Emerging drugs for the treatment of atopic dermatitis: a focus on phase 2 and phase 3 trials.

INTRODUCTION: Atopic dermatitis (AD) is an inflammatory skin condition that affects millions of pediatric and adult patients with well-studied impact on morbidity and quality of life. Management occurs in a stepwise fashion beginning with preventative measures before immunomodulators are introduced. However, challenges remain in treatment of moderate-to-severe atopic dermatitis that is refractory to first- and second-line treatments and there are only few topical anti-inflammatory options, especially for pediatric patients. AREAS COVERED: New medications are required to address these gaps as lesions may persist despite treatment or patients may discontinue treatment due to actual or anticipated adverse effects of mainstay medications. Emerging research into the pathophysiology of AD and the immune system at large has provided opportunities for novel interventions aimed at stopping AD mechanisms at new checkpoints. Clinical trials for 36 agents currently in phase 2 or phase 3 are evaluated with particular focus on the studies for, B244, CBP-201, tapinarof, lebrikizumab, nemolizumab, amlitelimab, and rocatinlimab as they explore novel pathways and have some of the most promising results. EXPERT OPINION: These clinical trials contribute to the evolution of AD treatment toward greater precision based on salient pathways with a particular focus on moderate-to-severe AD to enhance efficacy and minimize adverse effects.

Mental Health Disparities among Pre-Clinical Medical Students at Saint Louis University during the COVID-19 Pandemic.

The COVID-19 pandemic disproportionately affected racial and ethnic minorities. Medical students were also particularly impacted as they coped with increased stressors due to delayed medical training and a high prevalence of mental health conditions. This study investigates mental health disparities of underrepresented in medicine (URM) students at the Saint Louis University School of Medicine (SLUSOM). An anonymous online survey was distributed to first- and second-year medical students at SLUSOM in February 2021. The survey queried demographic information, lifestyle factors, and pandemic-related and institutional concerns. Mental health was assessed via the Generalized Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). Statistical tests were run with SPSS, version 27. A convenience sample of 87 students responded to the survey. Students who were categorized as URM were significantly more likely to be at risk of major depressive disorder during the pandemic. Concern about a lack of financial support was significantly greater among students categorized as URM. Concerns regarding a lack of financial support, mental health support, and decreased quality of medical training significantly predicted PHQ-9 scores. Our findings revealed several key factors that may exacerbate mental health disparities among URM students during the pandemic. Providing adequate financial and academic resources for URMs may improve mental health outcomes for similar adverse events in the future.

Patients' and Caregivers' Preferences for Mental Health Care and Support in Atopic Dermatitis.

Background: Atopic dermatitis (AD) has large mental health impacts for patients and caregivers, yet their preferences regarding how to relieve these impacts are poorly understood. Objective: To understand patients' and caregivers' preferences for AD-related mental health care and support. Methods: We surveyed 279 adult AD patients and 154 caregivers of children with AD across 26 countries regarding their AD-related mental health burden, preferred strategies for improving AD-related mental health, and experiences with mental health care in AD. Results: Caregivers reported significantly worse overall mental health (P = 0.01) and anxiety (P = 0.03) than adult patients when controlling for AD severity. Among adult patients, 58% selected treating the AD, 51% managing itch, 44% wearing clothing to cover up skin, 43% avoiding social situations, and 41% spending time alone, as strategies they felt would improve their own AD-related mental health. Caregivers selected managing itch and treating the AD most frequently for both their own (76% and 75%, respectively) and their children's (75% and 61%) mental health. Adult patients were less satisfied with mental health care from mental health providers versus nonmental health providers (P < 0.001). Conclusions: Effective AD management is the preferred method for improving mental health among patients as well as caregivers, who may experience the greatest mental health impacts. Self-care strategies should be considered in a shared decision-making approach.

Fruitful or unfruitful: strawberry and tomato specific immunoglobulin E testing at a tertiary pediatric center.

