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Background: Psychological and mental health difficulties are common in children and young people (CYP) living with skin conditions and can have a profound impact on wellbeing. There is limited guidance on how best to assess and support the mental health of this population, who are at risk of poor health outcomes., Objectives: To provide consensus-based recommendations on the assessment and monitoring of and support for mental health difficulties in CYP with skin conditions (affecting the skin, hair and nails); to address practical clinical implementation questions relating to consensus guidance; and to provide audit and research recommendations., Methods: This set of recommendations was developed with reference to the AGREE II instrument. A systematic review and literature appraisal was carried out. A multidisciplinary consensus group was convened, with two virtual panel meetings held: an initial meeting to discuss the scope of the study, to review the current evidence and to identify areas for development; and a second meeting to agree on the content and wording of the recommendations. Recommendations were then circulated to stakeholders, following which amendments were made and agreed by email., Results: The expert panel achieved consensus on 11 recommendations for healthcare workers managing CYP with skin conditions. A new patient-completed history-taking aid ('You and Your Skin') was developed and is being piloted., Conclusions: The recommendations focus on improved mental health assessments for CYP presenting with a skin condition, with clinical guidance and suggested screening measures included. Information on accessing psychological support for CYP, when required, is given, and recommendations for staff training in mental health and neurodiversity provided. Embedding a psychosocial approach within services treating CYP with skin disease should ensure that CYP with psychological needs are able to be identified, listened to, supported and treated. This is likely to improve health outcomes., Competing Interests: Conflicts of interest: T.McP. reported personal fees from Sanofi, AbbVie and L’Oreal outside the submitted work and is Trustee of Dipex Charity, being Lead Clinician on the Skins section of their patient experiences site Healthtalk.org and Expert Advisor to NICE and MHRA for matters relating to dermatology. J.R. is Expert Advisor to NICE and MHRA for matters relating to dermatology and Medical Advisor to Nottingham Eczema Support Group. R.A. reported personal fees from Pfizer, AbbVie and Sanofi outside the submitted work. R.B. reported personal fees from UCB outside the submitted work and is Chairperson for Action for XP and Trainee Representative for Psychoderm UK. P.B. reported personal fees from AbbVie, Pfizer, Novartis and L’Oreal outside the submitted work. A.B. reported grants and personal fees from AbbVie, Almirall, Bayer, Bristol Myers Squibb, Galderma, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi and UCB outside the submitted work and was Editor of Practical Psychodermatology (Wiley, 2014) and Psychodermatology in Clinical Practice (Springer), and was Chairman of Psychodermatology UK (2008–2020). T.B. is Clinical Director of NHSE for outpatient transformation and past President of British Association of Dermatologists (2020–2022). S.C. reported personal fees from Galderma, LEO and Incyte UK outside the submitted work, and is the Chair of Dermatology Council for England and of Derma and is Trustee for the British Dermatological Nursing Group (2018–current). T.C. is Executive Chair and author of the Primary Care Dermatology Society website and has undertaken work with the MHRA on isotretinoin. E.H. is Trustee of Changing Faces Charity. A.L. is Head of Services of the National Eczema Society. P.M. is Committee Member of Psychodermatology UK. C.M. is on the medical advisory board for National Eczema Society and Ichthyosis Support Group. G.N. is cofounder of Anathem and reported no conflicts of interest related to this work. A.P. is Chief Executive of the National Eczema Society. C.R. is past Chief Executive Officer of Eczema Outreach Support. S.S. reported personal fees from Pfizer outside the submitted work. J.S. is Expert Advisor to NICE on matters relating to paediatric dermatology and Medical Advisor to Nottingham Eczema Support Group. S.B. reported personal fees from AbbVie, Sanofi and Pfizer outside the submitted work and is Expert Advisor to MHRA on Dermatology matters and Co-Chair of Psychodermatology UK. No other disclosures were reported., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The parent of an adolescent patient noticed an upcoming appointment in the patient's portal account that should have remained confidential to the parent. As it turned out, this parent was directly accessing their child's adolescent patient portal account instead of using a proxy account. After investigation of this case, it was found that the adolescent account had been activated with the parent's demographic (i.e., phone/email) information. This case illustrates the challenges of using adult-centric electronic health record (EHR) systems and how our institution addressed the problem of incorrect portal account activations.Confidentiality is fundamental to providing healthcare to adolescents. To comply with the 21st Century Cures Act's information blocking rules, confidential information must be released to adolescent patients when appropriate while also remaining confidential from their guardians. While complying with this national standard, systems of care must also account for interstate variability in which services allow for confidential adolescent consent. Unfortunately, there are high rates of guardian access to adolescent portal accounts which may lead to unintended disclosure of confidential information. Therefore, measures must be taken to minimize the risk of inadvertent confidentiality breaches via adolescent patient portals.Our institution implemented a guardrail system that checks the adolescent patient's contact information against the contact information of their parent/guardian/guarantor. This guardrail reduced the rate of account activation errors after implementation. However, the guardrail can be bypassed when demographic fields are missing. Thus, ongoing efforts to create pediatric-appropriate demographic fields, clearly distinguishing patient from proxy, in the EHR and workflows for registration of proxy accounts in the patient portal are needed., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: For caregivers of adolescents and young adults with severe cognitive deficits, or "diminished capacity," access to the medical record can be critical. However, this can be a challenge when utilizing the electronic health record (EHR) as information is often restricted in order to protect adolescent confidentiality. Having enhanced access for these proxies would be expected to improve engagement with the health system for the families of these medically complex adolescents and young adults., Objectives: To describe a process for granting full EHR access to proxies of adolescents with diminished capacity and young adults who are legally conserved while respecting regulations supporting adolescent confidentiality., Methods: The first step in this initiative was to define the "diminished capacity" access class for both adolescents and young adults. Once defined, workflows utilizing best practice alerts were developed to support clinicians in providing the appropriate documentation. In addition, processes were developed to minimize the possibility of erroneously activating the diminished capacity access class for any given patient. To enhance activation, a support tool was developed to identify patients who might meet the criteria for diminished capacity proxy access. Finally, outreach and educations were developed for providers and clinics to make them aware of this initiative., Results: Since activating this workflow, proxies of 138 adolescents and young adults have been granted the diminished capacity proxy access class. Approximately 54% are between 12 and 17 years with 46% 18 years and older. Proxies for both age groups have engaged with portal functionality at higher rates when compared to institutional rates of use by proxies of the general pediatric population., Conclusion: With this quality improvement initiative, we were able to enhance EHR access and engagement of families of some of the most complex adolescent and young adult patients without inadvertently compromising adolescent confidentiality., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: To describe secondary care health care resource utilization (HCRU) for children and adolescents with atopic dermatitis (AD)., Patients and Methods: This UK chart review of patients with moderate-to-severe AD was conducted in four National Health Service hospitals. Cohorts were defined by age (children 6-11 years, adolescents 12-17) at first consultation. Eligible patients were selected consecutively, starting with the most recently consulting patient. At least 12 months' data were abstracted from medical records. Data were collected on HCRU, demographics/clinical characteristics, treatment, and patient-reported outcomes., Results: Data were abstracted for 55 patients. Most patients (80%) had severe AD at first referral, a mean (SD) of 3.2 (10.7) patient-reported flare episodes/patient/year-of-observation, and 18.5 (16.7) tests/scans/procedures/patient/year. Mean (SD) observation duration was 3.6 (1.8) years. Patients had tried mean (SD) 7.9 (5.3) treatments/patient/year of observation. Topical corticosteroids (TCS; 24.5% of prescriptions) were most frequently prescribed. Mean (SD) use of emollients/moisturizers, TCS, systemic corticosteroids, and systemic immunosuppressants was 30.9 (21.3), 21.1 (23.4), 1.7 (8.3), and 7.8 (8.2) months. There was a mean (SD) of 5.3 (2.9) consultations/patient/year-of-observation; 116 (10.7%) for flare. Most hospitalizations (87.5%) were for children; the 8/55 (15%) hospitalized patients (mean 2.0 hospitalizations/patient during observation period) spent 6.2 (SD: 5.1) nights in hospital/hospitalization. Earliest mean (SD) Children's Dermatology Life Quality Index score was 15.3 (7.2); latest was 12.9 (7.5)., Conclusion: Children and adolescents with moderate-to-severe AD had a high HCRU burden and small changes in quality of life, indicating that current treatments may provide suboptimal AD control in most cases., (© 2022 Wiley Periodicals LLC.)

