: Of a total of 204 asymptomatic neonates included in the study, 21 (10.3%) presented ultrasound signs of pneumothorax (Group A), and 183 (89.7%) had a normal lung ultrasound (Group B). Lung ultrasound was performed after a mean of 19 h of life (range 9-34). The presence of A-lines behind the sternum in the anterior transverse plane, at the intermammillary level, was observed in 100% of patients in Group A compared to no cases in Group B (p < 0.0001). The neonates of Group A presented the lung point located in the midclavicular line, indicative of a mild air leak. CONCLUSIONS: Lung ultrasound allows precise detection of suspected small-sized air leaks that can be detected in asymptomatic neonates. The true incidence of pneumothorax in asymptomatic neonates may be substantially higher than previously described in the literature.

Effect of Fish Oil Parenteral Emulsion Supplementation on Inflammatory Parameters after Esophagectomy.

(Background) Esophagectomy (EPG) presents high morbidity and mortality. Omega-3 fatty acids (ω-3FA) are a pharmaconutrient with benefits for postoperative morbidity. Studies of ω-3FA administered parenterally after esophagectomy are scarce. This study proposes to investigate the effect of combining fish oil lipid emulsions (LE) administered parenterally with enteral nutrition support. (Methods) Randomization was 1:1:1 in three groups: Group A received a LE mixture of 0.4 g/kg/day of fish oil and 0.4 g/kg/day of LCT/MCT 50:50, Group B received 0.8 g/kg/day of fish oil LE, and Group C received 0.8 g/kg/day of LCT/MCT 50:50. Variables were measured at recruitment time and day +1, +3, and +5. Inflammatory variables studied were Interlukin-6, C-reactive protein (CRP), tumoral necrosis factor-α (TNF-α), IL-10, IL-8 and CD25s. Safety, nutritional parameters and complications were analyzed. (Results) Administration of ω-3LE in the immediate postoperative period did not modulate the earlier inflammatory response. Statistically significant differences were found in IL-6 and CRP overall temporal evolution but were not found when studying the type of LE administered or in patients needing critical care. Administration of ω-3 resulted in safe and improved hypertriglyceridemia, depending on the dose. (Conclusions) ω-3FA has no impact on the early inflammatory postoperative response assessed for a short period but was safe. More studies for longer periods are needed.

A Simulation Modelling Study of Referral Distribution Policies in a Centralized Intake System for Surgical Consultation.

Delays beyond recommended wait times, especially for specialist services, are associated with adverse health outcomes. The Alberta Surgical Initiative aims to improve the referral wait time-the time between a referral is received at the central intake to the time a specialist sees the patient. Using the discrete event simulation modelling approach, we evaluated and compared the impact of four referral distribution policies in a central intake system on three system performance measures (number of consultations, referral wait time and surgeon utilization). The model was co-designed with clinicians and clinic staff to represent the flow of patients through the system. We used data from the Facilitated Access to Surgical Treatment (FAST) centralized intake referral program for General Surgery to parameterize the model. Four distribution policies were evaluated - next-available-surgeon, sequential, "blackjack," and "kanban." A sequential distribution of referrals for surgical consultation among the surgeons resulted in the worst performance in terms of the number of consultations, referral wait time and surgeon utilization. The three other distribution policies are comparable in performance. The "next available surgeon" model provided the most efficient and robust model, with approximately 1,000 more consultations, 100 days shorter referral time and a 14% increase in surgeon utilization. Discrete event simulation (DES) modelling can be an effective tool to illustrate and communicate the impact of the referral distribution policy on system performance in terms of the number of consultations, referral wait time and surgeon utilization.

Liquid Chromatography-Tandem Mass Spectrometry in Newborn Screening Laboratories.

Tandem mass spectrometry (MS/MS) is the most universal platform currently available for the analysis of enzymatic activities and biomarkers in dried blood spots (DBS) for applications in newborn screening (NBS). Among the MS/MS applications in NBS, the most common is flow-injection analysis (FIA-) MS/MS, where the sample is introduced as a bolus injection into the mass spectrometer without the prior fractionation of analytes. Liquid chromatography combined with MS/MS (LC-MS/MS) has been employed for second-tier tests to reduce the false-positive rate associated with several nonspecific screening markers, beginning two decades ago. More recently, LC-MS/MS has been applied to primary screening for new conditions for which FIA-MS/MS or other methods, including genomic screening, are not yet adequate. In addition to providing a list of the currently used LC-MS/MS-based assays for NBS, the authors share their experience regarding the maintenance requirements of LC-MS/MS vs. FIA-MS/MS systems. The consensus is that the maintenance of LC-MS/MS and FIA-MS/MS instrumentation is similar, and LC-MS/MS has the advantage of allowing for a larger number of diseases to be screened for in a multiplex, cost-effective fashion with a high throughput and an adequate turnaround time.

