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Competing Interests: Conflicts of interest J.M.C. serves on a data and safety monitoring board for Advarra and has served as a consultant for Novartis. M.D.V.’s spouse is an employee of Regeneron Pharmaceuticals. The other authors declare no conflicts of interest.

Background: Clinically assisted nutrition and hydration via percutaneous endoscopic gastrostomy (PEG) is a therapeutic option to ameliorate the difficulties associated with enhanced catabolism, weight loss, and dysphagia in Huntington's disease (HD)., Objectives: The objective is to provide insights into demographics, staging (Shoulson-Fahn), complications, weight trajectories, and survival rates in people with HD (pwHD) who underwent PEG., Methods: This retrospective study included 705 consecutive pwHD who attended our HD clinic between July 2006 and March 2024, of whom 52 underwent PEG. A control group (n = 52), comprising pwHD without PEG, were closely matched for sex, stage, age, CAG length, and disease burden score at PEG. The study was registered as a service evaluation at the National Hospital for Neurology and Neurosurgery., Results: PEG prevalence was 15.0% (n = 52/347) among manifest pwHD: 4.8% (n = 3/62) for Stage 3; 33.3% (n = 16/48) for stage 4; and 44.1% (n = 30/68) for stage 5. Commonest indications were dysphagia, weight loss, and inadequate oral intake. Complications included chest infection, tube dislodgement, and peristomal and skin infections. Modeling of weight trajectories after PEG found no difference between PEG and non-PEG groups. Mortality rate was 34.6% (n = 18/52) in the PEG and 36.5% (n = 19/52) in the non-PEG groups (P = 0.84). Treatment duration (until study endpoint or death) was 3.48 years (interquartile range = 1.71-6.02; range = 0.23-18.8), with 65.4% (n = 34/52) alive at the study endpoint., Conclusion: PEG in pwHD at-risk for weight loss may help slow weight loss. Prospective studies are required to strengthen PEG decision-making in pwHD. PEG survival was much longer than other dementias, highlighting the need to consider PEG independently in pwHD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy., Methods: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data., Results: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor., Conclusions: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD., (© 2024 The Author(s). Pediatric Dermatology published by Wiley Periodicals LLC.)

Cytokine blocking therapies have revolutionized the management of psoriasis and atopic dermatitis but can lead to the development of paradoxic psoriasis (PP). Patients treated with biologics should be closely monitored for the development of PP and other paradoxical eruptions (including inflammatory joint disease, inflammatory bowel disease, eczematous eruptions, lupus like eruptions, sarcoidal eruptions, and others) and occasionally the development of cutaneous T-cell lymphoma. Further understanding the immunologic mechanism of these processes will ultimately drive our understanding of and ability to predict and manage PPs., Competing Interests: Disclosure There are no funding sources. M. Abdelghaffar, S. Kottilil, and M.J. Murphy have nothing to disclose. J.M. Cohen serves on a data and safety monitoring board for Advarra and has received consulting fees from Novartis. W. Damsky has received research support from Pfizer, United States, Advanced Cell Diagnostics/Bio-techne, AbbVie, United States, Incyte, United States, and Bristol-Myers Squibb, United States; receives consulting fees from Eli Lilly, TWI Biotechnology, Incyte, Epiarx Diagnostics, Bristol Myers Squibb, and Boehringer Ingelheim; and receives licensing fees from EMD/Millipore/Sigma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest Yale (W.D.) has filed a preliminary patent application related to this approach. W.D. is a consultant for Pfizer, Incyte, Eli Lilly and TWi Biotechnology; has research funding from Pfizer, Advanced Cell Diagnostics/Bio-Techne and AbbVie; and receives licensing fees from EMD/Millipore/Sigma, all outside the submitted work. J.M.C. serves on a data and safety monitoring board for Advarra. M.J.M., K.S., E.H. and T.L. declare no conflicts of interest.

