Workplace Mistreatment, Career Choice Regret, and Burnout in Emergency Medicine Residency Training in the United States.

STUDY OBJECTIVE: The influence of workplace mistreatment on the well-being and career satisfaction of emergency medicine residents is unknown. This study examined the relationships between burnout, career choice regret, and workplace mistreatment in a national sample of emergency medicine residents. METHODS: This was a secondary analysis of a survey study on the prevalence of workplace mistreatment among emergency residents. Residents who reported emotional exhaustion or depersonalization at least once per week were considered to have burnout. Residents who reported dissatisfaction with their decision to become an emergency physician were considered to have career choice regret. Respondents also reported the type (discrimination, abuse, sexual harassment) and frequency of mistreatment over the academic year. Multivariable logistic regression, adjusting for program characteristics, was used to examine resident characteristics associated with burnout and career choice regret, with the frequency of mistreatment as a covariate. RESULTS: Of the 8,162 eligible residents, 7,680 (94.1 %) participated. About a third of respondents reported burnout (2,188 of 6,902, 31.7%), whereas a minority (224 of 6,923, 3.2%) reported career choice regret. Of the 7,087 responses on mistreatment frequency, 2,117 (29.9%) reported "a few times per year," and 1,296 (18.3%) reported "a few times per month or more." Compared with residents who never experienced mistreatment, residents who reported increasing frequencies of mistreatment were associated with having burnout-from mistreatment a few times per year (OR [odds ratio],1.6; 99% CI [confidence interval], 1.3 to 1.9) to a few times per month or more (OR, 3.3; 99% CI, 2.7 to 4.1). Compared with residents without burnout, residents who reported burnout were associated with having career choice regret (OR, 11.3; 99% CI, 7.0 to 18.1). After adjusting for burnout, there were no significant relationships between the frequency of mistreatment and career choice regret. CONCLUSIONS: Workplace mistreatment is associated with burnout, but not career choice regret, among emergency medicine residents. Efforts to address workplace mistreatment may improve emergency medicine residents' professional well-being.

PRAME-negativity in sclerosing nevi with pseudomelanomatous features supports classification as an indolent lesion.

BACKGROUND: Some dysplastic nevi, termed sclerosing nevi with pseudomelanomatous features, may have florid fibroplasia associated with features that cause melanoma to be a prominent consideration in the differential diagnosis. PRAME (PReferentially expressed Antigen in MElanoma) immunohistochemistry (IHC) has been shown to be a useful marker in the distinction of melanoma and nevus. PRAME expression in such sclerosing nevi with pseudomelanomatous features has not been evaluated to our knowledge. METHODS: Thirty-two sclerosing nevi with pseudomelanomatous features were stained with PRAME IHC, with positive labeling defined as staining of >75% of the cytomorphologically atypical lesional cells. RESULTS: All 32 cases had variable cytologic atypia, bridging of elongated rete, fibroplasia, and a vertically oriented trizonal appearance. Some cases (23/32) had centrally located flattening of the rete ridge pattern bilaterally flanked by fibroplasia associated with elongated rete. PRAME labeling was negative (<1% labeling) in 28/32 cases. Four cases, also interpreted as having negative labeling with PRAME, showed only weak nuclear positivity of <50% of the melanocytes within the pseudomelanomatous foci. p16 staining was positive in 28/28 lesions. CONCLUSIONS: Rare sclerosing nevi with pseudomelanomatous features (4/32; ~13%) had weak PRAME labeling of 25%-50% of atypical foci. Twenty-eight of 32 lesions had virtually no labeling with PRAME. PRAME results support classifying sclerosing nevi with pseudomelanomatous features as indolent lesions.

Acute Epstein-Barr virus infection resembling cutaneous T-cell lymphoma.

Primary, acute Epstein-Barr virus (EBV) infection is associated with a variety of cutaneous eruptions, including the viral exanthem of infectious mononucleosis and erythema multiforme. Latent, chronic EBV infection can rarely result in development of lymphoproliferative disorders with cutaneous manifestations; however, these disorders do not arise from primary infection. In this report, we present a case of primary, acute EBV infection presenting with histopathologic features closely mimicking aggressive cytotoxic cutaneous T-cell lymphoma.