Impact of Pain Neuroscience Education Program in Community Physiotherapy Context on Pain Perception and Psychosocial Variables Associated with It in Elderly Persons: A Ranzomized Controlled Trial.

This study investigated the long-term effect (six-months) of a Pain Neuroscience Education (PNE) program on pain perception, quality of life, kinesiophobia and catastrophism in older adults with multimorbidity and chronic pain. Fifty participants (n = 50) were randomly assigned to the pain education therapy group (PET; n = 24) and control group (CG; n = 26). The PET group received six sessions (i.e., once a week, 50 min) about neurophysiology of pain while the CG carried on with their usual life. Perception of pain through the visual analogue scale (VAS), quality of life (EQ-5D questionnaire), kinesiophobia (TSK-11) and catastrophism (PCS) were assessed after six months since the last PNE session. Statistically significant differences on VAS (t(48) = 44, p = 0.01, ES = 0.42 [0.13, 0.65]) was found in favor to PET group. No other statistically significant differences were found. This study found that the application of a PNE intervention in an isolated form was able to significantly reduce pain perception with low effect size in the long-term (six months after intervention) in elderly people with chronic pain.

Lung Ultrasound Scores Progress Differently in Extreme and Very Preterm Infants after Birth: A Multicentre Prospective Study.

INTRODUCTION: The lung ultrasound score (LUS) has been suggested to predict moderate-severe bronchopulmonary dysplasia (msBPD) in preterm infants. We aimed to assess LUS evolution after birth in preterm infants and the effect of gestational age. METHODS: This multicentre prospective observational study was performed with newborns born before 33 weeks of gestation. We created two groups: group 1 (23-27 weeks) and group 2 (28-32 weeks). We compared LUSs between the groups from birth until 36 weeks of postmenstrual age, and we estimated the LUS evolution in each group with a linear multilevel mixed-effects regression model. The effects of the need for surfactant or an msBPD diagnosis were also studied. RESULTS: We included 339 patients: 122 (36%) in group 1 and 217 (64%) in group 2. The infants in group 1 showed a steady progression in the LUS from birth until 4 weeks of age and a subsequent decrease; the infants in group 2 showed a progressive decrease in the LUS throughout the study. This progression varied significantly in the first weeks of life in infants who required surfactant at birth and after the first week of life in the patients diagnosed with msBPD. DISCUSSION/CONCLUSIONS: Extremely preterm infants showed persistently high LUSs during the first weeks of life, regardless of the progression to msBPD. In this group, the infants who did not require surfactant at birth exhibited an increase in their LUSs after the first week until their values were equal to the remaining infants in their group.

A multi-step approach to developing a health system evaluation framework for community-based health care.

BACKGROUND: Community-based health care (CBHC) is a shift towards healthcare integration and community services closer to home. Variation in system approaches harkens the need for a conceptual framework to evaluate outcomes and impacts. We set out to develop a CBHC-specific evaluation framework in the context of a provincial ministry of health planning process in Canada. METHODS: A multi-step approach was used to develop the CBHC evaluation framework. Modified Delphi informed conceptualization and prioritization of indicators. Formative research identified evaluation framework elements (triple aim, global measures, and impact), health system levels (tiers), and potential CBHC indicators (n = 461). Two Delphi rounds were held. Round 1, panelists independently ranked indicators on CBHC relevance and health system tiering. Results were analyzed by coding agreement/disagreement frequency and central tendency measures. Round 2, a consensus meeting was used to discuss disagreement, identify Tier 1 indicators and concepts, and define indicators not relevant to CBHC (Tier 4). Post-Delphi, indicators and concepts were refined, Tier 1 concepts mapped to the evaluation framework, and indicator narratives developed. Three stakeholder consultations (scientific, government, and public/patient communities) were held for endorsement and recommendation. RESULTS: Round 1 Delphi results showed agreement for 300 and disagreement for 161 indicators. Round 2 consensus resulted in 103 top tier indicators (Tier 1 = 19, Tier 2 = 84), 358 bottom Tier 3 and 4 indicators, non-CBHC measure definitions, and eight Tier 1 indicator concepts-Mortality/Suicide; Quality of Life, and Patient Reported Outcome Measures; Global Patient Reported Experience Measures; Cost of Care, Access to Integrated Primary Care; Avoidable Emergency Department Use; Avoidable Hospitalization; and E-health Penetration. Post Delphi results refined Tier 3 (n = 289) and 4 (n = 69) indicators, and identified 18 Tier 2 and 3 concepts. When mapped to the evaluation framework, Tier 1 concepts showed full coverage across the elements. 'Indicator narratives' depicted systemness and integration for evaluating CBHC. Stakeholder consultations affirmed endorsement of the approach and evaluation framework; refined concepts; and provided key considerations to further operationalize and contextualize indicators, and evaluate CBHC as a health system approach. CONCLUSIONS: This research produced a novel evaluation framework to conceptualize and evaluate CBHC initiatives. The evaluation framework revealed the importance of a health system approach for evaluating CBHC.