Introduction/aims: Factors associated with coronavirus disease 2019 (COVID-19) infection among the myasthenia gravis (MG) population are incompletely understood. This study aimed to characterize the behavior of MG patients during the pandemic and to examine risk factors associated with COVID-19 infection., Methods: A "COVID-19 Survey" was sent to MG Patient Registry participants in the summer of 2020 (CSS20) and winter of 2021 (CWS21). Survey results were summarized descriptively. Demographics, disease characteristics, medication use, and survey results were compared between those reporting COVID-19 diagnosis (COVID), COVID-19 like symptoms without diagnosis (COVID-Like), and asymptomatic participants., Results: A total of 454 and 665 participants completed the CSS20 and CWS21 surveys respectively; 326 participants completed both. Most continued follow-up visits and MG treatments. The frequency of COVID-like symptoms was similar between CSS20 and CWS21, while COVID-19 exposure (6% vs. 27%), COVID-19 testing among symptomatic individuals (35% vs. 78%), and COVID-19 diagnosis (0.2% vs. 6%) were higher in the CWS21. Cough, fever, fatigue, myalgia, anosmia/ageusia, and hospital and intensive care unit (ICU) admissions were more frequent in the COVID compared to the COVID-Like group. COVID-19 exposure (odds ratio [OR] 7.88), number of people in the household (OR 1.31), and report of MG exacerbation before the pandemic (OR 2.6) were independently associated with COVID-19 infection., Discussion: COVID-19 affected MG patients increasingly through the early pandemic. While face-to-face contact with a COVID-19 infected individual was an obvious risk factor, MG patients who had more people in the household and unstable disease were at elevated risk for COVID-19 infection., (© 2022 Wiley Periodicals LLC.)

The COVID-19 pandemic dramatically disrupted health care systems and delivery in the United States. Despite emotional, psychological, logistical, and financial stress, primary care clinicians responded to the challenges that COVID-19 presented and continued to provide essential health services to their communities. As the lead federal agency for primary care research, the Agency for Healthcare Research and Quality (AHRQ) identified a need to engage and support primary care in responding to COVID-19. AHRQ initiated a learning community from December 2020-November 2021 to connect professionals and organizations that support primary care practices and clinicians. The learning community provided a forum for participants to share learning and peer support, better understand the stressors and challenges confronting practices, ascertain needs, and identify promising solutions in response to the pandemic. We identified challenges, responses, and innovations that emerged through learning community engagement, information sharing, and dialog. We categorized these across 5 domains that reflect core areas integral to primary care delivery: patient-centeredness, clinician and practice, systems and infrastructure, and community and public health; health equity was crosscutting across all domains. The engagement of the community to identify real-time response and innovation in the context of a global pandemic has provided valuable insights to inform future research and policy, improve primary care delivery, and ensure that the community is better prepared to respond and contribute to ongoing and future health challenges., (© 2023 Annals of Family Medicine, Inc.)