Psoriasis and sarcoidosis are inflammatory skin and systemic diseases that may share a similar immunopathogenesis involving a Th1 and/or Th17 polarized immune response. Although the coexistence of sarcoidosis and psoriasis in the same individuals has been reported, the potential association between these diseases at a population-level in the United States has not been evaluated. To evaluate this association, we performed a matched cross-sectional study in the All of Us research program database. In the multivariable analysis of 4932 psoriasis cases and 19,728 controls, sarcoidosis was found to be significantly associated with psoriasis (OR 2.37 [95% CI 1.73-3.23], p < 0.001). The relative strength of this association between psoriasis and sarcoidosis may be, in part, explained by overlapping immunopathogenesis and common genetic susceptibility of these diseases. Taken together, these observations underscore the need for screening psoriasis patients for development of new cardiopulmonary symptoms. Further research into the mechanism of this relationship and its implications is warranted., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The degree to which sarcoidosis patients are affected by autoimmune diseases is poorly understood. Prior studies of autoimmune co-morbidities in sarcoidosis have focused on populations outside the USA or have been impeded by small sample sizes and limited scope. This case-control study evaluated the association between sarcoidosis and autoimmune diseases in a large, diverse cohort based in the USA., Methods: We used data from the All of Us research programme to conduct a case-control study involving patients ≥18 years old, from 2018 to the present, diagnosed with sarcoidosis. Sarcoidosis cases and age-, sex- and race-matched controls were identified in a 1:4 ratio. Autoimmune co-morbidities were compared between sarcoidosis patients and controls in univariable and multivariable analyses using logistic regression. The degree of association was measured using the odds ratio (OR)., Results: A total of 1408 sarcoidosis cases and 5632 controls were included in this study. Seven of 24 examined autoimmune diseases were significantly associated with sarcoidosis in our multivariable analysis ( P <  0.05). The composite variable of any autoimmune disease was also significantly associated with sarcoidosis (OR = 2.29, P <  0.001)., Conclusion: We demonstrate an association between sarcoidosis and multiple autoimmune diseases in a large and diverse cohort based in the USA. These results underscore the need for careful screening of sarcoidosis patients for concomitant autoimmune disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Competing Interests: Conflicts of interest the authors declare they have no conflicts of interest.

Competing Interests: The authors declare no conflicts of interest.

Competing Interests: The authors declare no conflicts of interest.

Acral dermatoses, including hyperkeratotic palmoplantar eczema (HPE), palmoplantar psoriasis (PP), and mycosis fungoides palmaris et plantaris (MFPP), can be challenging to diagnose clinically and histopathologically. In this setting, cytokine biomarkers may be able to help provide diagnostic clarity. Therefore, we evaluated IL-17A, IFN-γ, and IL-13 expression in PP, HPE, and MFPP and compared their expression profiles with nonacral sites. We used biopsy specimens from the Yale Dermatopathology database, selecting cases of HPE (n = 12), PP (n = 8), MFPP (n = 8), normal acral skin (n = 9), nonacral eczema (n = 10), and nonacral psoriasis (n = 10) with classic clinical and histopathologic features. IL17A mRNA expression by RNA in situ hybridization differentiated PP (median score 63.1 [interquartile range 9.4-104.1]) from HPE (0.8 [0-6.0]; P  = 0.003), MFPP (0.6 [0-2.6]; P  = 0.003), and normal acral skin (0 [0-0]; P < 0.001). Unexpectedly, both PP and HPE showed co-expression of IFNG and IL13 mRNA. In contrast, nonacral psoriasis and eczema showed divergent patterns of IFNG and IL13 mRNA expression. Taken together, we show that IL17A mRNA expression may be a useful biomarker of PP, and we further show that acral dermatoses exhibit distinct immunology compared to nonacral sites, with implications for clinical management., (© 2023 The Authors.)

Competing Interests: Conflicts of interest: B.K. has served as a consultant for AbbVie, Arena Pharmaceuticals, Concert Pharmaceutics, Eli Lilly and Pfizer; as an investigator for Concert Pharmaceuticals, Eli Lilly and Pfizer; and as a speaker for Eli Lilly and Pfizer. M.R. has served as a consultant for Merck, Janssen, Eli Lilly, Novartis, Processa Pharmaceuticals, AbbVie and Xentria; and receives research support from Processa Pharmaceuticals. W.D. has received research support from Pfizer, Incyte, Advanced Cell Diagnostics/Bio-Techne and AbbVie; served as a consultant for Eli Lilly, Incyte, Pfizer and TWi Biotechnology; and receives licensing fees for EMD/Millipore/Sigma. A.C., M.J.M., J.M.C. and J.B. declare they have no conflicts of interest.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4 + T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity., (© 2022. The Author(s).)

Objectives: To investigate the slowdown in mortality improvement in the United States, United Kingdom, and comparator countries observed in the first decade of the twenty-first century and critically evaluate proposed explanations., Methods: Change-point analysis to identify the year of change in comparison of national mortality trends and linear spline models in the investigation of subnational differences using data from the Human Mortality Database, Global Burden of Disease cause-specific data, and, for the United Kingdom, national statistics data. Consideration of the impact of using different methods to estimate overall mortality is also concluded together with a review of methodological assumptions made in previous studies., Results: The results confirm the slowdown in mortality improvement observed in the early twenty-first century but indicate that proposed explanations for this are inadequate on a range of counts., Discussion: Mortality improvement slowed down in the early twenty-first century but the explanations advanced, such as opioid use in the United States or influenza epidemics and austerity programs in the United Kingdom, seem unlikely to account for this. Further research considering longer-term life course and cohort influences is needed., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The purpose of this study was to determine if strategic placement of portable air purifiers would improve effectiveness of aerosol reduction in a space as compared to use as a general room air purifier. Two sizes of portable air purifiers were placed in two different positions intended to function similar to either a local exhaust ventilation hood or an air curtain to determine if strategic placement would lead to a reduction of particles in a worker's position at a desk in an office environment. Particle generators were used to introduce particulate into the air and personal aerosol monitors measured particles during each test condition. Results showed that when the medium room portable air purifiers used in this study were set to high, corresponding to 98 CFM, and placed near the breathing zone of each office worker with the unit's filter cover removed, the particle concentration was reduced 35% beyond the reduction that would be expected if the same units were placed on the floor behind the occupant's workstation. Results also indicated that the larger portable air purifier tested, positioned as close as reasonable to each occupant's breathing zone with the largest capture area possible (i.e., removing the unit's filter cover), delivers the best aerosol reduction performance. The authors concluded that as a layer of protection against transmission of airborne infectious organisms for office occupants, installing a portable air purifier, sized and operated similar to the units tested in this study on the desk 12 inches from the breathing zone of the worker, has the potential to reduce airborne particulate to a greater degree than if the same units were placed outside of the breathing zone, in the general cubicle area.