Background: Suspected strawberry and tomato (S/T) food allergy (FA) can be evaluated using specific immunoglobulin E (sIgE) testing despite its low specificity and positive predictive value. Objective: This study aims to understand ordering patterns for S/T sIgE testing and identify relevant factors to clinical decision-making. Methods: We retrospectively reviewed 814 patients with sIgE testing available for strawberries (651), tomatoes (276), or both (113) from January 2012 to May 2022 at a tertiary pediatric hospital. Patient demographics, provider specialty, and reasons for testing were collected. Student's t-test and multiple regression analyses were performed to test the association between the S/T sIgE level and clinically relevant outcome (CRO) status. Fisher's exact test and general linear models were used to evaluate and compare potential predictive factors for CRO status. Results: Allergy and immunology, gastroenterology, and general pediatrics ordered most S/T sIgE testing. Testing was ordered most frequently for non-IgE-mediated gastrointestinal symptoms, mild possible IgE-mediated reactions, and eczema. Testing was most often ordered for infants and school-age children. Mean sIgE levels were higher for S/T tests resulting in a CRO when controlling for other predictor variables (p = 0.015; p = 0.002 for S/T, respectively). Only 2.2% and 5.4% of tests resulted in a CRO for S/T, and severe allergy was rare. Testing for non-IgE-mediated GI symptoms or eczema, or in non-atopic patients, yielded no CROs. Exposure and reaction history of present illness (ERH) was associated with CROs (p < 0.001; p = 0.04) with a high negative predictive value (99.5%; 100%) and low positive predictive value (11.5%; 15.0%). ERH (p < 0.001, η2 = 0.073; p = 0.009, η2 = 0.123) was a more significant predictor than the sIgE level (p = 0.002, η2 = 0.037; p = 0.212, η2 = 0.030) for CRO status. Conclusion: The diagnosis of S/T food allergy is made primarily based on clinical history. S/T sIgE testing for children and adolescents should be avoided for patients without an ERH and in the workup of non-IgE-mediated GI symptoms. Testing for eczema and non-atopic patients is likely low-yield.

Provision of Food Allergy Care in the United Kingdom and United States: Current Issues and Future Directions.

Food allergy (FA) is a growing issue worldwide. The United Kingdom and United States are high-income, industrialized countries with reported increases in FA prevalence over the past few decades. This review compares delivery of FA care in the United Kingdom and United States and each country's response to the heightened demand and disparities for FA services. In the United Kingdom, allergy specialists are scarce and general practitioners (GPs) provide most allergy care. Whereas the United States has more allergists per capita than the United Kingdom, there is still a shortage of allergy services owing to the greater reliance on specialist care for FA in America and wide geographic variation in access to allergist services. Currently, generalists in these countries lack the specialty training and equipment to diagnose and manage FA optimally. Moving forward, the United Kingdom aims to enhance training for GPs so they may provide better quality frontline allergy care. In addition, the United Kingdom is implementing a new tier of semi-specialized GPs and increasing cross-center collaboration through clinical networks. The United Kingdom and United States aim to increase the number of FA specialists, which is critical at a time of rapidly expanding management options for allergic and immunologic diseases requiring clinical expertise and shared decision-making to select appropriate therapies. While these countries aim to grow their supply of quality FA services actively, further efforts to build clinical networks and perhaps recruit international medical graduates and expand telehealth services are necessary to reduce disparities in access to care. For the United Kingdom in particular, increasing quality services will require additional support from the leadership of the centralized National Health Service, which remains challenging.

A novel pulsatile blood pump design for cardiothoracic surgery: Proof-of-concept in a mock circulation.