Background: The COVID-19 pandemic has raised questions regarding the management of chronic skin diseases, especially in patients on systemic treatments. Data concerning the use of biologics in adults with psoriasis are reassuring, but data specific to children are missing. Moreover, COVID-19 could impact the course of psoriasis in children., Objectives: The aim of this study was therefore to assess the impact of COVID-19 on the psoriasis of children, and the severity of the infection in relation to systemic treatments., Methods: We set up an international registry of paediatric psoriasis patients. Children were included if they were under 18 years of age, had a history of psoriasis, or developed it within 1 month of COVID-19 and had COVID-19 with or without symptoms., Results: One hundred and twenty episodes of COVID-19 in 117 children (mean age: 12.4 years) were reported. The main clinical form of psoriasis was plaque type (69.4%). Most children were without systemic treatment (54.2%); 33 (28.3%) were on biologic therapies, and 24 (20%) on non-biologic systemic drugs. COVID-19 was confirmed in 106 children (88.3%) and 3 children had two COVID-19 infections each. COVID-19 was symptomatic for 75 children (62.5%) with a mean duration of 6.5 days, significantly longer for children on non-biologic systemic treatments (P = 0.02) and without systemic treatment (P = 0.006) when compared with children on biologics. The six children who required hospitalization were more frequently under non-biologic systemic treatment when compared with the other children (P = 0.01), and particularly under methotrexate (P = 0.03). After COVID-19, the psoriasis worsened in 17 cases (15.2%). Nine children (8%) developed a psoriasis in the month following COVID-19, mainly a guttate form (P = 0.01)., Discussion: Biologics appear to be safe with no increased risk of severe form of COVID-19 in children with psoriasis. COVID-19 was responsible for the development of psoriasis or the worsening of a known psoriasis for some children., (© 2022 European Academy of Dermatology and Venereology.)

Introduction/aims: We studied the progression of myasthenia gravis (MG) disease burden and medication adjustment among MG Patient Registry participants., Methods: Participants diagnosed with MG (age ≥18 years), registered between July 1, 2013 and July 31, 2018 and completing both 6- and 12-month follow-up surveys, were included in this investigation. Participants were grouped into high-burden (Myasthenia Gravis Activity of Daily Living scale [MG-ADL] score ≥6) and low-burden (MG-ADL <6) groups based on MG-ADL scores at enrollment. Demographics and disease history were compared between groups. MG-ADL score change and medication changes (escalation, no change, de-escalation) between enrollment and 12-month follow-up were compared between groups. Minimal symptom expression (MSE, MG-ADL <2) at 12 months was compared between groups. Logistic regression analysis was performed to study factors associated with MSE at 12 months., Results: In total, 520 participants (56% female) were included in high-burden (n = 248) and low-burden (n = 272) groups. Those in the high-burden group were more likely to be younger, female, and have shorter disease duration. At 12 months, MSE was achieved in 6% of the high-burden group and newly achieved (42 of 201, 21%) or maintained (52 of 71, 73%) in the low-burden group. In the multivariable analysis, being in the high-burden group and use of pyridostigmine were associated with less likelihood of MSE, whereas MG-ADL score improvement (>2 or >20%) at 6 months significantly increased the likelihood of achieving MSE at 12 months (P = .0004)., Discussion: In both groups, but more so in the high-burden group, patients infrequently achieved MSE after 1 year of MG treatment. Baseline low disease burden, improvement at 6 months and no pyridostigmine use were associated with a higher likelihood of MSE at 12 months., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Introduction: This study evaluated patient characteristics and treatment patterns according to weight in pediatric patients with psoriasis in a real-world setting., Methods: Primary care and specialist physicians treating pediatric patients with psoriasis aged 6-17 years in five European countries were surveyed in the 2019-2020 Adelphi Real World Pediatric Psoriasis Disease Specific Programme. At least two patients with current or previous biologic use were included per physician. Patient characteristics and treatment patterns were analyzed overall and for patients weighing 25-50 kg or more than 50 kg., Results: Data from 772 patients weighing 25-50 kg and 1147 weighing more than 50 kg were analyzed. Median age at diagnosis was significantly less in lighter than heavier patients (10.0 vs. 14.0 years; p < 0.001), as was median disease duration (2.2 vs. 3.0 years; p < 0.001). Topical treatments were prescribed in 59.0% of patients overall (70.3% of lighter and 51.4% of heavier patients; p < 0.001), and were used to treat mild rather than moderate-to-severe psoriasis. Conventional systemic use was low (10.8% of patients overall) and predominantly for moderate-to-severe psoriasis. In this biologic-enriched sample, most biologics (78.2%) were prescribed in older (> 13 years) patients. Biologic use increased with line of therapy (6.6% of first-line, 18.0% of second-line, 33.7% of third-line, 44.7% of fourth-line treatments)., Conclusion: Biologics are predominantly prescribed in older (> 13 years) and heavier (> 50 kg) patients, with little first- or second-line use. The low use of biologics in European pediatric patients with psoriasis may represent an unmet treatment need, as topical or conventional systemic agents remain the main treatment option for moderate or severe psoriasis in these patients through the treatment pathway., (© 2022. The Author(s).)

