Shared decision-making in psoriasis care: Evaluation of how patients' perception of clinicians' delivery of care changes by age and sex.

BACKGROUND: Shared decision-making (SDM) refers to a collaborative process in which clinicians assist patients in making medically informed, evidence-based decisions that align with their values and preferences. There is a paucity of literature on SDM in dermatology. OBJECTIVE: We aim to assess whether male and female psoriasis patients evaluate their clinicians' engagement in SDM differently across different age groups. METHODS: Cross-sectional study using data from the 2014-2017 and 2019 Medical Expenditure Panel Surveys (MEPS). RESULTS: A weighted total of 7,795,608 psoriasis patients were identified. SDM Scores ranged from 1 to 4, with 4 representing the most favorable patient evaluation of their clinicians' engagement in SDM. We conducted multivariate linear regression to compare mean SDM Scores in male psoriasis patients versus female psoriasis patients across different patient age groups. Female patients ages 60-69 perceived significantly greater clinician engagement in SDM compared to age-matched male patients (female patient perception of SDM 3.65 [95%CI:3.61-3.69] vs. male patient perception of SDM 3.50 [95%CI:3.43-3.58], p<0.005). The same trend of older female patients evaluating their clinicians' engagement in SDM significantly higher than their age-matched male counterparts exists for the age group >70 (p<0.005). No significant differences between male and female patients' evaluations of their clinicians' engagement in SDM were demonstrated in subjects younger than 60. All calculations were adjusted for demographic and clinical factors. CONCLUSIONS: Compared to older male psoriasis patients, older female psoriasis patients evaluated their clinicians to be more engaged in shared decision-making.

An OX-Tra'Ordinary Tale: The Role of OX40 and OX40L in Atopic Dermatitis.

The transmembrane glycoprotein OX40 receptor (OX40) and its ligand, OX40L, are instrumental modulators of the adaptive immune response in humans. OX40 functions as a costimulatory molecule that promotes T cell activation, differentiation, and survival through ligation with OX40L. T cells play an integral role in the pathogenesis of several inflammatory skin conditions, including atopic dermatitis (AD). In particular, T helper 2 (TH2) cells strongly contribute to AD pathogenesis via the production of cytokines associated with type 2 inflammation (e.g., IL-4, IL-5, IL-13, and IL-31) that lead to skin barrier dysfunction and pruritus. The OX40-OX40L interaction also promotes the activation and proliferation of other T helper cell populations (e.g., TH1, TH22, and TH17), and AD patients have demonstrated higher levels of OX40 expression on peripheral blood mononuclear cells than healthy controls. As such, the OX40-OX40L pathway is a potential target for AD treatment. Novel therapies targeting the OX40 pathway are currently in development, several of which have demonstrated promising safety and efficacy results in patients with moderate-to-severe AD. Herein, we review the function of OX40 and the OX40-OX40L signaling pathway, their role in AD pathogenesis, and emerging therapies targeting OX40-OX40L that may offer insights into the future of AD management.

Predictors of Unplanned Reoperation after Gender-affirming Mastectomy: An Analysis of the NSQIP Database.

