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Zusammenfassung Hintergrund und Ziel der Arbeit Seit Jahren werden Defizite der Qualität der Schmerztherapie im Krankenhaus beschrieben. Ziel der vorliegenden Untersuchung war es, Strukturen und Prozesse des Schmerzmanagements in internistischen Abteilungen darzustellen. Material und Methoden Die Datenerfassung erfolgte mittels eines standardisierten Telefoninterviews (nichtuniversitäre Abteilungen); bei universitären Abteilungen separat mittels eines Onlinefragebogens (SurveyMonkey®). Ergebnisse Daten von 139 nichtuniversitären Abteilungen (Rücklauf: 21 %) und 33 universitären Abteilungen (davon 21 vollständig beantwortete Fragebögen, Rücklauf 17 % bzw. 11 %) wurden erhoben. 441 von 619 kontaktierten nichtuniversitären Abteilungen lehnten die Teilnahme ausdrücklich ab, am häufigsten mit der Begründung, es bestünde kein Interesse am Thema Schmerzmanagement. In den 172 teilnehmenden Einrichtungen wurde Schmerz als eigenständiger Parameter in 89 % der nichtuniversitären Abteilungen (96 % universitär) regelmäßig während der Visite erfasst; schriftliche Behandlungsstandards zur Schmerztherapie lagen in 57 % der nichtuniversitären Abteilungen vor (54 % universitär). In 76 % der nichtuniversitären Krankenhäuser (100 % universitär) stand auch für die internistischen Patienten ein Akutschmerzdienst zur Mitbehandlung zur Verfügung, schriftliche Vereinbarungen zur Zusammenarbeit lagen bei 35 % vor (18 % universitär). Diskussion Die berichtete Umsetzung des Schmerzmanagements war in den teilnehmenden Abteilungen gut. Gleichwohl sind die Ergebnisse bei niedriger Teilnahme und häufiger Ablehnung mit der Begründung einer fehlenden Relevanz nur eingeschränkt aussagekräftig. Die erfassten Daten reflektieren daher vermutlich eine erhebliche positive Selektion und sind nicht als repräsentativ für das Schmerzmanagement in der inneren Medizin zu werten.

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Contains figures of most depleted δ13C values of selected early Eocene hyperthermals and age of volcanic ash layer MA-1 with graphical representation of error ranges. Additionally, tables of all δ13C data, organic carbon contents, thicknesses of clastic intervals, and details of U-Pb zircon analyses are provided.

Summary Widespread peat formed early after the Last Glacial Maximum (LGM) in what is today’s Central North Sea. Here, we present insights into peat cored at 43 m water depth in the German exclusive economic zone (EEZ). Peat layers of generally a few centimeters thickness were recovered from multicores and from one gravity core at three sites. Porewaters in these samples document a slight hydrocarbon enrichment in the peats. Ethane, propane and butane were also found and may either document paleoseepage from an underlying oil-mature source rock and adsorption in the peat organic matter or, likely, peat-specific gases. The latter hypothesis is supported by accompanying abundant unsaturated analogues (i.e., ethene and propene). Peats were formed in a variable environmental setting with the majority of extractable organic matter consisting of higher plant wax material. However, in two samples also different amounts of a C20 highly branched isoprenoid (HBI) were found, which likely records abundant diatoms typical for an oligotrophic lake environment. In addition, all peat samples contained a suite of bacterial hopanes, hopenes and fernenes, recording strongly fluctuating methane-flux and methane-turnover during peat-formation with partially high 13C-depletions of