High-throughput screening for prescribing cascades among real world statin initiators.

PURPOSE: Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been performed to our knowledge. METHODS: We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes ("marker" classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005-2019). Order of initiation and secular trend-adjusted sequence ratios were calculated for each statin-marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed. RESULTS: We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin-marker class dyad signals, of which 35.6% (n = 57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43-46), opioids + non-opioid combination analgesics (81, 95% CI 74-91), and first-generation cephalosporins (204, 95% CI 175-246). CONCLUSIONS: Using high-throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin-related adverse events.

Association between gabapentinoids and oedema treated with loop diuretics: A pooled sequence symmetry analysis from the USA and Denmark.

AIMS: To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. METHODS: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. RESULTS: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years. CONCLUSION: We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries.

Evaluation of the key prescription sequence symmetry analysis assumption using the calcium channel blocker: Loop diuretic prescribing cascade.

OBJECTIVES: To evaluate the prescription sequence symmetry analysis assumption regarding balance between marker drug (i.e., medication used to treat a drug-induced adverse event) initiation rates before and after initiation of an index drug (i.e., medication that is potentially associated with the drug-induced adverse event) in the absence of prescribing cascades, we used a well-described example of loop diuretic initiation to treat dihydropyridine calcium channel blockers (DH CCB)-induced edema. STUDY DESIGN AND SETTING: The University of Florida Health Integrated Data Repository from June 2011 and July 2018 was used to assess temporal prescribing of DH CCB and loop diuretics within the prescription sequence symmetry analysis framework. Validation of the prescribing cascade was performed via clinical expert chart review. RESULTS: Among patients without heart failure who were initiated on DH CCB, 26 and 64 loop diuretics initiators started within 360 days before versus after DH CCB initiation, respectively, resulting in an adjusted sequence ratio (aSR) of 2.27 (95% CI, 1.44-3.58). Overall, 35 (54.7%) patients were determined to have a prescribing cascade. Removing patients who experienced a prescribing cascade resulted in an aSR of 1.05, 95% CI 0.62-1.78). CONCLUSION: Loop diuretic initiation rates before and after DH CCB initiation for reasons other a prescribing cascade were similar, thus confirming the prescription sequence symmetry analysis assumption.

Emergency Medicine Residency Does Not Reduce a Racial Minority-Based Test Performance Gap.

BACKGROUND: Health care inequity is corrected more readily when safe, high-quality care is provided by physicians who reflect the gender, race, and ethnicity of patient communities. It is important to train and evaluate racially diverse physicians involved in residency training. OBJECTIVE: This study sought to determine any test-taking differences for black Emergency Medicine (EM) residents and whether any such differences would narrow as residency progressed. METHODS: This was an observational, cross-sectional study that reviewed performance (scaled scores) on the American Board of Emergency Medicine (ABEM) In-Training Examination (ITE) for 2018, 2019, and 2020. The study included EM residents in 3-year programs who took the ITE. A linear regression model was used for the variables of race, which included black physicians and white physicians (reference group), and level of training (EM resident year 1 [EM1] as the reference group). RESULTS: There were 9591 residents included; 539 were black and 9052 were white. Mean scaled scores were higher as a function of training level. Regression showed a scaled score intercept of 73.51. The ITE score increased for all groups as a function of training level (EM2 ß = +5.45, p < 0.0001; EM3 ß = +8.09, p < 0.0001). The regression coefficient for black residents was -5.87 (p < 0.0001). There was relative improvement by training level compared with improvement in the reference group, but this difference was not materially or statistically significant. CONCLUSION: In this study of the ABEM ITE, a test-taking performance gap identified early in residency for black physicians persisted into late residency.

Home therapies to improve disability, activity, and quality of life in military personnel with subacute low back pain: Secondary outcome analysis of a randomized controlled trial.