Background: Antibody-based therapies that inhibit proinflammatory cytokine signaling are commonly used in dermatology. Paradoxically, these medications may induce or exacerbate inflammatory disorders., Objective: To summarize the spectrum of manifestations, incidence, timing, potential mechanisms of, and general management approaches to paradoxical cutaneous reactions induced by cytokine-targeted antibodies in dermatology., Methods: We performed a systematic review and analysis of published cases of cutaneous paradoxical reactions (PRs) reported in association with tumor necrosis factor α, interleukin (IL) 12/23 (p40), IL-17A/17R, IL-23 (p19), and IL-4Rα inhibitors., Results: We identified 313 articles reporting 2049 cases of PRs. Tumor necrosis factor α inhibitors resulted in 91.2% (1869/2049) of all cases, followed by IL-17/17R (3.5%), IL-4Rα (2.7%), IL-12/23 (2.4%), and IL-23 (0.01%) inhibitors. Psoriasiform and eczematous eruptions were the most commonly reported, but a wide spectrum of patterns were described. Phenotypically overlapping reaction patterns were common. Time to onset typically ranged from weeks to months but could occur more than a year later. Improvement or resolution upon discontinuation of the inciting drug was common., Limitations: This was a retrospective analysis., Conclusions: Familiarity with the clinical features of PRs from cytokine-blocking antibodies may facilitate efficient recognition and management., Competing Interests: Conflicts of interest Dr Vesely's spouse is employed by Regeneron. Dr Damsky is a consultant for Eli Lilly, has received research funding from Pfizer, and receives licensing fees from EMD/Sigma/Millipore in unrelated work. Author Murphy and Dr Cohen have no conflicts of interest to declare., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

A company COVID-19 Heating, Ventilation, and Air Conditioning Guideline was implemented globally, as part of a larger control measure toolset, to minimize the potential for SARS-CoV-2 aerosol transmission. The COVID-19 Heating, Ventilation, and Air Conditioning Guideline informed and provided the process to optimize existing ventilation systems, set occupancy duration limits, and set clearance periods for a given space. Aerosol transmission modeling was used extensively to determine space limitations to reduce the potential for aerosol transmission in various manufacturing, lab, warehouse, aircraft, and administrative workspaces. This paper focuses on the modeling completed for administrative spaces (e.g., offices, conference rooms, restrooms, elevators) due to their lower ventilation rates, higher occupant densities, and greater vocalization levels. A detailed description of how the Guideline was implemented, with examples showing the evaluation and determinations made for specific spaces, is provided. World-wide implementation of this Guideline, as one of the layers of protection, was a key component in the overall strategy to reduce aerosol transmission of the SARS-CoV-2 virus.