Background: Gender-affirming mastectomy (GAM) is a gender-affirmation surgery designed to remove or reduce breast tissue, with or without nipple reconstruction. GAM is the most commonly performed gender-affirmation surgery and risk factors associated with unplanned return to the operating room and reoperation continue to be investigated. This is the largest study of transgender and nonbinary patients undergoing GAM to determine predictors of unplanned reoperation. Methods: The National Surgical Quality Improvement Program database was queried for patients undergoing GAM from 2012 to 2020. The primary outcome was the incidence of unplanned reoperation within 30 days postoperatively. The secondary outcome was the indication for unplanned reoperation within this period. Descriptive statistics were calculated. Bivariate analysis and multivariate logistic regression were performed to determine significant predictors of reoperation after GAM. Results: A total of 2316 patients underwent GAM, of whom 2.2% (n = 51) underwent unplanned reoperation of the chest. The most common indication for unplanned reoperation was hematoma (n = 41, 71.9%) followed by abscess (n = 5, 8.8%). Significant predictors of reoperation were corticosteroid use [adjusted odds ratio (aOR) 95% confidence interval (CI) 5.07 (1.07-23.89)] and diabetes [aOR (CI) 10.98 (3.0-40.33)]. Hispanic/Latinx ethnicity [aOR (CI) 3.19 (1.22-8.33)] and corticosteroid use [aOR (CI) 6.81 (1.45-31.98)] were significant predictors of unplanned reoperation for hematoma evacuation after GAM. Conclusions: Diabetes mellitus and corticosteroid use were associated with unplanned reoperation after GAM. Ethnic correlations remain to be better elucidated as well as the effect of intersectionality. These findings can be used to guide patient selection and surgical decision-making.

Management of tinea capitis in infants and children in the United States: A national survey of pediatric dermatologists.

This study aimed to evaluate the current management of tinea capitis in the United States, specifically focusing on patients aged 0-2 months, 2 months to 2 years, and 2 years to 18 years. An online survey, distributed through the Pediatric Dermatology Research Alliance and the Society of Pediatric Dermatology, revealed the following preferences: fluconazole for those under 2 months, griseofulvin for those aged 2 months to 2 years, and terbinafine for those aged 2 years and older. There exists inter-provider variation in tinea capitis treatment regimens within the pediatric dermatology community.

The impact of current investigational drugs for acne on future treatment strategies.

INTRODUCTION: Acne vulgaris is one of the most prevalent diseases worldwide with a considerably high cost and a burden on quality of life. There are currently many topical and systemic therapies for acne; however, many are limited by their local adverse event profile. This review provides an update on current, novel Phase I and II trials for acne vulgaris. AREAS COVERED: This review searched the National Institutes of Health US National Library of Medicine online database of clinical trials (ClinicalTrials.gov) for ongoing Phase I and II trials. Only papers discussing novel therapies were discussed, and combinations of previously FDA-approved drugs were excluded. EXPERT OPINION: The current investigational approaches to acne treatment reflect an attempt to mitigate the underlying cause of acne pathogenesis. By targeting key mechanisms involved, studies aim to show long-term improvement with less frequent treatment use. This provides potential for more tolerable treatments with better patient adherence, in turn leading to increased efficacy.

Ocular manifestations in a cohort of 43 patients with KBG syndrome.

Ophthalmological conditions are underreported in patients with KBG syndrome, which is classically described as presenting with dental, developmental, intellectual, skeletal, and craniofacial abnormalities. This study analyzed the prevalence of four ophthalmological conditions (strabismus, astigmatism, myopia, hyperopia) in 43 patients with KBG syndrome carrying variants in ANKRD11 or deletions in 16q24.3 and compared it to the literature. Forty-three patients were recruited via self-referral or a private Facebook group hosted by the KBG Foundation, with 40 of them having pathogenic or likely pathogenic variants. Virtual interviews were conducted to collect a comprehensive medical history verified by medical records. From these records, data analysis was performed to calculate the prevalence of ophthalmological conditions. Out of the 40 participants with pathogenic or likely pathogenic variants, strabismus was reported in 9 (22.5%) participants, while astigmatism, myopia, and hyperopia were reported in 11 (27.5%), 6 (15.0%), and 8 (20.0%) participants, respectively. Other reported conditions include anisometropia, amblyopia, and nystagmus. When compared to the literature, the prevalence of strabismus and refractive errors is higher than other studies. However, more research is needed to determine if variants in ANKRD11 play a role in abnormal development of the visual system. In patients with established KBG syndrome, screening for misalignment or refractive errors should be done, as interventions in patients with these conditions can improve functioning and quality of life.

Survey of Pediatric Critical Care Fellows on Postresuscitation Debriefing.