BACKGROUND: Low back pain (LBP) is an urgent military health concern with implications for fitness, quality of life (QoL) and disability. PURPOSE: This secondary outcome analysis from a randomized controlled trial (RCT) was to determine if the addition of neuromuscular electrical stimulation core strength training (NMES) or progressive exercise (PEP)in conjunction with primary care management (PCM) was more effective than PCM alone. METHODS: This randomized controlled trial (RCT assigned 128 service members to the three intervention groups. The outcomes included changes in perceived disability (Oswestry Disability Index), health-related quality of life (SF-12v2), pain during activity (Clinical Back Pain Questionnaire), and daily steps walked in service members with subacute LBP. FINDINGS: Over a 9-week intervention, perceived disability, SF-12v2 physical component summary, and activity associated with pain improved in all groups. Home therapies were helpful to reduce perceived disability, QoL and pain during activity in service members with subacute LBP. DISCUSSION: These non-pharmacological options provide other home-managed approaches for those in the subacute LBP phase.

The Emergency Medicine Physician Workforce: Projections for 2030.

STUDY OBJECTIVE: The goals of this study were to determine the current and projected supply in 2030 of contributors to emergency care, including emergency residency-trained and board-certified physicians, other physicians, nurse practitioners, and physician assistants. In addition, this study was designed to determine the current and projected demand for residency-trained, board-certified emergency physicians. METHODS: To forecast future workforce supply and demand, sources of existing data were used, assumptions based on past and potential future trends were determined, and a sensitivity analysis was conducted to determine how the final forecast would be subject to variance in the baseline inputs and assumptions. Methods included: (1) estimates of the baseline workforce supply of physicians, nurse practitioners, and physician assistants; (2) estimates of future changes in the raw numbers of persons entering and leaving that workforce; (3) estimates of the productivity of the workforce; and (4) estimates of the demand for emergency care services. The methodology assumes supply equals demand in the base year and estimates the change between the base year and 2030; it then compares supply and demand in 2030 under different scenarios. RESULTS: The task force consensus was that the most likely future scenario is described by: 2% annual graduate medical education growth, 3% annual emergency physician attrition, 20% encounters seen by a nurse practitioner or physician assistant, and 11% increase in emergency department visits relative to 2018. This scenario would result in a surplus of 7,845 emergency physicians in 2030. CONCLUSION: The specialty of emergency medicine is facing the likely oversupply of emergency physicians in 2030. The factors leading to this include the increasing supply of and changing demand for emergency physicians. An organized, collective approach to a balanced workforce by the specialty of emergency medicine is imperative.

Use of negative controls in a prescription sequence symmetry analysis to reduce time-varying bias.

PURPOSE: There is an increased use in the (prescription) sequence symmetry analysis (PSSA); however, limited studies have incorporated a negative control, and no study has formally quantified and controlled for within-patient time-varying bias using a negative control. Our aim was to develop a process to incorporate the effect of negative controls into the main analysis of a PSSA. METHODS: Using a previously assessed dihydropyridine calcium channel blocker (DH-CCB) and loop diuretic PSSA, we directly compared the adjusted sequence ratios (aSRs) of DH-CCBs to each of the two negative control index drugs (levothyroxine and angiotensin converting enzyme [ACE] inhibitor/angiotensin-2 receptor blocker [ARB]) using the ratio of the aSRs to estimate a relative aSR with a Z test. Further, we utilized the relative aSR in stratum-specific analyses and varying exposure windows. RESULTS: The relative aSR of DH-CCBs decreased from 1.87 to 1.72 (95% CI 1.66-1.78) using levothyroxine as a negative control index drug. ACE inhibitor/ARB negative control index drug resulted in an aSR of 1.27 thus reducing the relative aSR for DH-CBB from 1.84 to 1.45 (95% CI 1.41-1.49). When restricting the exposure window to 180 and 90 days, the relative aSR of DH-CCBs increased to 1.68 (95% CI 1.62-1.74) and 1.86 (95% CI 1.78-1.94), respectively, relative to the ACE inhibitor/ARB negative control index drug. CONCLUSION: We illustrated how to incorporate negative control index drugs into a PSSA and generate relative aSRs. Stratum-specific assessments and varying the exposure windows while using negative control index drugs can yield more informative results.

Doctors' reporting of mental health stigma and barriers to help-seeking.