Background: Severe neuropsychiatric outcomes have been reported in individuals exposed to isotretinoin, but the evidence is inconclusive and complicated by several methodological limitations., Objectives: To establish and quantify the association between isotretinoin use for acne and 1-year incident neuropsychiatric adverse outcomes., Methods: A propensity score-matched cohort study of electronic medical records between the years 2013 and 2019 with patients followed up for 1 year after their index dispensed prescription was conducted. The database included over 12 million patients aged 12-27 years. We analysed data for individuals with acne in this age range with a dispensed prescription for isotretinoin or a control prescription. Outcomes included diagnoses of any incident sleep or mental health disorder, or nonfatal self-harm within 1 year of the index prescription., Results: We included 30 866 patients prescribed isotretinoin for their acne, 44 748 prescribed oral antibiotics, 108 367 prescribed topical anti-acne agents and 78 666 patients with acne but without an anti-acne prescription. After propensity score matching for baseline confounders, the odds ratio (OR) for any incident neuropsychiatric outcomes in patients with acne exposed to isotretinoin was 0·80 [95% confidence interval (CI) 0·74-0·87] compared with those on oral antibiotics; 0·94 (95% CI 0·87-1·02) compared with those using topical anti-acne medicines; and 1·06 (95% CI 0·97-1·16) compared with those without a prescription for anti-acne medicines. Patients exposed to isotretinoin experienced significantly more incident physical symptoms than patients in any of the three comparison cohorts., Conclusions: Isotretinoin was not independently associated with excess adverse neuropsychiatric outcomes at the population level. When monitoring potential adverse outcomes during isotretinoin treatment, clinicians should also consider the high mental health burden associated with treatment-resistant acne and the potential contribution of physical side-effects of prescribed medication on mental health., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background and Objectives: (1) To identify patient reported outcome measures (PROMs) which have been used to screen and assess mental health symptoms in studies of youth with skin disease. (2) To critically appraise their evidence base in this population., Methods: A systematic literature search was conducted within PubMed and PsycINFO combining search terms for pediatric populations, dermatology, screening and assessment tools, and psychological and psychiatric conditions, to identify PROMs which screened or assessed for mental health symptoms in youth with skin disease. PROMs which had undergone validation within this population were assessed for quality and evidence base using the COSMIN risk of bias tool., Results: One hundred eleven PROMs which assess mental health symptoms in studies of youth with skin disease were identified. These included generic mental health scales which are extensively validated in different populations. Only one PROM, the "Skin Picking Scale-Revised" has undergone specific validation in youth with skin disease. This showed poor quality of evidence for content validity and therefore cannot be recommended., Conclusion: There is an urgent need to identify mental health problems early and treat proactively to improve outcomes in youth with skin disease. This review highlights the current lack of consensus around the best way to assess our patients. It is likely that existing generic mental health methods and PROMS will be appropriate for our needs. More work is required to examine the utility, feasibility, and acceptability of existing generic, validated mental health screening tools in youth with skin disease., (© 2022 Wiley Periodicals LLC.)