Purpose: Current guidelines recommend debriefing following medical resuscitations to improve patient outcomes. The goal of this study was to describe national trends in postresuscitation debriefing practices among pediatric critical care medicine (PCCM) fellows to identify potential gaps in fellow education. Methods: A 13-item survey was distributed to fellows in all 76 ACGME-accredited PCCM programs in the United States in the spring of 2021. The online survey addressed frequency and timing of debriefings following medical resuscitations, whether formal training is provided, which medical professionals are present, and providers' comfort level leading a debriefing. Results were analyzed using descriptive statistics. Results: A total of 102 responses (out of a possible N of 536) were gathered from current PCCM fellows. All fellows (100%) reported participation in a medical resuscitation. Only 21% stated that debriefings occurred after every resuscitation event, and 44% did not follow a structured protocol for debriefing. While 66% reported feeling very or somewhat comfortable leading the debriefing, 19% felt either somewhat uncomfortable or very uncomfortable. A vast majority (92%) of participating fellows believed that debriefing would be helpful in improving team member performance during future resuscitations, and 92% expressed interest in learning more about debriefing. Conclusions: The majority of PCCM fellows do not receive formal training on how to lead a debriefing. Given that 74% of fellows in our study did not feel very comfortable leading a debriefing but almost universally expressed that this practice is useful for provider well-being and performance, there is a clear need for increased incorporation of debriefing training into PCCM curricula across the United States.

Soluble CX3CL1-expressing retinal pigment epithelium cells protect rod photoreceptors in a mouse model of retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is an inherited retinal disease that results in photoreceptor degeneration, leading to severe vision loss or blindness. Due to its genetic heterogeneity, developing a new gene therapy to correct every genetic mutation contributing to its progression is infeasible. Photoreceptor transplantation can be harnessed to restore vision; however, this approach is limited by poor cell survival and synaptic integration into the neural retina. Thus, we developed a combined cell and gene therapy that is expected to protect photoreceptors in most, if not all, cases of RP. METHODS: Human embryonic stem cells (hESCs) modified with our FailSafe™ system were genetically engineered to overexpress sCX3CL1, an inhibitor of microglia activation that has been shown to preserve photoreceptor survival and function in mouse models of RP, independent of the genetic cause. These cells were differentiated into human retinal pigment epithelium (hRPE) cells and used as therapeutic cells due to their longevity and safety, both of which have been demonstrated in preclinical and clinical studies. Transgenic hRPE were delivered into the subretinal space of immunodeficient mice and the rd10 mouse model of RP to evaluate donor cell survival and retention of transgene expression. The outer nuclear layer was quantified to assess photoreceptor protection. RESULTS: Transgenic FailSafe™ hRPE (FS-hRPE) cells can survive for at least four months in the retina of immunodeficient mice and retain transgene expression. However, these cells do not persist beyond two weeks post-injection in the retina of immunocompetent rd10 recipients, despite Cyclosporine A treatment. Nevertheless, sCX3CL1-expressing FailSafe™ hRPE cells prevented photoreceptor degeneration in a local acting manner during the duration of their presence in the subretinal space. CONCLUSIONS: Transgenic hESCs differentiate into hRPE cells and retain sCX3CL1 transgene expression both in vitro and in vivo. Moreover, hRPE cells delivered to the subretinal space of rd10 mice prevented photoreceptor degeneration in a local-acting manner, suggesting that this approach could have applications for preserving photoreceptors in specific subregions of the retina, such as the macula. Overall, our study not only reveals the potential of a combined cell and gene therapy for the treatment of RP, but also the possibility of using hRPE cells to deliver therapeutic biologics in situ to treat diseases over long-term.

Kinetic analysis of RNA cleavage by coronavirus Nsp15 endonuclease: Evidence for acid-base catalysis and substrate-dependent metal ion activation.