BACKGROUND: Pulsatile perfusion during extracorporeal circulation is a promising concept to improve perfusion of critical organs. Clinical benefits are limited by the amount of pulsatile energy provided by standard pumps. The present study investigated the properties of a novel positive displacement blood pump in a mock circulation. METHODS: The pump was attached to an aortic model with a human-like geometry and compliance as a pseudo patient. Hemodynamic data were recorded while the pump settings were adjusted systematically. RESULTS: Using a regular oxygenator, maximum flow was 2.6 L/min at a pressure of 27 mm Hg and a frequency (F) of 90 bpm. Pulse pressure (PP; 28.9 mm Hg) and surplus hemodynamic energy (SHE; 26.1% of mean arterial pressure) were highest at F = 40 bpm. Flow and pressure profiles appeared sinusoid. Using a low-resistance membrane ventilator to assess the impact of back pressure, maximum flow was 4.0 L/min at a pressure of 58.6 mm Hg and F = 40 bpm. At F = 40 bpm, PP was 58.7 mm Hg with an SHE of 33.4%. SHE decreased with increasing flow, heart rate, and systolic percentage but surpassed 10% with reasonable settings. CONCLUSIONS: The present prototype achieved sufficient flow and pressure ranges only in the presence of a low-resistance membrane ventilator. It delivered supraphysiologic levels of pulse pressure and SHE. Further modifications are planned to establish this concept for adult pulsatile perfusion.

Genetic/Environmental Contributions and Immune Dysregulation in Children with Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common skin conditions in humans. AD affects up to 20% of children worldwide and results in morbidity for both patients and their caregivers. The basis of AD is an interplay between genetics and the environment characterized by immune dysregulation. A myriad of mutations that compromise the skin barrier and/or immune function have been linked to AD. Of these, filaggrin gene (FLG) mutations are the most evidenced. Many other mutations have been implicated in isolated studies that are often unreplicated, creating an archive of genes with potential but unconfirmed relevance to AD. Harnessing big data, polygenic risk scores (PRSs) and genome-wide association studies (GWAS) may provide a more practical strategy for identifying the genetic signatures of AD. Epigenetics may also play a role. Staphylococcus aureus is the most evidenced microbial contributor to AD. Cutaneous dysbiosis may result in over-colonization by pathogenic strains and aberrant skin immunity and inflammation. Aeroallergens, air pollution, and climate are other key environmental contributors to AD. The right climate and/or commensals may improve AD for some patients.

Algorithm-based approach to focal liver lesions in contrast-enhanced ultrasound.

Focal liver lesions are commonly encountered. Grey-scale and Doppler sonographic characteristics of focal liver lesions are often non-specific and insufficient to conclusively characterise lesions as benign or malignant. Contrast-enhanced ultrasound is useful for the characterisation of FLLs in patients who are unable to undergo contrast-enhanced computed tomography or magnetic resonance imaging. It is also easily available and relatively cheap. However, interpretation of contrast-enhanced ultrasound can be challenging without a systematic approach. In this pictorial essay, we highlight an algorithm-based approach to FLLs and discuss the characteristic contrast-enhanced ultrasound features of commonly encountered and clinically significant focal liver lesions.

Outcomes of patent ductus arteriosus ligation in very low birth weight premature infants: A retrospective cohort analysis.