Objectives: To examine factors associated with declaration of disability by medical students and doctors, and the association of declared disability with academic performance., Design: Observational study using record-linked data collected between 2002 and 2018., Setting: UK Medical Education Database is a repository of data relating to training of medical students and doctors. Disability and other data are record-linked., Participants: All students starting at a UK medical school between 2002 and 2018 (n=135 930)., Main Outcome Measures: Declared disability was categorised by the Higher Education Statistics Authority. Outcomes related to undergraduate academic performance included scores in the educational performance measure (EPM), prescribing safety assessment and situational judgement test. Performance in postgraduate examinations was studied, as well as prior attainment in school examinations and aptitude tests., Results: Specific learning disability (SLD) was the most commonly declared disability (3.5% compared with the next most commonly declared disability at 1.0% of n=129 345 all cases in the study), and during the period covered by the data, SLD declarations increased from 1.4% (n=6440 for students starting in 2002) to 4.6% (n=8625 for students starting in 2018). In a logistic regression, the following factors predicted recording of SLD on entry to medical school ((exp(B)±95% CI), p<0.0001 unless otherwise stated): attendance at a fee-paying school (2.306±0.178), graduate status (1.806±0.205), participation of local areas quintile (1.089±0.030), age (1.034±0.012). First year medical students were less likely to declare SLD if they were from a non-white ethnic background (Asian/Asian British 0.324±0.034, black/black British 0.571±0.102, mixed 0.731±0.108, other ethnic groups 0.566±0.120), female (0.913±0.059; p=0.007) or from a low index of multiple deprivation quintile (0.963±0.029); p=0.017. In univariate analysis with Bonferroni corrections applied for multiple tests, no significant difference was observed in the recording of SLD according to socioeconomic class (χ 2 =5.637, p=1), whether or not a student's parents had a higher education (χ 2 =0.140, p=1), or whether or not a student had received a United Kingdom Clinical Aptitude Test (UKCAT) bursary (χ 2 =7.661, p=0.068). Students who declared SLD at some point in medical school (n=4830) had lower EPM normalised deviate values (-0.390) than those who did not (-0.119) (F=189.872, p<0.001). Those for whom SLD was recorded were as likely to complete the course successfully as those who did not declare disability (93.0% successful completion by those for whom SLD declared from year 1 (n=2480), 92.2% by those for whom SLD declared after year 1 (n=2350), 91.6% by those for whom SD not declared at any point (n=85 180)) (χ 2 =6.905, p=0.032). Of 3580 first year students who declared SLD, 43.1% had not sat the UKCAT Special Educational Needs aptitude test (which gives extra time for those with special educational needs), while 28% of 2400 registrants for whom SLD was recorded as medical students did not declare it at General Medical Council registration., Conclusions: Substantial increases in declaration of SLD may reflect changes in the social and legal environment during the period of the study. Those who declare SLD are just as likely to gain a primary medical qualification as those who do not. For some individuals, disability declaration appears to depend on context, based on differences in numbers declaring SLD before, during and after medical school., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare their competing interests as per below. Otherwise, there is: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Michael Murphy: no competing interest declared. Jon Dowell: UKMED Advisory Board member and chair of the UKMED research group. Daniel Smith is employed by the GMC as data analyst working on the UKMED project., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: It's usually considered a violation of professional ethics for health care workers, including nurses, to refuse to work during mass medical emergencies, especially if their refusal is over concerns like compensation. Strikes and other forms of work stoppage may result in harm to patients and, therefore, violate professional obligations of beneficence. However, in rare circumstances a health care worker's choice to remain on the job despite risk or potential harm to themselves or even their family may be considered beyond their professional obligation. During a pandemic such as COVID-19, the ethical calculus (that is, finding the right balance between beneficence and harm before deciding on a course of action) must take account of a confluence of factors, including the risks to present patients, future patients, and health care workers; the severity and duration of the risks; and the availability of ameliorative or protective steps that reduce risk and harm. The principle of beneficence to both future patients and health care workers may be thwarted if the risk analysis is confined only to short-term concerns (that is, to concerns occurring within a narrow temporal window). If a significantly elevated risk has been demonstrated to affect nurses and other health care workers of color disproportionately, racial justice must also be considered. The purpose of this article is to assess the moral framework of a work stoppage by nurses during a pandemic., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Sangivamycin is a nucleoside analog that is well tolerated by humans and broadly active against phylogenetically distinct viruses, including arenaviruses, filoviruses, and orthopoxviruses. Here, we show that sangivamycin is a potent antiviral against multiple variants of replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with half-maximal inhibitory concentration in the nanomolar range in several cell types. Sangivamycin suppressed SARS-CoV-2 replication with greater efficacy than remdesivir (another broad-spectrum nucleoside analog). When we investigated sangivamycin's potential for clinical administration, pharmacokinetic; absorption, distribution, metabolism, and excretion (ADME); and toxicity properties were found to be favorable. When tested in combination with remdesivir, efficacy was additive rather than competitive against SARS-CoV-2. The proven safety in humans, long half-life, potent antiviral activity (compared to remdesivir), and combinatorial potential suggest that sangivamycin is likely to be efficacious alone or in combination therapy to suppress viremia in patients. Sangivamycin may also have the ability to help combat drug-resistant or vaccine-escaping SARS-CoV-2 variants since it is antivirally active against several tested variants. Our results support the pursuit of sangivamycin for further preclinical and clinical development as a potential coronavirus disease 2019 therapeutic.

Innovative game-based training methods that leverage the ubiquity of cellphones and familiarity with phone-based interfaces have the potential to transform the training of public health practitioners in low-income countries such as Liberia. This article describes the design, development, and testing of a prototype of the Figure It Out mobile game. The prototype game uses a disease outbreak scenario to promote evidence-based decision-making in determining the causative agent and prescribing intervention measures to minimize epidemiological and logistical burdens in resource-limited settings. An initial prototype of the game developed by the US team was playtested and evaluated by focus groups with 20 University of Liberia Masters of Public Health (UL MPH) students. Results demonstrate that the learning objectives-improving search skills for identifying scientific evidence and considering evidence before decision-making during a public health emergency-were considered relevant and important in a setting that has repeatedly and recently experienced severe threats to public health. However, some of the game mechanics that were thought to enhance engagement such as trial-and-error and choose-your-own-path gameplay, were perceived by the target audience as distracting or too time-consuming, particularly in the context of a realistic emergency scenario. Gameplay metrics that mimicked real-world situations around lives lost, money spent, and time constraints during public health outbreaks were identified as relatable and necessary considerations. Our findings reflect cultural differences between the game development team and end users that have emphasized the need for end users to have an integral part of the design team; this formative evaluation has critically informed next steps in the iterative development process. Our multidisciplinary, cross-cultural and cross-national design team will be guided by Liberia-based public health students and faculty, as well as community members who represent our end user population in terms of experience and needs. These stakeholders will make key decisions regarding game objectives and mechanics, to be vetted and implemented by game design experts, epidemiologists, and software developers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sinnatwah, Kenneh, Coker, Harmon-Gray, Zankah, Day, Hubbell, Murphy, Izzo, Kong, Sylwester, Long, Bertozzi and Skrip.)