Understanding the functional properties of severe acute respiratory syndrome coronavirus 2 nonstructural proteins is essential for defining their roles in the viral life cycle, developing improved therapeutics and diagnostics, and countering future variants. Coronavirus nonstructural protein Nsp15 is a hexameric U-specific endonuclease whose functions, substrate specificity, mechanism, and dynamics are not fully defined. Previous studies report that Nsp15 requires Mn2+ ions for optimal activity; however, the effects of divalent ions on Nsp15 reaction kinetics have not been investigated in detail. Here, we analyzed the single- and multiple-turnover kinetics for model ssRNA substrates. Our data confirm that divalent ions are dispensable for catalysis and show that Mn2+ activates Nsp15 cleavage of two different ssRNA oligonucleotide substrates but not a dinucleotide. Biphasic kinetics of ssRNA substrates demonstrates that Mn2+ stabilizes alternative enzyme states that have faster substrate cleavage on the enzyme. However, we did not detect Mn2+-induced conformational changes using CD and fluorescence spectroscopy. The pH-rate profiles in the presence and absence of Mn2+ reveal active-site ionizable groups with similar pKas of ca. 4.8 to 5.2. An Rp stereoisomer phosphorothioate modification at the scissile phosphate had minimal effect on catalysis supporting a mechanism involving an anionic transition state. However, the Sp stereoisomer is inactive because of weak binding, consistent with models that position the nonbridging phosphoryl oxygen deep in the active site. Together, these data demonstrate that Nsp15 employs a conventional acid-base catalytic mechanism passing through an anionic transition state, and that divalent ion activation is substrate dependent.

Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome.

Ankyrin Repeat Domain 11 (ANKRD11) gene mutations are associated with KBG syndrome, a developmental disability that affects multiple organ systems. The function of ANKRD11 in human growth and development is not clear, but gene knockout or mutation are lethal in mice embryos and/or pups. In addition, it plays a vital role in chromatin regulation and transcription. Individuals with KBG syndrome are often misdiagnosed or remain undiagnosed until later in life. This is largely due to KBG syndrome's varying and nonspecific phenotypes as well as a lack of accessible genetic testing and prenatal screening. This study documents perinatal outcomes for individuals with KBG syndrome. We obtained data from 42 individuals through videoconferences, medical records, and emails. 45.2% of our cohort was born by C-section, 33.3% had a congenital heart defect, 23.8% were born prematurely, 23.8% were admitted to the NICU, 14.3% were small for gestational age, and 14.3% of the families had a history of miscarriage. These rates were higher in our cohort compared to the overall population, including non-Hispanic and Hispanic populations. Other reports included feeding difficulties (21.4%), neonatal jaundice (14.3%), decreased fetal movement (7.1%), and pleural effusions in utero (4.7%). Comprehensive perinatal studies about KBG syndrome and updated documentation of its phenotypes are important in ensuring prompt diagnosis and can facilitate correct management.

Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans.

BACKGROUND: Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH). METHODS: The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (INa-L) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique. RESULTS: Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (P<0.05, versus 0/15 in controls) and were induced by an INa-L enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. INa-L density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by INa-L blocker ranolazine or mexiletine. CONCLUSIONS: LVH enhances INa-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. INa-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.

KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients.

Genetic variants in Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families with molecularly confirmed diagnoses. Twelve individuals have de novo variants, three have inherited variants, and one is inherited from a parent with low-level mosaicism. The mode of inheritance was unknown for nine individuals. Twenty are truncating variants, and the remaining five are missense (three of which are found in one family). We present a protocol emphasizing the use of videoconference and artificial intelligence (AI) in collecting and analyzing data for this rare syndrome. A single clinician interviewed 25 individuals throughout eight countries. Participants' medical records were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were analyzed by the GestaltMatcher and DeepGestalt, Face2Gene platform (FDNA Inc, USA) algorithms. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Behavioral issues and global developmental delays were widely present. Neurologic abnormalities including seizures and/or EEG abnormalities were common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Almost a quarter (24%) were diagnosed with attention deficit hyperactivity disorder and 28% were diagnosed with autism spectrum disorder. Based on the data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity.