Background: In children, psoriasis can be challenging to diagnose. Difficulties arise from differences in the clinical presentation compared with adults., Objectives: To test the diagnostic accuracy of previously agreed consensus criteria and to develop a shortlist of the best predictive diagnostic criteria for childhood psoriasis., Methods: A case-control diagnostic accuracy study in 12 UK dermatology departments (2017-2019) assessed 18 clinical criteria using blinded trained investigators. Children (< 18 years) with dermatologist-diagnosed psoriasis (cases, N = 170) or a different scaly inflammatory rash (controls, N = 160) were recruited. The best predictive criteria were identified using backward logistic regression, and internal validation was conducted using bootstrapping., Results: The sensitivity of the consensus-agreed criteria and consensus scoring algorithm was 84·6%, the specificity was 65·1% and the area under the curve (AUC) was 0·75. The seven diagnostic criteria that performed best were: (i) scale and erythema in the scalp involving the hairline, (ii) scaly erythema inside the external auditory meatus, (iii) persistent well-demarcated erythematous rash anywhere on the body, (iv) persistent erythema in the umbilicus, (v) scaly erythematous plaques on the extensor surfaces of the elbows and/or knees, (vi) well-demarcated erythematous rash in the napkin area involving the crural fold and (vii) family history of psoriasis. The sensitivity of the best predictive model was 76·8%, with specificity 72·7% and AUC 0·84. The c-statistic optimism-adjusted shrinkage factor was 0·012., Conclusions: This study provides examination- and history-based data on the clinical features of psoriasis in children and proposes seven diagnostic criteria with good discriminatory ability in secondary-care patients. External validation is now needed., (© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Olmesartan medoxomil (OLM) is only available in the United States as tablets. The United States Pharmacopoeia (USP) has placed OLM on its priority list of preparations that require stability data to support practitioner compounding. Objective: The purpose of the study was to develop a stability-indicating assay and then determine the beyond-use date (BUD) for an extemporaneous OLM suspension. Methods: A reverse-phase high-performance liquid chromatography (HPLC) assay was developed and validated according to guidelines for USP official compounded monographs. OLM 2 mg/mL suspensions were compounded with Ora-Sweet and Ora-Plus and stored at room temperature or in a refrigerator. Suspensions were assayed periodically over 90 days for OLM concentration and observed for physical stability. The pH was measured at the beginning and end of the study. Results: The OLM concentration remained above 97% of the starting concentration for 90 days when stored in the refrigerator and above 94% of the starting concentration for 90 days when stored at room temperature. The suspension pH did not change and indicators of physical stability were unchanged for 90 days. Conclusion: OLM 2 mg/mL suspensions were chemically and physically stable at room temperature and in the refrigerator for 90 days. The BUD may be set at 90 days under either storage condition., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Purpose: Managing confidential adolescent health information in patient portals presents unique challenges. Adolescent patients and guardians electronically access medical records and communicate with providers via portals. In confidential matters like sexual health, ensuring confidentiality is crucial. A key aspect of confidential portals is ensuring that the account is registered to and utilized by the intended user. Inappropriately registered or guardian-accessed adolescent portal accounts may lead to confidentiality breaches., Methods: We used a quality improvement framework to develop screening methodologies to flag guardian-accessible accounts. Accounts of patients aged 12-17 were flagged via manual review of account emails and natural language processing of portal messages. We implemented a reconciliation program to correct affected accounts' registered email. Clinics were notified about sign-up errors and educated on sign-up workflow. An electronic alert was created to check the adolescent's email prior to account activation., Results: After initial screening, 2,307 of 3,701 (62%) adolescent accounts were flagged as registered with a guardian's email. Those accounts were notified to resolve their logins. After five notifications over 8 weeks, 266 of 2,307 accounts (12%) were corrected; the remaining 2,041 (88%) were deactivated., Conclusions: The finding that 62% of adolescent portal accounts were used/accessed by guardians has significant confidentiality implications. In the context of the Cures Act Final Rule and increased information sharing, our institution's experience with ensuring appropriate access to adolescent portal accounts is necessary, timely, and relevant. This study highlights ways to improve patient portal confidentiality and prompts institutions caring for adolescents to review their systems and processes., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background/objective: Weight loss is a predictor of shorter survival in amyotrophic lateral sclerosis (ALS). We performed serial measures of body composition using Dual-energy X-ray Absorptiometry (DEXA) in ALS patients to explore its utility as a biomarker of disease progression., Methods: DEXA data were obtained from participants with ALS (enrollment, at 6- and 12- months follow ups) and Parkinson's disease (enrollment and at 4-month follow up) as a comparator group. Body mass index, total lean mass index, appendicular lean mass index, total fat mass index, and percentage body fat at enrollment were compared between the ALS and PD cohorts and age-matched normative data obtained from the National Health and Nutrition Examination Survey database. Estimated monthly changes of body composition measures in the ALS cohort were compared to those of the PD cohort and were correlated with disease progression measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)., Results: The ALS cohort (N = 20) had lower baseline total and appendicular lean mass indices compared to the PD cohort (N = 20) and general population. Loss in total and appendicular lean masses were found to be significantly associated with follow-up time. Low baseline percentage body fat (r = 0.72, p = 0.04), loss of percentage body fat (r = 0.81, p = 0.01), and total fat mass index (r = 0.73, p = 0.04) during follow up correlated significantly with monthly decline of ALSFRS-R scores in ALS cohort who had 2 or more follow-ups (N = 8)., Conclusion: Measurement of body composition with DEXA might serve as a biomarker for rapid disease progression in ALS., Competing Interests: The authors have declared that no competing interests exist.

Background: Thioguanine (TG) is available only in the form of 40 mg tablets in the United States, and the patient population in which TG is used comprises mostly children. Recognizing its importance as a therapeutic agent and limited stability data for its compounded preparation, the United States Pharmacopoeia has listed TG in its priority list of compounded preparations monographs. Objective: The goal of the present study was to generate stability data and establish a beyond-use date for compounded TG suspension. Methods: Suspensions were compounded using TG tablets and ORA-Plus and ORA-Sweet as vehicles. A robust high-performance liquid chromatography method was developed and validated. TG and guanine (G) in suspensions were quantified immediately after compounding and at regular intervals for 90 days. Physical stability of suspensions was evaluated by observation of organoleptic properties. Results: Results from the study indicate that average TG levels in suspensions remained above 90% of the starting concentration and G formation was less than 2.5% for 90 days. There was no statistically significant difference in the amount of TG degraded over 90 days between suspensions stored at room temperature and in refrigerated conditions. There was also no statistically significant difference in G concentration of suspensions between day 0 and day 90. Conclusion: TG suspensions are stable for 90 days when stored at room temperature or refrigerated conditions and the beyond-use date can be set to 90 days., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Water activity refers to the amount of water in a system that is available for microbial growth. Commercial water activity meters are precision instruments with the ability to determine water activity to within 0.001 units and carry prices of $10,000 or more. The purpose of the study was to build a robust water activity meter from commercially available components and measure the water activity of liquids commonly used in compounded formulations. SHT-85 sensors were connected to an Adafruit Feather HUZZAH microcontroller. Standard salt slurries and common oral liquid vehicles were monitored in airtight containers until equilibrium was reached. Standard curves were used to convert sensor outputs to water activity values. The standard curves were linear with R2 >0.99. Oral liquid vehicles showed water activity values between 0.62 and 0.99. Samples equilibrated within 9.5 hours in 16-ounce jars or 2.5 hours in 20-mL vials. Stirring the sample during measurement reduced equilibration time in 16-ounce jars, but not in 20-mL vials. The inexpensive meter was accurate and precise in measuring the water activity of standards and selected oral vehicles. An accurate and precise water activity meter was constructed at a cost of approximately $150. Common oral formulation components have a water activity of >0.6, the United States Pharmacopeial threshold for requiring a preservative. Pharmacists should use caution when diluting preserved vehicles., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