INTRODUCTION: Patent ductus arteriosus (PDA) can be a significant hemodynamic problem in preterm infants leading to increased morbidity and mortality. PDA ligation is therefore considered an urgent procedure in infants who have failed medical therapy. However, there is controversy regarding optimal timing and decision to operate. This study aimed to evaluate the outcomes and efficacy of PDA ligation in very low birth weight premature infants. METHODS: We performed a retrospective review of our institution's database and included very low birth weight premature infants (<1500 g) who underwent PDA ligation from 2008 to 2019 among 6 centers within the Southern California Kaiser Permanente network system. Indications for PDA ligation were variable but included congestive heart failure, respiratory failure, necrotizing enterocolitis, renal failure, and contraindications to medical therapy. PDA ligations were performed via thoracotomy incisions with ligations using a clip or tie. The primary outcome measure was mortality, and secondary outcomes included various postoperative morbidities. RESULTS: A total of 449 patients met criteria and were included in the study. The mean birth weight was 735 g (125 g-1460 g), and mean gestational age was 25 weeks (21-36 weeks). The mean operating room time was 28 min (9-84 min). 97% of PDAs were clipped, and 3% were tied. Comorbidities at the time of operation included bronchopulmonary dysplasia (59%), retinopathy of prematurity (39%), intraventricular hemorrhage (28%), and necrotizing enterocolitis (10%). There were 2 (0.4%) operative deaths, 15 (3%) deaths within 30 days, and 20 (4%) deaths within 1 year. Other postoperative outcomes included recurrent laryngeal nerve injury (1%), chylothorax (1%), pneumothorax (0.4%), and 3 (0.6%) reoperations. DISCUSSION: Very low birthweight premature infants with hemodynamically and clinically significant PDA are complicated patients. The risks of surgical ligation must be weighed against the potential clinical benefits. The mortality rate in our patient group within our hospital system is lower than those reported in the literature. Surgical ligation appears to be a safe and acceptable option for treatment of this complex problem, especially when medical therapy fails. Further studies are needed to elucidate specific independent risk factors that are associated with morbidity and mortality to further improve outcomes. LEVEL OF EVIDENCE RATING: Level II TYPE OF STUDY: Prognosis study.

Aeroallergens in Atopic Dermatitis and Chronic Urticaria.

PURPOSE OF REVIEW: While aeroallergens are a well-established trigger of asthma and allergic rhinitis, their role in allergic skin diseases such as atopic dermatitis and chronic urticaria remains controversial. This paper reviews the pathophysiology and clinical evidence for aeroallergens in these allergic skin diseases and summarizes current strategies for evaluation and management. RECENT FINDINGS: Current evidence implicates aeroallergens as triggers of cutaneous reactions in atopic dermatitis. Direct skin contact is the likely route of trigger. Aeroallergens may also trigger chronic urticaria, though mechanistic studies are limited. These allergens may cross the skin barrier and directly trigger neurons to release substance P, resulting in mast cell degranulation and dumping of histamine and prostaglandin D2. Many studies link aeroallergen sensitization to chronic urticaria, and case reports suggest the utility of avoidance strategies. The role of aeroallergens as a trigger is clear in atopic dermatitis and becoming emergent in chronic urticaria. Skin prick testing or serum-specific immunoglobulin E testing may be used to determine sensitivities. Management at this time centers on avoidance, and further studies are necessary to evaluate the efficacy of aeroallergen immunotherapy for both conditions.

Medical student anxiety and depression in the COVID-19 Era: Unique needs of underrepresented students.

Background: The COVID-19 pandemic has caused significant morbidity, mortality, and mental health consequences. Few studies have examined the mental toll of COVID-19 on United States (US) medical students, who experience greater rates of depression and anxiety than the general population. Students who identify as underrepresented in medicine (URM) may experience even greater mental health adversities than non-URM peers. This study examines COVID-19's impact on preclinical medical student anxiety and depression and unique challenges disproportionately affecting URM students during the initial phase of the pandemic. Methods: Medical students at four US institutions completed an anonymous survey including the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) questionnaires for depression and anxiety. Participants provided information on demographics, past mental health difficulties, and concerns during the pandemic. Chi-square and Mann-Whitney U tests were performed using SPSS. Results: During the initial phase of the pandemic, URMs were 3.71 times more likely to be in the at-risk category on GAD-7 than non-URM peers. Before COVID-19, there was no significant difference between self-reported feelings or diagnoses of anxiety between groups. During the COVID-19 pandemic, there were significant differences in feelings of increased anxiety between URM (Mdn = 76) and non-URM (Mdn = 49) students, U = 702.5, P < 0.001, feelings of increased sadness between URM (Mdn = 49) and non-URM (Mdn = 34) students, U = 1036.5, P = 0.042, concern for new financial difficulty between URM (Mdn = 50) and non-URM students (Mdn = 7), U = 950.5, P = 0.012, and concern about lack of mental health support from their academic institution between URM (Mdn = 18) and non-URM students (Mdn = 9), U = 1083, P = 0.036 (one-tailed). Discussion: Large-scale crises such as COVID-19 may exacerbate mental health disparities between URM and non-URM students. Medical schools should consider increasing financial and mental health support for URM students in response to these significant adverse events.