Competing Interests: The authors declare no conflicts of interest.

Competing Interests: The authors declare no conflicts of interest.

Importance: Persistent erythema multiforme (PEM) is poorly understood and lacks effective therapies other than glucocorticoids., Objective: To report outcomes following treatment of PEM with Janus kinase (JAK) inhibition and to elucidate cytokine drivers of erythema multiforme (EM)., Design, Setting, and Participants: This was a retrospective case series of 4 patients with PEM treated with tofacitinib and/or upadacitinib in 2015 to 2021 at the dermatology clinics of 2 major tertiary referral centers. Four consecutive patients with PEM refractory to multiple treatment approaches were treated. In 1 patient, skin biopsy specimens were obtained for RNA sequencing and proteomic analysis before and during treatment. Molecular findings were validated through RNA in situ hybridization analysis of cytokine expression in biopsy specimens from a total of 12 patients with EM (3 treated with tofacitinib in this study and 9 historic samples)., Interventions: Treatment with tofacitinib, 5 to 10 mg, twice daily or upadacitinib, 15 mg, once daily., Main Outcomes and Measures: Change in PEM activity was assessed in all 4 patients treated with a JAK inhibitor. Median (range) follow-up was 20.5 months (10.0-36.0 mo)., Results: The study population of 4 female patients had a mean (SD) age of 46.2 (13.7) years and a mean (SD) disease duration of 21.75 (11.30) years. Marked clinical improvement was noted in all 4 patients. In 1 patient with a robust improvement following treatment with tofacitinib, RNA sequencing identified interferon gamma (IFN-γ) and interleukin 15 (IL-15) as cytokines with activity both highly upregulated at baseline in lesional skin and subsequently suppressed following tofacitinib treatment. Measurement of IFNG- and IL15-positive cells in additional EM biopsy specimens of 12 patients showed significant upregulation of IFNG (8.72 cells per mm; 95% CI, 2.60-14.84) and IL15 (14.13 cells per mm; 95% CI, 0.14-28.11) compared with normal skin (P = .008 and P = .045, respectively)., Conclusions and Relevance: The results of this case series study suggest that JAK inhibition may be effective in treating PEM and that IFN-γ and IL-15 may be important cytokine mediators of the disease.

Competing Interests: Declaration of interests MDV's spouse is an employee of Regeneron Pharmaceuticals. WD has received research funding from Pfizer, serves as a consultant for Eli Lilly, Pfizer, and Twi Biotechnology, and receives licensing fees from MilliporeSigma. MJM declares no competing interests.

Competing Interests: The authors declare no conflicts of interest.

Background: There is a growing body of in-vitro and in-vivo laboratory research on the skin bioactive properties of macroalgae., Objective: We sought to examine the scientific literature for evidence supporting the clinical safety and efficacy of macroalgae-derived ingredients in cosmeceuticals., Methods: We performed a systematic review of scientific and medical electronic databases for published, peer-reviewed, randomized controlled trials and nonrandomized reports on the clinical bioactivity of topical macroalgae extracts in skin., Results: Several human studies report scientific data supporting the safety and efficacy of macroalgae-based skincare products, focusing on skin-moisturizing, anti-melanogenic, and anti-cellulite (slimming) benefits., Conclusions: Further clinical research is necessary to determine the long-term safety, efficacy, optimal concentration and formulation of macroalgae extracts in cosmeceuticals with respect to previously reported and yet uninvestigated skin-directed potential functionally and bioactivity., Competing Interests: DISCLOSURES: Ms. Dow is the founder of si SKIN Organics®. Dr. Murphy reports no conflicts of interest relevant to the content of this article., (Copyright © 2021. Matrix Medical Communications. All rights reserved.)