BACKGROUND: Medical practitioners experience high levels of mental disorders but may be reluctant to seek care. AIMS: To determine medical practitioner attitudes towards other doctors with anxiety/depression, barriers to seeking mental healthcare, treatments received for depression and the effects of age. METHODS: Data from the National Mental Health Survey of Doctors and Medical Students, conducted in Australia, were analysed (N = 10 038 medical practitioners). Attitudes to anxiety/depression were assessed with 12 statements (total stigma score, range 12-60). Barriers to seeking professional help, and coping strategies used, for anxiety/depression were measured. Practitioners with a history of depression were asked what personal supports and treatments were received. Practitioners were compared by age-younger (40 years and younger), middle-aged (41-60) and older (61+). RESULTS: Attitudes and help-seeking behaviours varied with age. Older doctors had a more positive outlook and less total stigma, with the exception that they believed a doctor with anxiety/depression was less reliable. Younger practitioners were most likely to report barriers, such as confidentiality, impact on career progression and registration, to seeking help. For practitioners with depression, counselling and counselling plus medication were most likely to be received by the younger and middle-aged groups, whereas medication alone was most likely to be received by the middle-aged and older groups. CONCLUSIONS: Stigmatizing attitudes towards mental disorder and barriers to help-seeking remain prevalent within the medical profession. Our results suggest doctors' health programs should address mental health stigma in younger practitioners and facilitate education about psychological treatments in older practitioners.

Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline.

ESGE recommends offering stone extraction to all patients with common bile duct stones, symptomatic or not, who are fit enough to tolerate the intervention.Strong recommendation, low quality evidence.ESGE recommends liver function tests and abdominal ultrasonography as the initial diagnostic steps for suspected common bile duct stones. Combining these tests defines the probability of having common bile duct stones.Strong recommendation, moderate quality evidence.ESGE recommends endoscopic ultrasonography or magnetic resonance cholangiopancreatography to diagnose common bile duct stones in patients with persistent clinical suspicion but insufficient evidence of stones on abdominal ultrasonography.Strong recommendation, moderate quality evidence.ESGE recommends the following timing for biliary drainage, preferably endoscopic, in patients with acute cholangitis, classified according to the 2018 revision of the Tokyo Guidelines:- severe, as soon as possible and within 12 hours for patients with septic shock- moderate, within 48 - 72 hours- mild, elective.Strong recommendation, low quality evidence.ESGE recommends endoscopic placement of a temporary biliary plastic stent in patients with irretrievable biliary stones that warrant biliary drainage.Strong recommendation, moderate quality of evidence.ESGE recommends limited sphincterotomy combined with endoscopic papillary large-balloon dilation as the first-line approach to remove difficult common bile duct stones. Strong recommendation, high quality evidence.ESGE recommends the use of cholangioscopy-assisted intraluminal lithotripsy (electrohydraulic or laser) as an effective and safe treatment of difficult bile duct stones.Strong recommendation, moderate quality evidence.ESGE recommends performing a laparoscopic cholecystectomy within 2 weeks from ERCP for patients treated for choledocholithiasis to reduce the conversion rate and the risk of recurrent biliary events. Strong recommendation, moderate quality evidence.

More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.

BACKGROUND: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. OBJECTIVE: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. METHODS: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. RESULTS: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. LIMITATIONS: This clinical review was retrospective. CONCLUSION: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

Emergency medicine practice environment and impact on concert examination performance.

OBJECTIVE: The ABEM ConCert Examination is a summative examination that ABEM-certified physicians are required to pass once in every 10-year cycle to maintain certification. This study was undertaken to identify practice settings of emergency physicians, and to determine if there was a difference in performance on the 2017 ConCert between physicians of differing practice types and settings. METHODS: This was a mixed methods cross sectional-study, using a post-examination survey and test performance data. All physicians taking the 2017 ConCert Examination who completed three survey questions pertaining to practice type, practice locations, and teaching were included. These three questions address different aspects of academia: self-identification, an academic setting, and whether the physician teaches. RESULTS: Among 2796 test administrations of the 2017 ConCert Examination, 2693 (96.3%) completed the three survey questions about practice environment. The majority (N = 2054; 76.3%) self-identified as primarily being a community physician, 528 (19.6%) as academic, and 111 (4.1%) as other. The average ConCert Examination score for community physicians was 83.5 (95% CI, 83.3-83.8); the academic group was 84.8 (95% CI, 84.3-85.3); and the other group was 82.3 (95% CI, 81.1-83.6). After controlling for initial ability as measured by the Qualifying Examination score, there was no significant difference in performance between academic and community physicians (p = .10). CONCLUSIONS: Academic emergency physicians and community emergency physicians scored similarly on the ConCert. Working at a community teaching hospital was associated with higher examination performance. Teaching medical learners, especially non-emergency medicine residents, was also associated with better examination performance.