BACKGROUND. Undifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments. METHODS. Sixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing. RESULTS. Thirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS. CONCLUSIONS. In patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression. Fil: de Jesus, Adriana A.. National Institute Of Allergy And Infectious Diseases; Estados Unidos Fil: Hou, Yangfeng. Shandong University; China Fil: Brooks, Stephen. National Institute Of Arthritis And Musculoskeletal And Skin Diseases; Estados Unidos Fil: Malle, Louise. cahn School of Medicine at Mount Sinai; Estados Unidos Fil: Biancotto, Angelique. No especifíca; Fil: Huang, Yan. National Institute Of Allergy And Infectious Diseases; Estados Unidos Fil: Calvo, Katherine R.. National Institutes of Health; Estados Unidos Fil: Marrero, Bernadette. No especifíca; Fil: Moir, Susan. No especifíca; Fil: Oler, Andrew J.. National Institute Of Allergy And Infectious Diseases ; Estados Unidos Fil: Deng, Zuoming. National Institute Of Arthritis And Musculoskeletal And Skin Diseases; Estados Unidos Fil: Montealegre Sanchez, Gina A.. National Institute Of Allergy And Infectious Diseases ; Estados Unidos Fil: Ahmed, Amina. No especifíca; Fil: Allenspach, Eric. Washington State University; Estados Unidos Fil: Arabshahi, Bita. Virginia Commonwealth University; Estados Unidos Fil: Behrens, Edward. University of Pennsylvania; Estados Unidos Fil: Benseler, Susanne. University of Calgary; Canadá Fil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bout Tabaku, Sharon. No especifíca; Fil: Brescia, AnneMarie C.. No especifíca; Fil: Brown, Diane. No especifíca; Fil: Burnham, Jon M.. University of Pennsylvania; Estados Unidos Fil: Caldirola, Maria Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina Fil: Carrasco, Ruy. No especifíca; Fil: Chan, Alice Y.. University of California; Estados Unidos Fil: Cimaz, Rolando. Università degli Studi di Milano; Italia Fil: Dancey, Paul. Janeway Children's Hospital And Rehabilitation Centre; Canadá Fil: Dare, Jason. University of Arkansas for Medical Sciences; Estados Unidos Fil: DeGuzman, Marietta. Baylor College Of Medicine; Estados Unidos Fil: Dimitriades, Victoria. No especifíca; Fil: Ferguson, Ian. University of Yale. School of Medicine; Estados Unidos Fil: Ferguson, Polly. University of Iowa; Estados Unidos Fil: Finn, Laura. University of Washington; Estados Unidos Fil: Gattorno, Marco. No especifíca; Fil: Grom, Alexei A.. No especifíca; Fil: Hanson, Eric P.. No especifíca; Fil: Hashkes, Philip J.. No especifíca; Fil: Hedrich, Christian M.. University of Liverpool; Reino Unido Fil: Herzog, Ronit. University of New York; Estados Unidos Fil: Horneff, Gerd. Universitat zu Köln; Alemania Fil: Jerath, Rita. Augusta University; Estados Unidos Fil: Kessler, Elizabeth. University of Missouri; Estados Unidos Fil: Kim, Hanna. No especifíca; Fil: Kingsbury, Daniel J.. No especifíca; Fil: Laxer, Ronald M.. University Of Toronto. Hospital For Sick Children; Canadá Fil: Lee, Pui Y.. Children's Hospital Boston; Estados Unidos Fil: Lee Kirsch, Min Ae. Technische Universität Dresden; Alemania Fil: Lewandowski, Laura. No especifíca; Fil: Li, Suzanne. Hackensack University Medical Center; Estados Unidos Fil: Lilleby, Vibke. Oslo University Hospital; Noruega Fil: Mammadova, Vafa. Azerbaijan Medical University; Azerbaiyán Fil: Moorthy, Lakshmi N.. Robert Wood Johnson Medical School; Estados Unidos Fil: Nasrullayeva, Gulnara. Azerbaijan Medical University; Azerbaiyán Fil: O'Neil, Kathleen M.. Riley Hospital for Children; Estados Unidos Fil: Onel, Karen. Hospital for Special Surgery; Estados Unidos Fil: Ozen, Seza. Hacettepe University; Turquía Fil: Pan, Nancy. Hospital for Special Surgery; Estados Unidos Fil: Pillet, Pascal. Children Hospital Pellegrin-Enfants; Francia Fil: Piotto, Daniela G.P.. Universidade Federal de Sao Paulo; Brasil Fil: Punaro, Marilynn G.. University of Texas; Estados Unidos Fil: Reiff, Andreas. University of Nebraska; Estados Unidos Fil: Reinhardt, Adam. University of Nebraska; Estados Unidos Fil: Rider, Lisa G.. No especifíca; Fil: Rivas Chacon, Rafael. Nicklaus Children’s Hospital; Estados Unidos Fil: Ronis, Tova. Children’s National Health System; Estados Unidos Fil: Rösen Wolff, Angela. Technische Universität Dresden; Alemania Fil: Roth, Johannes. Children’s Hospital of Eastern Ontario; Canadá Fil: Mckerran Ruth, Natasha. Medical University of South Carolina; Estados Unidos Fil: Rygg, Marite. Norwegian University of Science and Technology; Noruega Fil: Schmeling, Heinrike. University of Calgary; Canadá Fil: Schulert, Grant. Children’s Hospital Medical Center; Estados Unidos Fil: Scott, Christiaan. University of Cape Town; Sudáfrica Fil: Seminario, Gisella. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Shulman, Andrew. University of California at Irvine; Estados Unidos Fil: Sivaraman, Vidya. Nationwide Children’s Hospital; Estados Unidos Fil: Son, Mary Beth. Boston Children’s Hospital; Estados Unidos Fil: Stepanovskiy, Yuriy. Shupyk National Medical Academy for Postgraduate Education; Ucrania Fil: Stringer, Elizabeth. Dalhousie University Halifax; Canadá Fil: Taber, Sara. Hospital for Special Surgery; Estados Unidos Fil: Terreri, Maria Teresa. Universidade Federal de Sao Paulo; Brasil Fil: Tifft, Cynthia. No especifíca; Fil: Torgerson, Troy. University of Washington; Estados Unidos Fil: Tosi, Laura. Children’s National Health System; Estados Unidos Fil: van Royen Kerkhof, Annet. Wilhelmina Children’s Hospital Utrech; Países Bajos Fil: Wampler Muskardin, Theresa. New York University School of Medicine; Estados Unidos Fil: Canna, Scott W.. University of Pittsburgh; Estados Unidos Fil: Goldbach Mansky, Raphaela. National Institute Of Allergy And Infectious Diseases ; Estados Unidos