Background: Assessing the pre- and post-test probability of disease in the context of routine health care is challenging. We wished to study how test performance parameters relating to clinical utility vary by clinical indication in a 'real-world' setting., Methods: The diagnostic accuracy of serum total B 12 and Active-B 12 ® (holotranscobalamin) was evaluated in a primary care population, using serum methylmalonic acid as the reference standard. We used electronic requesting to establish the clinical indication for each request. Routine requests from primary care for serum total B 12 were included if creatinine was also measured and estimated glomerular filtration rate was at least 60 mL/min/1.73 m 2 ., Results: Clinical indications included peripheral neuropathy ( n  = 168), anaemia ( n  = 168), cognitive decline ( n  = 125), suspected dietary deficiency ( n  = 76), other ( n  = 362). For peripheral neuropathy, the area under the receiver operator curve ± 95% confidence interval (AUC ± CI) was 0.63 (0.54-0.71) ( P  = 0.002) for total B 12 and 0.68 (0.60-0.77) ( P  < 0.0001) for Active-B 12 ®. For anaemia, AUC ± CI was 0.56 (0.47-0.66) ( P  = 0.10) for total B 12 and 0.69 (0.59-0.78) ( P  < 0.0001) for Active-B 12 ®. For cognitive decline, AUC ± CI was 0.54 (0.43-0.65) ( P  = 0.26) for total B 12 and 0.69 (0.58-0.80) ( P  = 0.0002) for Active-B 12 ®. The pre-post-test change in probability of disease varied by clinical indication., Conclusion: Combining diagnostic accuracy studies and electronic testing in a 'real-world' setting allows clinical utility to be assessed by clinical indication. Wider application of this would permit more personalised laboratory medicine. In this study, diagnostic performance of total B 12 and Active-B 12 ® varied across all indications. Active-B 12 ® provided better discrimination, but this may have reflected the cut-offs used.

Background: Disorders of hyperpigmentation, such as melasma, postinflammatory pigmentary alteration, and lentigines, pose significant cosmetic concerns for women of Hispanic or Latino race and ethnicity. Natural ingredients are gaining popularity as alternative, safe, and effective topical depigmenting agents., Objective: We sought to review clinical studies evaluating the use of natural ingredients in the topical management of hyperpigmentation in Hispanic and Latino women., Methods: We conducted a systematic review of scientific and medical electronic databases to identity randomized controlled trials (RCTs) and nonrandomized reports on topical natural agents for the treatment of disorders of hyperpigmentation, using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines., Results: Our review of the literature revealed relatively few (N=7) clinical studies (including six RCTs) that evaluated the topical management of hyperpigmentation using natural ingredients with specific reference to women of Hispanic or Latino race and ethnicity. Despite limited research data, a small number (N=7) of natural ingredients demonstrated efficacy and safety as depigmenting agents in this cohort, including niacinamide, soy, azelaic acid, ascorbic acid, licorice, emblica, and belides., Conclusion: Several natural ingredients have scientific data supporting their potential efficacy as topical treatments for disorders of hyperpigmentation in women of Hispanic or Latino race and ethnicity. However, the paucity of robust cosmetic trials in this setting reflects the generalized low representation of Hispanic and Latino individuals in clinical studies of other skin conditions. Many in-vivo cutaneous trials of natural ingredients are limited by their study design, including with respect to subject selection and short duration. Further research is needed to determine long-term efficacy, safety, optimal concentration, and formulation of natural ingredients for the topical management of hyperpigmentation in Hispanic and Latino women., Competing Interests: DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article., (Copyright © 2021. Matrix Medical Communications. All rights reserved.)

Detection of individual cytokines in routine biopsies from patients with inflammatory skin diseases has the potential to personalize diagnosis and treatment selection, but this approach has been limited by technical feasibility. We evaluate whether a chromogen-based RNA in situ hybridization approach can be used to detect druggable cytokines in psoriasis and atopic dermatitis. A series of psoriasis (n = 20) and atopic dermatitis (n = 26) biopsies were stained using RNA in situ hybridization for IL4 , IL12B (IL-12/23 p40), IL13 , IL17A , IL17F, IL22 , IL23A (IL-23 p19), IL31 , and TNF (TNF-α). NOS2 and IFNG , canonical psoriasis biomarkers, were also included. All 20 of the psoriasis cases were positive for IL17A , which tended to be the predominant cytokine, although some cases had relatively higher levels of IL12B , IL17F, or IL23A . The majority of cytokine expression in psoriasis was epidermal. A total of 22 of 26 atopic dermatitis cases were positive for IL13 , also at varying levels; a subset of cases had significant IL4, IL22, or IL31 expression. Patterns were validated in independent bulk RNA-sequencing and single-cell RNA-sequencing datasets. Overall, RNA in situ hybridization for cytokines appears highly specific with virtually no background staining and may allow for individualized evaluation of treatment-relevant cytokine targets in biopsies from patients with inflammatory skin disorders., (© 2021 The Authors.)

Granulomatous pigmented purpuric dermatoses (PPD) are rarely reported. We present a case of granulomatous PPD in a 7-year-old boy, one of only two pediatric cases with reported solitary disease. The pathogenesis of unilesional granulomatous PPD may be different from the more commonly described multifocal/widespread disease variant., (© 2021 Wiley Periodicals LLC.)