Robotic surgery for the treatment of achalasia.

OBJECTIVE: To describe the experience of the robotic approach for achalasia surgery in a tertiary center. MATERIAL AND METHODS: Patients with achalasia who underwent robotic surgery between May 2010 and April 2019 were analyzed. The study variables were collected in a prospective database and a descriptive analysis was performed. RESULTS: 45 patients (55.6% male) with a mean age of 44 years were included. The main symptom at diagnosis was dysphagia. 19 patients (42.2%) received endoscopic treatment prior to surgery, mostly pneumatic dilation (84.2%). Heller's myotomy associated with Toupet fundoplication was the surgical technique of choice, with a mean operative time of 211 min. The average stay was 5 days. There were 2 postoperative perforations (4.4%). Perioperative mortality was 0%. The mean follow-up was 64 months. At 3 and 5 years, a significant decrease in the Eckardt score was observed and the manometric study showed a decrease in the lower esophageal sphincter pressure at rest of 58% and 70%, respectively, with persistence of hypomotility of the esophageal body. Pathological gastroesophageal reflux was diagnosed in two patients (5.4%) and 4 (10.8%) presented recurrence of symptoms, requiring endoscopic pneumatic dilations. In 2 cases, the dilations were not effective, so an endoscopic myotomy was considered. CONCLUSIONS: In our experience, robotic surgery is a safe and effective procedure for the treatment of achalasia.

Interactive Visualization Applications in Population Health and Health Services Research: Systematic Scoping Review.

BACKGROUND: Simple visualizations in health research data, such as scatter plots, heat maps, and bar charts, typically present relationships between 2 variables. Interactive visualization methods allow for multiple related facets such as numerous risk factors to be studied simultaneously, leading to data insights through exploring trends and patterns from complex big health care data. The technique presents a powerful tool that can be used in combination with statistical analysis for knowledge discovery, hypothesis generation and testing, and decision support. OBJECTIVE: The primary objective of this scoping review is to describe and summarize the evidence of interactive visualization applications, methods, and tools being used in population health and health services research (HSR) and their subdomains in the last 15 years, from January 1, 2005, to March 30, 2019. Our secondary objective is to describe the use cases, metrics, frameworks used, settings, target audience, goals, and co-design of applications. METHODS: We adapted standard scoping review guidelines with a peer-reviewed search strategy: 2 independent researchers at each stage of screening and abstraction, with a third independent researcher to arbitrate conflicts and validate findings. A comprehensive abstraction platform was built to capture the data from diverse bodies of literature, primarily from the computer science and health care sectors. After screening 11,310 articles, we present findings from 56 applications from interrelated areas of population health and HSR, as well as their subdomains such as epidemiologic surveillance, health resource planning, access, and use and costs among diverse clinical and demographic populations. RESULTS: In this companion review to our earlier systematic synthesis of the literature on visual analytics applications, we present findings in 6 major themes of interactive visualization applications developed for 8 major problem categories. We found a wide application of interactive visualization methods, the major ones being epidemiologic surveillance for infectious disease, resource planning, health service monitoring and quality, and studying medication use patterns. The data sources included mostly secondary administrative and electronic medical record data. In addition, at least two-thirds of the applications involved participatory co-design approaches while introducing a distinct category, embedded research, within co-design initiatives. These applications were in response to an identified need for data-driven insights into knowledge generation and decision support. We further discuss the opportunities stemming from the use of interactive visualization methods in studying global health; inequities, including social determinants of health; and other related areas. We also allude to the challenges in the uptake of these methods. CONCLUSIONS: Visualization in health has strong historical roots, with an upward trend in the use of these methods in population health and HSR. Such applications are being fast used by academic and health care agencies for knowledge discovery, hypotheses generation, and decision support. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/14019.

Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex.

Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. In this study, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week old) (n = 9) and nonblistered epidermis (n = 11) obtained from 11 patients with EBS. Transcriptomic analysis of blistered epidermis in patients with EBS revealed a set of 1,276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in the epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-α, IL-1ß, IL-2, IL-6, phosphatidylinositol 3-kinase, and mTOR. The 1,276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2,423 drugs using the Connectivity Map CLUE platform. The mTOR inhibitors and phosphatidylinositol 3-kinase inhibitors most opposed the EBS signature. To determine whether mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of two patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and a notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.

Genetic factors associated with alterations in liver function test results in adult hospitalized patients treated with parenteral nutrition: A substudy of a clinical trial.

OBJECTIVES: The presence of phytosterols in vegetable-based lipid emulsions has been associated with alterations in the results of liver function tests (LFTs). Serum levels of phytosterols are under strict genetic control. T-allele carriers in rs41360247 and C-allele carriers in rs4245791 of ABCG8genes are associated with higher phytosterolemia. The objective of this study was to determine the association between these single-nucleotide polymorphisms (SNPs) and LFT result alterations in an adult hospitalized population treated with parenteral nutrition. METHODS: This is a substudy of a previous clinical trial (EudraCT 2014-003597-17). It included adult hospitalized patients who had received at least 7 d of parenteral nutrition with 0.8 g/kg/d of an olive/soybean lipid emulsion, randomized 1:1 to receive the same olive/soybean emulsion or 100% fish oil at a dose of 0.4 g/kg/d for 7 d. Plasma phytosterols and their fractions, rs41360247 and rs4245791 of ABCG8 genes, and LFT were determined. Analyses of variance were performed to determine the association between the SNPs and LFT values, as well as total phytosterol values and their fractions. Simple linear regressions were performed to analyze LFT variations and the different interactions of the SNPs studied with phytosterols and their fractions. Interactions of the synergic variable plasma phytosterol and its fractions with SNPs allow us to study the interaction of the SNPs with phytosterols with a regression. RESULTS: We included 19 participants. In the multivariate model, total phytosterols, sitosterol, and lanosterol were positively associated with increases in γ-glutamyltransferase. Significant increases with stigmasterol were associated with the T allele of rs41360247, whereas campesterol showed only a tendency to increase that was not significant. Increases in alkaline phosphatase were associated with T-rs41360247 independent of the presence of phytosterols. With stigmasterol, C-allele carriers of rs4245791 showed a tendency to increase, and also for sitosterol and lanosterol, although independent of the SNP analyzed. Increases in alanine aminotransferase were positively associated with total phytosterol and sitostanol, whereas lanosterol and stigmasterol were associated with the presence of the T allele of rs41360247. CONCLUSIONS: With both SNPs rs41360247 and rs4245791, the alteration in parameters of liver function in adult patients with short-term parenteral nutrition is conditional.

Manejo de la estenosis mitral durante el embarazo / Management of mitral stenosis during pregnancy

Las cardiopatías complican alrededor del 4 por ciento de los embarazos; y representan la principal causa no obstétrica de muerte materna. Las lesiones valvulares tienen una alta prevalencia, siendo la estenosis mitral la de peor pronóstico durante el embarazo. El presente artículo tiene como objetivo exponer las recomendaciones del Servicio Nacional de Cardiopatía y Embarazo para el manejo de la estenosis mitral durante la gestación. Resulta crucial la evaluación de la anatomía valvular y la severidad de la enfermedad. Lesiones moderadas a severas deben ser tratadas con betabloqueadores cardioselectivos y comisurotomía percutánea electiva, si la anatomía es favorable. Si hay retención de volumen están indicados los diuréticos. Entre las drogas de uso obstétrico están contraindicadas las prostaglandinas, el nifedipino y el fenoterol. El momento de terminación del embarazo depende de la edad gestacional y de la aparición de signos de descompensación materna o fetal, en cuyo caso tienen indicación de cesárea(AU)

Heart disease complicates about 4 percent of pregnancies; and represent the leading non-obstetric cause of maternal death. Valvular lesions have a high prevalence, being mitral stenosis the one with the worst prognosis during pregnancy. This article aims to present the recommendations of the National Heart Disease and Pregnancy Service for the management of mitral stenosis during pregnancy. Evaluation of valve anatomy and disease severity is crucial. Moderate to severe injuries should be treated with cardioselective beta-blockers and elective percutaneous commissurotomy, if the anatomy is favorable. If there is volume retention, diuretics are indicated. Among the drugs for obstetric use, prostaglandins, nifedipine and fenoterol are contraindicated. The time of termination of pregnancy depends on the gestational age and the appearance of signs of maternal or fetal decompensation, in which case they have an indication for cesarean section(AU)