Hemodynamic Comparison of Stent-Grafts for the Treatment of Aortoiliac Occlusive Disease.

PURPOSE: To compare the flow patterns and hemodynamics of the AFX stent-graft and the covered endovascular reconstruction of aortic bifurcation (CERAB) configuration using laser particle image velocimetry (PIV) experiments. MATERIALS AND METHODS: Two anatomically realistic aortoiliac phantoms were constructed using polydimethylsiloxane polymer. An AFX stent-graft with a transparent cover made with a new method was inserted into one phantom. A CERAB configuration using Atrium's Avanta V12 with transparent covers made with a previously established method was inserted into the other phantom, both modified stent-grafts were suitable for laser PIV, enabling visualization of the flow fields and quantification of time average wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). RESULTS: Disturbed flow was observed at the bifurcation region of the AFX, especially at the end systolic velocity (ESV) time-point where recirculation was noticeable due to vortical flow. In contrast, predominantly unidirectional flow was observed at the CERAB bifurcation. These observations were confirmed by the quantified hemodynamic results from PIV analysis where mean TAWSS of 0.078 Pa (range: 0.009-0.242 Pa) was significantly lower in AFX as compared with 0.229 Pa (range: 0.013-0.906 Pa) for CERAB (p<0.001). Mean OSI of 0.318 (range: 0.123-0.496) in AFX was significantly higher than 0.252 (range: 0.055-0.472) in CERAB (p<0.001). Likewise, mean RRT of 180 Pa-1 (range: 9-3603 Pa-1) in AFX was also significantly higher than 88 Pa-1 (range: 2-840 Pa-1) in CERAB (p=0.0086). CONCLUSION: In this in vitro study, the flow pattern of a modified AFX stent-graft was found to be more disturbed especially at the end systolic phase, its hemodynamic outcomes less desirable than CERAB configuration. CLINICAL RELEVANCE: While the AFX stent-graft has an advantage over the CERAB configuration in eliminating radial mismatch, and maintaining the anatomical bifurcation for future endovascular intervention, this in vitro study revealed that the associated lower TAWSS, higher OSI and RRT may predispose to thrombosis and are, thus, less desirable as compared to a CERAB configuration. Further investigation is warranted to confirm whether these findings translate into the clinical setting.

Pediatric Surgeons' Adoption of an Innovative Laparoscopic Technique for Inguinal Hernia Repair: A Mixed Methods Study.

Purpose: We studied adoption of an innovative laparoscopic technique for pediatric inguinal hernia repair by pediatric surgeons and pediatric urologists following dissemination of evidence for its benefits. Methods: This mixed methods study included children who received inguinal hernia repairs during 2017-2019 and their surgeons. We examined surgeons' adoption and use of the innovative technique and rates of ipsilateral recurrence and metachronous contralateral repair. In-depth interviews with surgeons were used to identify themes regarding attitudes and practices regarding the adoption of surgical innovations. Results: No ipsilateral recurrences were noted among open repairs after 1.5 years of average follow-up, while 1.54% (7/453) of unilateral and 0.50% (3/606 sides) of bilateral innovative surgeries required ipsilateral repair after 1.3 years of average follow-up. Among unilateral cases, metachronous contralateral repairs were performed in 1.63% (8/490) of open and 0.44% (2/453) of innovative surgeries. Surgeon interviews identified approaches to continued learning and change; the role of departmental culture, norms, and resources; and technical issues specific to pediatric surgery and pediatric inguinal hernia repair. Conclusions: Outcomes may have improved over time as a consequence of learning. Differences among surgeons and departments influenced the speed of adoption. Surgeons linked the collegial model used when adopting the new technique to the apprenticeship model used during their training. We propose research into the collegial model to improve translation of evidence-based surgical innovations into practice. Level of Evidence: Level III.