Background Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of unknown etiology, which lasts for greater than 6 weeks with onset before 16 years of age. JIA is the most common chronic rheumatic disease in children. NSAIDs have been the mainstay of initial management with naproxen (NAP) being commonly used, but they may cause serious side effects such as gastric ulcers which can be reduced by concomitant administration of proton pump inhibitors, such as esomeprazole (ESO). Methods Primary objective was to evaluate the safety and tolerability of 3 fixed doses of NAP/ESO in JIA patients aged 12 to 16 years. Forty-six children and adolescents with JIA by International League of Associations for Rheumatology criteria, mean age of 13.6 years, from 18 US sites were prospectively enrolled over 2 years and followed for up to 6 months. Doses of the NAP/ESO fixed combination were based on baseline weight. The exploratory efficacy outcome was assessed with the ACR Pediatric-30, − 50, − 70, − 90 Response and the Childhood Health Assessment Questionnaire (CHAQ) discomfort and functional scores at months 1, 3, and 6 as change from baseline. Occurrence and causality were assessed for treatment emergent AEs (TEAEs) and discontinuations were monitored monthly. Results Forty-six patients received at least 1 dose of naproxen/esomeprazole and 36 completed the trial. Thirty-seven (80.4%) had at least 1 treatment emergent adverse event (TEAE) and, with the exception of 2 events in one patient, all of the TEAEs were mild or moderate. Frequent TEAEs (≥5% of patients) were upper respiratory tract and gastrointestinal related. Eleven (23.9%) had at least 1 TEAE considered to be related to study drug. Four patients (8.7%) discontinued due to a TEAE with one of these being the only serious AE reported, acute hepatitis. Mean number of active joints at baseline was 3.1. Improvement in JIA signs and symptoms occurred at most assessments and by month 6, the percentage of patients with an ACR Pediatric-30, − 50, − 70, and − 90 Response was 47.1, 38.2, 32.4, and 17.6%, respectively. The percent of patients achieving ACR Pediatric response increased over time. CHAQ discomfort improved at each assessment and functional scores improved at all assessments for ‘Arising, Walking, and Activities’ with several improved for ‘Dressing and Grooming, Eating, Hygiene, and Grip’. There was no indication of a dose-related efficacy effect. Conclusion NAP/ESO was well tolerated in JIA patients aged 12 to 16 years with high levels of response to ACR criteria. No new safety signals were identified for the well-characterized components of this fixed dosed JIA treatment, which was developed to reduce the risk of gastric ulcers. Trial registration Clinicaltrials.gov, NCT01544114. Registered February 21, 2012. Electronic supplementary material The online version of this article (10.1186/s12969-018-0260-y) contains supplementary material, which is available to authorized users.

Nacre is a hierarchical multi-composite matrix consisting of mineral plate-like structures stacked up similar to brick and mortar. When impacted with a projectile this type of structure is expected to reduce the overall shock loading into the system as well as projectile velocity as a consequence of variations in structural stiffness between the composite plates and the organic interlayers. Bio-mimicked nacre derived from alumina as the base ceramic is also shown to have increased fracture toughness over an alumina monolith. One challenge to building the nacre alumina structure is the design and processing of the composite mineral plates which should be comprised of roughly 90-95% nano-filler and 5-10% organic binder. In order for these plates to accurately mimic the nacre mineral plates they must also emulate aspect ratios on the order of 1:10 to 1:20. This paper will discuss the design and processing of nacre-alumina plates for studies into the impact behavior of nacre composites.

ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Background During clinic training in medical school, the learning environment plays a pivotal role in molding medical student’s behavior. A systematic assessment of patient care learning environments needs to be conducted. With two medical schools utilizing limited pediatric patient base, student evaluations indicated dissatisfaction with inpatient and general clinic experiences. Objectives The objective of this study was to generate a profile of clinic and inpatient strengths and weaknesses. This study received exempt approval. Patients and Methods The Dundee Ready Education Environment Measure (DREEM) questionnaire was administered to students over the course of 3 academic years after inpatient and clinic assignments (2-week deployments each) in the 8-week clerkship. DREEM identifies student academic self-perceptions, perceptions of teachers, and perceptions of the educational atmosphere. Fifty questions are rated from 4 = strongly agree to 0 = strongly disagree for a total of 200. Anonymous responses were grouped by assignment and analyzed using Kruskal-Wallis test. Participants were asked for up to 3 suggestions to improve the rotation. An immersion/crystallization framework was used to identify themes. Two authors independently coded suggestions, and then discussed the themes to reach a consensus. Results Overall results from DREEM indicated students’ perceptions were positive for different learning environments. No statistical differences were noted between subscales. Thematic analysis identified concerns with scheduling, lack of teaching, and non-specific feedback. Conclusions DREEM did not identify measurable deficiencies in the learning environment. However, thematic analysis uncovered specific issues that are currently being addressed.

Purpose This report will describe a case of orbital pseudotumor that is associated with underlying Crohn's disease in a pediatric patient. Observations An 8-year-old male with a past medical history of chronic constipation who presented to the ophthalmologist in July 2017 with a 7-month history double vision, left upper lid ptosis, left abducens nerve palsy, and an abnormal thyroid test. The patient's family history was negative for any autoimmune disease including, juvenile idiopathic arthritis, rheumatoid arthritis, thyroid disease, type 1 diabetes mellitus or inflammatory bowel disease. Diagnosis of orbital pseudotumor of the left eye was made based on CT scan findings and he was then treated with a one-week course of oral prednisone. After resolution of his initial symptoms, he presented a month later with swelling in his left eye and was treated with a 6-month steroid taper with resolution of symptoms. In June 2018, the patient presented with swelling in his right eye and was treated with prednisone plus steroid sparing agents. Extraocular muscle biopsy was negative for IgG4 related disease, fungal infection, or malignant lymphoma and workup for sarcoidosis and granulomatosis with polyangiitis was unremarkable. In September 2018, the patient presented with bloody stools, diagnosed and treated for a perirectal abscess. Subsequent colonoscopy performed in January 2019 confirmed Crohn's disease. He is currently undergoing treatment with adalimumab and is in remission in terms of orbital pseudotumor. Conclusion and Importance In conclusion, although the association between orbital pseudotumor and Crohn's disease is very rare, medical professionals should remember this connection when a patient presents with idiopathic orbital pseudotumor. To rule out this possibility, we recommend a thorough history of GI findings should be taken on the initial patient encounter. Crohn's disease may be an underlying cause of certain cases of orbital pseudotumor, and treatment and control of the underlying Crohn's disease may help to reduce recurrence rates of orbital pseudotumor. Additional studies need to be performed to better understand the association between the two diseases.

Background: Direct observations with focused feedback are critical components for medical student education. Numerous challenges exist in providing useful comments to students during their clerkships. Students’ evaluations of the clerkship indicated they were not receiving feedback from preceptors or house officers. Objective: To encourage direct observation with feedback, Structured Patient Care Observation (SPCO) forms were used to evaluate third-year medical students during patient encounters. Design: In 2014-2015, third-year medical students at a Midwestern medical school completing an 8-week pediatrics clerkship provided experiences on inpatient wards and in ambulatory clinics. Students were expected to solicit feedback using the SPCO form. Results/Findings: A total of 121 third-year medical students completed the pediatrics clerkship. All of the students completed at least one SPCO form. Several students had more than one observation documented, resulting in 161 SPCOs submitted. Eight were excluded for missing data, leaving 153 observations for analysis. Encounter settings included hospital (70), well-child visits (34), sick visits (41), not identified (8). Observers included attending physicians (88) and residents (65). The SPCOs generated 769 points of feedback, comments coalesced into themes of patient interviews, physical examination, or communication with patients and family. Once themes were identified, comments within each theme were further categorized as either actionable or reinforcing feedback. Discussion: SPCOs provided a structure to receive formative feedback from clinical supervisors. Within each theme, reinforcing feedback and actionable comments specific enough to be useful in shaping future encounters were identified.