The Association Between Maintaining American Board of Emergency Medicine Certification and State Medical Board Disciplinary Actions.

BACKGROUND: In certain medical specialties, board certification is associated with a lower risk of state medical board disciplinary actions. OBJECTIVE: The association between maintaining American Board of Emergency Medicine (ABEM) certification and state medical disciplinary actions had not been studied. This study was undertaken to determine if maintaining ABEM certification was associated with a lower risk of disciplinary action. METHODS: This investigation was a historical cohort study using Cox regression. Physicians who did not have a lapse in ABEM certification were compared with physicians who had a lapse to determine the risk of disciplinary action. Lapsing was determined at the expiration of the initial certificate. This study included all physicians who obtained initial ABEM certification from 1980-2005. Additional covariates of interest included the number of attempts on the ABEM Qualifying Examination (1 vs. >1), the geographic region of the physician's residence, and the country of medical school. RESULTS: There were 23,002 physicians in the study cohort. Of these, 3370 (14.7%) let their certification lapse after initial certification. There were 701 (3.0%) physicians with disciplinary events. Lapsed physicians had higher rates of disciplinary actions than physicians who did not lapse (6.4% vs. 2.5%). ABEM-certified physicians who did not lapse were significantly less likely to be disciplined as physicians who let their certificate lapse (hazard ratio 0.50 [95% confidence interval 0.42-0.59]). CONCLUSIONS: The absolute incidence of physicians with a disciplinary action in this study cohort was low (3.0%). Maintaining ABEM certification was associated with a lower risk of state medical board disciplinary actions.

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy.

BACKGROUND: Bullous disorders associated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established. OBJECTIVE: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy. METHODS: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018. RESULTS: We identified 9 of 853 patients who developed bullous eruptions (∼1%) that were treated with an-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSIONS: Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents.

Squamous proliferations on the legs of women: Qualitative examination of histopathology, TP53 sequencing, and implications for diagnosis in a series of 30 cases.

BACKGROUND: Women with multiple squamous cell carcinomas (SCCs) of the legs have a striking clinical phenotype. Numerous tumors can develop in a short period of time. OBJECTIVE: Because histopathologic findings can vary in women with multiple SCC lesions, from keratoacanthoma-like to well-differentiated SCC, we hypothesized that TP53 variants might shed light on the appropriate classification. METHODS: We sequenced TP53 in 30 SCCs from 6 women who had multiple SCCs on their legs during a 21-month time frame. RESULTS: Histopathologic analysis showed 16 of the 30 lesions did not have prominent cytologic atypia and were distinguished by having expanded follicle-like structures composed of large, glassy, eosinophilic keratinocytes; these lesions resembled keratoacanthoma and were categorized as keratoacanthoma-like squamous proliferations (KASPs). The 14 remaining tumors had more prominent cytologic atypia and remained classified as SCC. Twenty of 30 tumors (including the KASPs) from the 6 different patients lacked detectable TP53 mutations. Ten of the 14 tumors that remained classified as SCC had detectable TP53 mutations. LIMITATIONS: This is a small series. CONCLUSION: These findings suggest that some cutaneous squamous proliferations on the legs of women with multiple lesions lack prominent cytologic atypia as well as TP53 mutations and might be more akin to keratoacanthoma than SCC or might represent a reactive phenomenon.

Refinement of screening for familial pancreatic cancer.

OBJECTIVE: Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. METHODS: IAR from non-CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. RESULTS: 253 IAR with a median age of 48 (25-81) years underwent screening with a median of 3 (1-11) screening visits during a median follow-up of 28 (1-152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30). CONCLUSIONS: It appears safe to start screening for PDAC in IAR of non-CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.

New insights into Brunner syndrome and potential for targeted therapy.

We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.