Seronegative autoimmune enteropathy with duodenal sparing and colonic clues in an adult female.

Autoimmune enteropathy (AIE) is a rare immune disorder of the gut seldom found in adults and characterized by uncontrollable diarrhea resulting in malabsorption. While AIE is known to be pan-enteric, virtually all cases have presented with altered duodenal histology following known patterns with or without macroscopic change. We describe a unique case of seronegative AIE lacking typical duodenal manifestations in a 43-year-old female. To our knowledge, this is the first report of AIE lacking usual duodenal histologic changes, which resulted in missed diagnosis for years. Ultimately, crypt epithelial apoptosis, mononuclear inflammation of the lamina propria, and goblet cell loss of intestinal mucosa besides the duodenum clinched the diagnosis of AIE. Colonic histologic abnormalities consistent with AIE in the setting of diarrhea with malnutrition despite duodenal sparing should prompt suspicion for AIE given the pan-enteric nature of this disease.

Reliability of a close-range photogrammetry technique to measure ankle kinematics during active range of motion in place.

BACKGROUND: As the risk of ankle turn during daily activity is very high, studying ankle kinematics in place is important for ankle sprain prevention. The close-range photogrammetry (CRP) technique is used to measure ankle kinematics during active range of motion (AROM) in place. The purpose of the study was to assess the reliability of CRP to measure ankle kinematics. METHODS: Twenty adults were recruited and fourteen retro-reflective targets were mounted on the skin of their right feet. Imaging sensors were self-calibrated using a bundle adjustment technique, and the images were downloaded with Australis photogrammetric software. Three trials were conducted and reliability coefficients were used to assess agreement between them. RESULTS: Reliability was almost perfect and the results show that the intraclass correlation coefficient (ICC) of ankle angle values were (dorsiflexion = 0.96), (plantarflexion = 0.81), (inversion = 0.92), (eversion = 0.95), (internal rotation = 0.92), and (external rotation = 0.78). The overall intraclass correlation coefficient was 0.89 and the standard error of the measurement (SEM) values ranged from (0.37° to 6.18°). CONCLUSIONS: The results indicate that the CRP technique was able to reliably measure ankle kinematics. The results may support and enhance knowledge related to ankle AROM in the clinical arena.

A novel roller pump for physiological flow.

Having physiological correct flow waveforms is a key feature for experimental studies of blood flow, especially in the process of developing and testing a new medical device such as stent, mechanical heart valve, or any implantable medical device that involves circulation of blood through the device. It is also a critical part of a perfusion system for cardiopulmonary bypass and extracorporeal membrane oxygenation procedures. This study investigated the feasibility of a novel roller pump for use in experimental flow phantoms. Flow rates of carotid flow profile measured directly with the ultrasonic flow meter matched well with the reference flow rates programmed into the machine with similarity index of 0.97 and measured versus programmed flow rates at specific time-points of peak systolic velocity (PSV): 0.894 vs 0.880, end systolic velocity (ESV): 0.333 vs 0.319, and peak diastolic velocity (PDV): 0.514 vs 0.520 L/min. Flow rates derived from video analysis of the pump motion for carotid, suprarenal, and infrarenal flows also matched well with references with similarity indices of 0.99, 0.99, and 0.96, respectively. Measured flow rates (mean/standard deviation) at PSV, ESV, and PDV time-points for carotid: 0.883/0.016 vs 0.880, 0.342/0.007 vs 0.319, and 0.485/0.009 vs 0.520; suprarenal: 3.497/0.014 vs 3.500, 0.004/0.003 vs 0, and 1.656/0.073 vs 1.453; infrarenal: 4.179/0.024 vs 4.250, -1.147/0.015 vs -1.213, and 0.339/0.017 vs 0.391 L/min, respectively. The novel roller pump is suitable for benchtop testing of physiological flow.