Peer-run wellness centers provide safe places in the community for individuals with psychiatric disorders to develop personal and community supports, feel needed, and be accepted and grow. Until now, these centers have existed only in the community, not in the state hospital setting. The current article chronicles the development of what the authors believe is the first peer-run wellness center on the grounds of a state psychiatric hospital. After 8 years of operation, the center has served hundreds of visitors. In that time, centers have opened in the state's other state hospitals and contributed to peer presence in the hospitals' units and treatment malls. The benefits of peer-run wellness centers are important in the hospital setting as well as the community. Despite institutional barriers, the center was able to address the needs of hospitalized individuals while informing a more recovery-oriented inpatient culture. [ Journal of Psychosocial Nursing and Mental Health Services, 56 (12), 31–35.]

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01724580","term_id":"NCT01724580"}}NCT01724580 and {"type":"clinical-trial","attrs":{"text":"NCT02974595","term_id":"NCT02974595"}}NCT02974595. FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't;Erratium en J Clin Invest. 2016 Feb 1;126(2):795. doi: 10.1172/JCI86020: https://www.jci.org/articles/view/86020 Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production. Yes

Juvenile idiopathic arthritis in temporomandibular joints (TMJs) is often treated with intra-articular steroid injections, which can inhibit condylar growth. The purpose of this study was to compare simvastatin (a cholesterol-lowering drug that reduces TMJ inflammation) with the steroid triamcinolone hexacetonide in experimental TMJ arthritis.Joint inflammation was induced by injecting complete Freund's adjuvant (CFA) into the TMJs of 40 growing Sprague Dawley rats; 4 other rats were left untreated. In the same intra-articular injection, one of the following was applied: (1) 0.5 mg of simvastatin in ethanol carrier, (2) ethanol carrier alone, (3) 0.15 mg of triamcinolone hexacetonide, (4) 0.5 mg of simvastatin and 0.15 mg of triamcinolone hexacetonide, or (5) nothing additional to the CFA. The animals were killed 28 days later, and their mandibles were evaluated morphometrically and with microcomputed tomography.The analysis showed that the TMJs subjected to CFA alone had decreased ramus height compared with those with no treatment (P0.05). Groups that had injections containing the steroid overall had decreases in weight, ramus height, and bone surface density when compared with the CFA-alone group (P0.0001). Groups that had injections containing simvastatin, however, had overall increases in weight (P0.0001), ramus height (P0.0001), condylar width (P0.05), condylar bone surface density (P0.05), and bone volume (P0.0001) compared with the groups receiving the steroid injections, and they were not different from the healthy (no treatment) group.Treatment of experimentally induced arthritis in TMJs with intra-articular simvastatin preserved normal condylar bone growth.

Background Autosplenectomy, as a result of sickle cell disease, is an important risk factor for severe malaria. While molecular methods are helpful in providing rapid and accurate infection detection and species identification, the effect of hyposplenism on result interpretation during the course of infection should be carefully considered. Case presentation A 32-year old autosplenectomized Nigerian male with severe sickle cell disease was referred to the National Institutes of Health for allogenic hematopoietic stem cell transplant. Despite testing negative for malaria by both smear and PCR 2 weeks after arrival in the USA, the patient developed fever and diffuse bilateral lower rib cage and upper abdominal pain 2 weeks later and subsequently tested positive for Plasmodium falciparum. Parasitaemia was tracked over time by microscopy and nucleic acid tests to evaluate the therapeutic response in the setting of hyposplenism. The patient showed prompt resolution of patent infection by microscopy but remained positive by molecular methods for > 30 days after treatment initiation. Conclusion While molecular testing can provide sensitive Plasmodium nucleic acid detection, the persistence of Plasmodium nucleic acids following adequate treatment in functionally asplenic patients can lead to a diagnostic dilemma. In such patients, clinical response and peripheral blood smears should guide patient management following treatment. Nonetheless, in pre-transplant patients at high-risk for pre-existing Plasmodium infections, highly sensitive molecular assays can be useful to rule out infection prior to transplantation.

Background & Aims Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. Results RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

We report about a 58-year-old man with a chronic and treatment-naive hepatitis C virus (HCV) infection of genotype 1b, who had undergone autologous stem cell transplantation twice due to multiple myeloma. Subsequently, a high-level viremic reactivation of an occult hepatitis B virus (HBV) infection and also a reverse seroconversion was observed. Furthermore, a sustained spontaneous remission of HCV infection was seen. Antiviral therapy of HBV infection was initiated with tenofovir. Seven months after therapy initiation, the patient acquired an "anti-HBc-only" status. Antiviral therapy with tenofovir is still continued. The patient is in a good clinical condition.