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes (Clec4e, Marcksl1, Cxcl1, and Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies.

Atypical Subacute Cutaneous Lupus in a Patient on Apixaban Anticoagulation Therapy: A Case Report and Review of the Literature.

Subacute cutaneous lupus erythematosus (SCLE) is a rare cutaneous lupus erythematosus (CLE) subtype manifesting in middle-aged Caucasians with photo-distributed papulosquamous or annular lesions. Drug-induced SCLE (DI-SCLE) forms present in a similar manner but direct oral anticoagulants are rarely implicated. We report an unusual case of SCLE in a 37-year-old African American patient with a history of unprovoked deep vein thromboses (DVT) who presented with new-onset photoprotected polymorphic lesions two months after the initiation of apixaban anticoagulation therapy. Our case demonstrates the heterogeneous nature of SCLE presentation and highlights the possibility of apixaban as a potential causative agent of DI-SCLE in immunogenetically susceptible individuals. Moreover, we hypothesize on the etiopathogenesis of our patient's atypical presentation.

A Mouse Model to Investigate the Role of Cancer-associated Fibroblasts in Tumor Growth.

Cancer-associated fibroblasts (CAFs) can play an important role in tumor growth by creating a tumor-promoting microenvironment. Models to study the role of CAFs in the tumor microenvironment can be helpful for understanding the functional importance of fibroblasts, fibroblasts from different tissues, and specific genetic factors in fibroblasts. Mouse models are essential for understanding the contributors to tumor growth and progression in an in vivo context. Here, a protocol in which cancer cells are mixed with fibroblasts and introduced into mice to develop tumors is provided. Tumor sizes over time and final tumor weights are determined and compared among groups. The protocol described can provide more insight into the functional role of CAFs in tumor growth and progression.

The cardiac repair benefits of inflammation do not persist: evidence from mast cell implantation.

Multiple mechanisms contribute to progressive cardiac dysfunction after myocardial infarction (MI) and inflammation is an important mediator. Mast cells (MCs) trigger inflammation after MI by releasing bio-active factors that contribute to healing. c-Kit-deficient (Kit(W/W-v) ) mice have dysfunctional MCs and develop severe ventricular dilatation post-MI. We explored the role of MCs in post-MI repair. Mouse wild-type (WT) and Kit(W/W-v) MCs were obtained from bone marrow (BM). MC effects on fibroblasts were examined in vitro by proliferation and gel contraction assays. MCs were implanted into infarcted mouse hearts and their effects were evaluated using molecular, cellular and cardiac functional analyses. In contrast to WT, Kit(W/W-v) MC transplantation into Kit(W/W-v) mice did not improve cardiac function or scar size post-MI. Kit(W/W-v) MCs induced significantly reduced fibroblast proliferation and contraction compared to WT MCs. MC influence on fibroblast proliferation was Basic fibroblast growth factor (bFGF)-dependent and MC-induced fibroblast contractility functioned through transforming growth factor (TGF)-ß. WT MCs transiently rescue cardiac function early post-MI, but the benefits of BM cell implantation lasted longer. MCs induced increased inflammation compared to the BM-injected mice, with increased neutrophil infiltration and infarct tumour necrosis factor-α (TNF-α) concentration. This augmented inflammation was followed by increased angiogenesis and myofibroblast formation and reduced scar size at early time-points. Similar to the functional data, these beneficial effects were transient, largely vanishing by day 28. Dysfunctional Kit(W/W-v) MCs were unable to rescue cardiac function post-MI. WT MC implantation transiently enhanced angiogenesis and cardiac function. These data suggest that increased inflammation is beneficial to cardiac repair, but these effects are not persistent.

PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo.

Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copper-dependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, long-lasting inhibition of the enzyme after a single low dose in vivo. PXS-4681A irreversibly inhibits the enzyme with an apparent Ki of 37 nM and a kinact of 0.26 min(-1) with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-α, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.