The neuroactive metabolites of the steroid hormones progesterone (P4) and testosterone (T) are GABAergic modulators that influence cognition, yet, the specific effect of P4 and T on brain network activity remains poorly understood. Here, we investigated if a fundamental oscillatory network activity pattern, often related to cognitive control, frontal midline theta (FMT) oscillations, are modulated by steroids hormones, P4 and T. We measured the concentration of P4 and T using salivary enzyme immunoassay and FMT oscillations using high-density electroencephalography (EEG) during eyes-open resting-state in 55 healthy women and men. Electrical brain activity was analyzed using Fourier analysis, aperiodic signal fitting, and beamformer source localization. Steroid hormone concentrations and biological sex were used as predictors for scalp and source-estimated amplitude of theta oscillations. Elevated concentrations of P4 predicted increased amplitude of FMT oscillations across both sexes, and no relationship was found with T. The positive correlation with P4 was specific to the frontal midline electrodes and survived correction for the background aperiodic signal of the brain. Using source localization, FMT oscillations were localized to the frontal-parietal network (FPN). Additionally, theta amplitude within the FPN, but not the default mode network, positively correlated with P4 concentration. Our results suggest that P4 concentration modulates brain activity via upregulation of theta oscillations in the FPN., (© 2020 Society for Psychophysiological Research.)

Background: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD)., Objectives: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations., Methods: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis., Results: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions., Conclusions: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objective: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG)., Methods: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups., Results: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone., Conclusions: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone., Clinicaltrialsgov Identifier: NCT00294658., Classification of Evidence: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone., (© 2020 American Academy of Neurology.)

Introduction: Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scales were compared using the data from the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) study., Methods: Correlation between QMG and MG-ADL raw and change-from-baseline scores was calculated every 3 months for 60 months based on treatment groups and minimal manifestation status (MMS)., Results: QMG and MG-ADL change-from-baseline scores correlated significantly, with increasing strength of correlation over time, in both treatment groups. QMG and MG-ADL raw scores correlated significantly in both treatment groups, with increasing correlation only in the prednisone-alone group. Correlation between raw scores was weaker in patients who were in MMS, demonstrating a "floor effect" on the MG-ADL scale. Raw QMG scores could be modeled assuming a normal distribution, whereas raw MG-ADL scores could not be modeled this way., Discussion: The floor effect and skewed distribution of the MG-ADL measure should be taken into account in the design of myasthenia gravis clinical trials., (© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

Background: To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years., Methods: Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36 months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures., Results: Nineteen children underwent surgery (median age 17 months, range 3.7 to 21.3), and mean follow-up was 22.8 months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains., Conclusions: These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Darier's disease is a rare genodermatosis typically characterized by scaly or crusted papules. Usual management comprises topical and oral treatments, however medical therapy may be inadequate in cases of severe disease. For these patients, further treatment options may include the use of carbon dioxide (CO 2 ) laser therapy or surgical excision with skin grafting. We describe a unique situation in which both CO 2 laser therapy and surgical excision were trialed in comparable areas within a single patient. Superior outcomes over a 7-year follow up period have been seen with the use of CO 2 laser therapy.

Topical pain therapy offers several potential advantages as an alternative or adjunct to oral analgesic therapy, including decrease in concurrent oral drug use, lower abuse potential, lower side effects and toxicity, and localized effects. A variety of drugs and cream bases designed to promote transdermal delivery allow for unlimited customization of compounded topical pain creams (CTPC) for specific patients. The purpose of this study was to understand why patients begin CTPC therapy, their perceptions of CTPC therapy, and their level of satisfaction with CTPC therapy. A self-administered survey was distributed to patients receiving a compounded prescription. There were 107 responses from CTPC users. The typical CTPC user was a 67 year old woman with pain in the neck, back, or feet. The median duration of CTPC use was 4.5 months. Pain specialists, general practitioners, podiatrists, and orthopedists were the primary prescribers of CTPC. The prescriber was the first person to suggest CTPC for most patients. The majority of patients had insurance coverage for the CTPC and paid an average of $24.41 out of pocket per prescription. Most patients were highly satisfied with all aspects of CTPC and were more satisfied with CTPC than other medications they had used for the medical condition previously.

Adolescence is a critical period in both physical and psychological development. Skin conditions are very common in this age group, and are known to impart a considerable psychological burden, with higher rates of both anxiety and depression in those with chronic skin disease. The Department of Health has identified the specialized needs of adolescents as they transition from paediatric to adult services as a key priority, with emphasis on providing 'developmentally appropriate healthcare'. However, in spite of this, there are very few dedicated transitional clinics in the UK with appropriate psychosocial support. We have demonstrated in our own clinical practices that a dedicated teenage and young adult dermatology clinic with embedded specialist psychological support can deliver effective dermatological care to young people with a variety of skin conditions. We call for a greater focus on achieving developmentally appropriate care for adolescents across the UK to address the unmet transitional and psychological care needs in this population., (© 2019 British Association of Dermatologists.)