&ldquo;Hispanic&rdquo; and &ldquo;Latino&rdquo; (also known as Mestizo) describe a diverse racial and ethnic group, with a range of cultures, languages, and biological ancestry. It includes individuals of Mexican, Central-to-South American, and Spanish-Caribbean (eg, Cuban, Puerto Rican, and Dominican) descent.1 Individuals of Hispanic/Latino race and ethnicity represent a heterogenous group of people with different skin tones and Fitzpatrick phototypes. Hispanic/Latinos are the fastest growing population in the United States (US) - projected to increase from 55 million in 2014 to 119 million in 2060, an increase of 115%.2 By 2060, more than one-quarter (29%) of the US is projected to be Hispanic/Latino.2.

Increasing the Ni content of LiNi x Mn y Co 1- x - y O 2 (NMC) cathodes can increase the capacity, but additional stability is needed to improve safety and longevity characteristics. In order to achieve this improved stability, Mg and Zr were added during the coprecipitation to uniformly dope the final cathode material. These dopants reduced the capacity of the material to some extent, depending on the concentration and calcination temperature. However, these dopants can impart substantial stabilization. It was found that the degree of stabilization is strongly dependent on the calcination temperature of the material. In addition, we used synchrotron X-ray diffraction during thermal breakdown to better understand why the different dopants impact the thermal stability and confirm the stabilization effects of the dopants.

Through collaboration with Inuit hunters, we examined the stomach contents of 142 seals (ringed seals [Phoca hispida; n = 135], bearded seals [Erignathus barbatus; n = 6], and one harbour seal [Phoca vitualina; n = 1]) hunted between 2007 and 2019 from communities around Nunavut to assess whether seals in the eastern Canadian Arctic ingest and retain plastics in their stomachs. The seals in this study ranged from juveniles to adults of up to 30 years of age, and 55% of the seals were males. We found no evidence of plastic ingestion in any of the seals suggesting that seals in Nunavut are not accumulating plastics (>425 μm) in their stomachs. These data provide important baseline information for future plastic pollution monitoring programs in the Arctic., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Atrial fibrillation (AF)-the most common arrhythmia-significantly increases the risk of stroke and heart failure. Although catheter ablation can restore normal heart rhythms, patients with persistent AF who develop atrial fibrosis often undergo multiple failed ablations, and thus increased procedural risks. Here, we present personalized computational modelling for the reliable predetermination of ablation targets, which are then used to guide the ablation procedure in patients with persistent AF and atrial fibrosis. First, we show that a computational model of the atria of patients identifies fibrotic tissue that, if ablated, will not sustain AF. Then, we report the results of integrating the target ablation sites in a clinical mapping system and testing its feasibility in ten patients with persistent AF. The computational prediction of ablation targets avoids lengthy electrical mapping and could improve the accuracy and efficacy of targeted AF ablation in patients while eliminating the need for repeat procedures.

Aims: Efforts to improve ablation success rates in persistent atrial fibrillation (AF) patients by targeting re-entrant driver (RD) sites have been hindered by weak mechanistic understanding regarding emergent RDs localization following initial fibrotic substrate modification. This study aimed to systematically assess arrhythmia dynamics after virtual ablation of RD sites in computational models., Methods and Results: Simulations were conducted in 12 patient-specific atrial models reconstructed from pre-procedure late gadolinium-enhanced magnetic resonance imaging scans. In a previous study involving these same models, we comprehensively characterized pre-ablation RDs in simulations conducted with either 'average human AF'-based electrophysiology (i.e. EPavg) or ±10% action potential duration or conduction velocity (i.e. EPvar). Re-entrant drivers seen under the EPavg condition were virtually ablated and the AF initiation protocol was re-applied. Twenty-one emergent RDs were observed in 9/12 atrial models (1.75 ± 1.35 emergent RDs per model); these dynamically localized to boundary regions between fibrotic and non-fibrotic tissue. Most emergent RD locations (15/21, 71.4%) were within 0.1 cm of sites where RDs were seen pre-ablation in simulations under EPvar conditions. Importantly, this suggests that the level of uncertainty in our models' ability to predict patient-specific ablation targets can be substantially mitigated by running additional simulations that include virtual ablation of RDs. In 7/12 atrial models, at least one episode of macro-reentry around ablation lesion(s) was observed., Conclusion: Arrhythmia episodes after virtual RD ablation are perpetuated by both emergent RDs and by macro-reentrant circuits formed around lesions. Custom-tailoring of ablation procedures based on models should take steps to mitigate these sources of AF recurrence.