Skin conditions are common in adolescence and impart considerable psychological burden. The Department of Health has identified the specialized needs of adolescents transitioning from paediatric to adult services as a priority, yet there are few dedicated transitional clinics in the UK providing appropriate psychosocial support. We have established a monthly Teenage and Young Adult (TYA) dermatology clinic dedicated to managing teenagers and young adults with skin disease alongside open-access psychological support. Demographic data and Teenagers' Quality of Life Index (T-QoL) measures were recorded for all patients in 2016. To evaluate patient experience, two online surveys were conducted. Statistically significant improvements in the T-QoL were recorded for patients with the most common skin condition (eczema) attending for repeat assessment by the psychologist. Patients reported high satisfaction rates in both patient experience surveys. These results demonstrate that specialized adolescent care both is well received and can improve outcomes for these patients., (© 2019 British Association of Dermatologists.)

Objectives: There are few data directly from patients regarding their experiences with compounded prescriptions (CRx). The purpose of this study was to determine how patients initiated CRx use and how they perceived their CRx therapy., Methods: A cross-sectional mailed national survey design was used. Participating pharmacies distributed questionnaires to their patients when dispensing CRx. The questionnaire contained items relating to patient demographics, previous use of CRx, how the patient came to use CRx, how the pharmacy was chosen, and satisfaction with the CRx., Results: Four hundred ninety-four usable responses were received. Respondents were predominantly female (82.3%) with an average age of 60.5 years. Most respondents received their CRx by mail or delivery service (78.2%). The average duration of CRx use was 30 months. Patients with insurance paid an average of $50.04 for the CRx, whereas uninsured patients paid an average of $116.20. Hormone replacement therapy (HRT; 50.1%) and pain management (23.1%) were the most frequent indications for CRx therapy. CRx were primarily used to replace (68.1%) rather than supplement (31.9%) previous medications. The prescriber was the first person to suggest CRx therapy (78.9%), and the prescriber's recommendation was important in choosing the compounding pharmacy (89.6%) for most patients. More than 95% of patients were satisfied with all aspects of CRx therapy except cost. Patients judged CRx as equally good or better than previous medications they had used for their medical condition., Conclusion: Respondents used CRx for HRT, pain treatment, and a variety of medical conditions. CRx were used primarily to replace other medications because of treatment failure or intolerable adverse effects. Respondents were satisfied with all aspects of CRx therapy with the exception of out-of-pocket cost. The prescriber's recommendation was the single most important factor in a patient choosing to use CRx and in choosing a compounding pharmacy., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Dysregulation of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in psychiatric disorders. Music therapy (MT) has been shown to modulate heart-rate variability (HRV) and salivary stress markers, physiological markers of the ANS and HPA axes, respectively. Given the prominent role of arousal and stress physiology in many psychiatric disorders, MT has the potential to provide therapeutic benefits in psychiatry. Active MT requires patients to engage rhythmically with music; in contrast, passive MT requires patients to listen to music, eliminating the rhythmic movement seen in active MT. Yet, it remains unknown whether active or passive MT differentially modulates arousal and stress physiology. We contrasted the effects of active and passive MT experiences to examine the differential impact of rhythmic movement on the ANS and HPA axes in healthy participants. Individuals (N = 16) participated in a crossover study of 40 min of an active MT and a passive MT intervention. HRV recordings and saliva samples were collected both before and after each intervention. The high-frequency component (HF) and the ratio of low-frequency to high-frequency components (LF/HF) were calculated as cardiac markers of parasympathetic and sympathetic ANS activation, respectively. Saliva samples were analyzed for alpha-amylase and cortisol, markers of the sympathetic ANS and HPA axes, respectively. Active MT and passive MT interventions differentially modulated LF/HF, where active MT decreased LF/HF and passive MT increased LF/HF. These results indicate that MT affects the ANS and suggests that differences in engagement between active MT and passive MT lead to a differential modulation of the sympathetic ANS., (© American Music Therapy Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours arising in the gastrointestinal tract. Early detection, before metastasis occurs, is important as complete surgical excision achieves cure. Approximately 85% of GISTs are associated with mutations in the KIT gene, and although the majority of GISTs are sporadic, familial GISTs have been identified. Several families with multiple GIST tumours have also been described with various cutaneous findings including hyperpigmentation, multiple lentigines, vitiligo and urticaria pigmentosa. We discuss a 6-year-old boy who presented with an unusual pattern of hyperpigmentation in association with a family history of GIST. A causative KIT mutation was identified in DNA from the pigmented skin and from the resected GIST, and the patient was referred to the Paediatric Gastroenterology department for GIST screening. The term 'GIST cutaneous hyperpigmentation disease' has been suggested previously for the association of familial GIST with cutaneous hyperpigmentation caused by a germline KIT mutation., (© 2018 British Association of Dermatologists.)