Background Communicating abnormal results to requesting clinicians is an essential part of clinical authorisation. Guidance from the Royal College of Pathologists on communication of critical/unexpected results is issued as 'advice to pathologists'. The 2017 guidelines advise rapid communication of serum potassium results ≤2.5 mmol/L and ≥6.5 mmol/L. Little is known about what happens after the results have been communicated. We wished to establish answers to the following questions: Are phoned results acted on? If so, when? What is the outcome of any action taken? Methods A prospective study of primary care potassium results authorised out of hours was undertaken. Potassium requests from primary care were retrieved from the laboratory information management system. The potassium result was recorded, along with other data. Data were analysed for potassium results that were validated out of hours (18:00 h-08:00 h). Results Over six months, 220 potassium results <3.1 mmol/L and >5.9 mmol/L from primary care were validated out of hours. A subset of these (27) were phoned to the general practice out of hours 'hub', and 16 patients referred to hospital out of hours, on account of the potassium results. The remaining potassium results phoned out of hours were acted on subsequently. Conclusions Critical potassium results were phoned urgently and are acted on, although not always out of hours. For potassium results phoned out of hours, the most frequent action was to refer to hospital out of hours. Different actions occurred for similar potassium results, reflecting the fact that actions taken and their urgency depend on the patient, the clinician and the practice policy for handling results.

Focal impulse and rotor mapping (FIRM) involves intracardiac detection and catheter ablation of re-entrant drivers (RDs), some of which may contribute to arrhythmia perpetuation in persistent atrial fibrillation (PsAF). Patient-specific computational models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) has the potential to non-invasively identify all areas of the fibrotic substrate where RDs could potentially be sustained, including locations where RDs may not manifest during mapped AF episodes. The objective of this study was to carry out multi-modal assessment of the arrhythmogenic propensity of the fibrotic substrate in PsAF patients by comparing locations of RD-harboring regions found in simulations and detected by FIRM (RD sim and RD FIRM ) and analyze implications for ablation strategies predicated on targeting RDs. For 11 PsAF patients who underwent pre-procedure LGE-MRI and FIRM-guided ablation, we retrospectively simulated AF in individualized atrial models, with geometry and fibrosis distribution reconstructed from pre-ablation LGE-MRI scans, and identified RD sim sites. Regions harboring RD sim and RD FIRM were compared. RD sim were found in 38 atrial regions (median [inter-quartile range (IQR)] = 4 [3; 4] per model). RD FIRM were identified and subsequently ablated in 24 atrial regions (2 [1; 3] per patient), which was significantly fewer than the number of RD sim -harboring regions in corresponding models ( p < 0.05). Computational modeling predicted RD sim in 20 of 24 (83%) atrial regions identified as RD FIRM -harboring during clinical mapping. In a large number of cases, we uncovered RD sim -harboring regions in which RD FIRM were never observed (18/22 regions that differed between the two modalities; 82%); we termed such cases "latent" RD sim sites. During follow-up (230 [180; 326] days), AF recurrence occurred in 7/11 (64%) individuals. Interestingly, latent RD sim sites were observed in all seven computational models corresponding to patients who experienced recurrent AF (2 [2; 2] per patient); in contrast, latent RD sim sites were only discovered in two of four patients who were free from AF during follow-up (0.5 [0; 1.5] per patient; p < 0.05 vs. patients with AF recurrence). We conclude that substrate-based ablation based on computational modeling could improve outcomes.

Electrocardiographic mapping (ECGI) detects reentrant drivers (RDs) that perpetuate arrhythmia in persistent AF (PsAF). Patient-specific computational models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) identify all latent sites in the fibrotic substrate that could potentially sustain RDs, not just those manifested during mapped AF. The objective of this study was to compare RDs from simulations and ECGI (RD sim /RD ECGI ) and analyze implications for ablation. We considered 12 PsAF patients who underwent RD ECGI ablation. For the same cohort, we simulated AF and identified RD sim sites in patient-specific models with geometry and fibrosis distribution from pre-ablation LGE-MRI. RD sim - and RD ECGI -harboring regions were compared, and the extent of agreement between macroscopic locations of RDs identified by simulations and ECGI was assessed. Effects of ablating RD ECGI /RD sim were analyzed. RD sim were predicted in 28 atrial regions (median [inter-quartile range (IQR)] = 3.0 [1.0; 3.0] per model). ECGI detected 42 RD ECGI -harboring regions (4.0 [2.0; 5.0] per patient). The number of regions with RD sim and RD ECGI per individual was not significantly correlated ( R = 0.46, P = ns). The overall rate of regional agreement was fair (modified Cohen's κ 0 statistic = 0.11), as expected, based on the different mechanistic underpinning of RD sim - and RD ECGI . nineteen regions were found to harbor both RD sim and RD ECGI , suggesting that a subset of clinically observed RDs was fibrosis-mediated. The most frequent source of differences (23/32 regions) between the two modalities was the presence of RD ECGI perpetuated by mechanisms other than the fibrotic substrate. In 6/12 patients, there was at least one region where a latent RD was observed in simulations but was not manifested during clinical mapping. Ablation of fibrosis-mediated RD ECGI (i.e., targets in regions that also harbored RD sim ) trended toward a higher rate of positive response compared to ablation of other RD ECGI targets (57 vs. 41%, P = ns). Our analysis suggests that RDs in human PsAF are at least partially fibrosis-mediated. Substrate-based ablation combining simulations with ECGI could improve outcomes.