Objective: To investigate financial skill decline over a 6-year period in persons with mild cognitive impairment (MCI) presumed due to Alzheimer's disease (AD)., Methods: Study participants were cognitively normal (CN) older adults (n = 82) and adults with MCI (n = 91) based on consensus conference diagnosis. Participants completed baseline and up to six annual follow-up assessments that included standardized financial skills measurement (Financial Capacity Instrument; FCI; nine FCI domain and two global scores). We examined FCI change over time using mixed-model repeated measures analysis adjusted for baseline age and follow-up duration., Results: At baseline, the CN group performed better than the MCI group across both global and seven domain scores. Group × Time interaction effects (all p's <.02) were found for all global and domain scores. The largest interaction effects were observed for complex domains of Financial Conceptual Knowledge, Checkbook Management, Bank Statement Management, and Bill Payment (all p's <.0001). Annualized decline in the MCI group's global scores, calculated in relation to CN group performance, was 10-17% over the initial 3-year time span and 22-24% at 6 years. Decline in FCI domain scores ranged from 6% (Knowledge of Assets/Estate) to 22% (Investment Decision-Making) at 3 year follow-up, and from 15% (Basic Monetary Skills) to 37% (Financial Judgment) at 6 year follow-up., Conclusions: Over a 6-year period, persons with MCI demonstrated significant declines in multiple financial skills and in particular financial judgment. The findings highlight the importance of ongoing oversight by family members and clinicians of financial skills and activities in persons with MCI.

Objective: Prednisone is a first-line immunosuppressive treatment for myasthenia gravis (MG), whereas short-term and long-term adverse effects (AEs) are a limiting factor in its usage., Method: The MG patient registry is a patient-driven, nation-wide database with patients of age ≥18 years, who were diagnosed with MG and live in the United States. Custom-designed "prednisone-steroid use and MG" survey was sent out to MG registry participants as part of semi-annual follow-up. Data were collected and analyzed for frequency., Results: A total of 398 MG participants (21% response rate) completed the survey, including 173 men and 225 women. Among them, 298 reported current (174) or past (288) prednisone intake. Current prednisone dosage varied from 0.5 to 75 mg (median 10 mg, IQR 7-20), dosing frequency was daily in 132 (76%) and every other day in 31 (18%). Peak prednisone dose was commonly between 25 mg and 60 mg (Median 50 mg, IQR 25-60); however, doses more than 60 mg daily were reported in 59 (20%). Prednisone AEs were reported more commonly in women (95% vs 81%, p < 0.0001). Women reported more intolerable AEs (77% vs 50%, p < 0.00001) and less willingness to accept a dose increase (26% vs 44%, p = 0.03) compared with men., Conclusions: Prednisone is commonly used in the treatment of MG, with highly variable dosages and dosing frequencies reflecting the absence of a standard guideline. Intolerable AEs were more commonly reported among women and was associated with unwillingness to accept a dose increase. Consensus guidelines and their validation are required to guide prednisone treatment for MG.

Rhythmic entrainment-defined as a stable temporal relationship between external periodic signals and endogenous rhythmic processes-allows individuals to coordinate with environmental rhythms. However, the impact of inter-individual differences on entrainment processes as a function of the tempo of external periodic signals remain poorly understood. To better understand the effects of endogenous differences and varying tempos on rhythmic entrainment, 20 young healthy adults participated in a spontaneous motor tempo (SMT) task and synchronization-continuation tasks at three experimental tempos (50, 70, and 128 bpm; 1200, 857, and 469 ms inter onset interval (IOI)). We hypothesized that SMT task performance and tempo would influence externally paced synchronization-continuation task behavior. Indeed, intrinsic rhythmicity assessed through the SMT task predicted performance in the externally paced task, allowing us to characterize differences in entrainment behavior between participants with low and high endogenous rhythmicity. High rhythmicity individuals, defined by better SMT performance, deviated from externally paced pulses sooner than individuals with low rhythmicity, who were able to maintain externally paced pulses for longer. The magnitude of these behavioral differences depended on the experimental tempo of the synchronization-continuation task. Our results indicate that differences in intrinsic rhythmicity vary between individuals and relate to tempo-dependent entrainment performance.

Naevus sebaceous (NS) is a congenital cutaneous hamartoma, which typically occurs on the head and neck. Historically, the treatment of choice was excision in infancy because of the potential for malignant transformation; however, recent studies suggest that this risk is < 1% and unlikely in childhood. We sent a questionnaire to UK dermatologists and plastic surgeons to investigate current management practice of NS. We found that almost a third of dermatologists still recommend excision for malignancy prevention, while over 90% of plastic surgeons consider excision, with 64% citing malignancy prevention as the reason. Plastic surgeons most commonly recommended excision in childhood, whereas dermatologists waited until adulthood. We have shown there is significant variation in practice across the UK in the management of naevus NS. It is important that patients across the UK receive the same standard of care, and therefore we advocate the development of evidence-based guidance for treatment of naevus NS., (© 2018 British Association of Dermatologists.)

Survival with a good quality of life after cardiac arrest continues to be abysmal. Coordinated resuscitative care does not end with the effective return of spontaneous circulation (ROSC)-in fact, quite the contrary is true. Along with identifying and appropriately treating the precipitating cause, various components of the post-cardiac arrest syndrome also require diligent observation and management, including post-cardiac arrest neurologic injury and myocardial dysfunction, systemic ischemia-reperfusion phenomenon with potential consequent multiorgan failure, and the various sequelae of critical illness. There is growing evidence that an early invasive approach to coronary reperfusion with percutaneous coronary intervention, together with active targeted temperature management and optimization of hemodynamic, ventilator, and metabolic parameters, may improve survival and neurologic outcomes in cardiac arrest survivors. Neuroprognostication is complex, as are survivorship issues and long-term rehabilitation. Our paramedics, emergency physicians, and resuscitation specialists are all to be congratulated for ever-increasing success with ROSC… but now the real work begins., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere.

Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease., Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance., Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens., Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies., Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens., Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.