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BackgroundSome factors associated with severe COVID-19 outcomes have been identified in patients with psoriasis (PsO) and inflammatory/autoimmune rheumatic diseases, namely older age, male sex, comorbidity burden, higher disease activity, and certain medications such as rituximab. However, information about specificities of patients with PsO, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), including disease modifying anti-rheumatic drugs (DMARDs) specifically licensed for these conditions, such as IL-17 inhibitors (IL-17i), IL-23/IL-12 + 23 inhibitors (IL-23/IL-12 + 23i), and apremilast, is lacking.ObjectivesTo determine characteristics associated with severe COVID-19 outcomes in people with PsO, PsA and axSpA.MethodsThis study was a pooled analysis of data from two physician-reported registries: the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), comprising patients with PsO/PsA, and the COVID-19 Global Rheumatology Alliance (GRA) registry, comprising patients with PsA/axSpA. Data from the beginning of the pandemic up to 25 October, 2021 were included. An ordinal severity outcome was defined as: 1) not hospitalised, 2) hospitalised without death, and 3) death. A multivariable ordinal logistic regression model was constructed to assess the relationship between COVID-19 severity and demographic characteristics (age, sex, time period of infection), comorbidities (hypertension, other cardiovascular disease [CVD], chronic obstructive lung disease [COPD], asthma, other chronic lung disease, chronic kidney disease, cancer, smoking, obesity, diabetes mellitus [DM]), rheumatic/skin disease (PsO, PsA, axSpA), physician-reported disease activity, and medication exposure (methotrexate, leflunomide, sulfasalazine, TNFi, IL17i, IL-23/IL-12 + 23i, Janus kinase inhibitors (JAKi), apremilast, glucocorticoids [GC] and NSAIDs). Age-adjustment was performed employing four-knot restricted cubic splines. Country-adjustment was performed using random effects.ResultsA total of 5008 individuals with PsO (n=921), PsA (n=2263) and axSpA (n=1824) were included. Mean age was 50 years (SD 13.5) and 51.8% were male. Hospitalisation (without death) was observed in 14.6% of cases and 1.8% died. In the multivariable model, the following variables were associated with severe COVID-19 outcomes: older age (Figure 1), male sex (OR 1.53, 95%CI 1.29-1.82), CVD (hypertension alone: 1.26, 1.02-1.56; other CVD alone: 1.89, 1.22-2.94; vs no hypertension and no other CVD), COPD or asthma (1.75, 1.32-2.32), other lung disease (2.56, 1.66-3.97), chronic kidney disease (2.32, 1.50-3.59), obesity and DM (obesity alone: 1.36, 1.07-1.71; DM alone: 1.85, 1.39-2.47; obesity and DM: 1.89, 1.34-2.67; vs no obesity and no DM), higher disease activity and GC intake (remission/low disease activity and GC intake: 1.96, 1.36-2.82; moderate/severe disease activity and no GC intake: 1.35, 1.05-1.72; moderate/severe disease activity and GC intake 2.30, 1.41-3.74; vs remission/low disease activity and no GC intake). Conversely, the following variables were associated with less severe COVID-19 outcomes: time period after 15 June 2020 (16 June 2020-31 December 2020: 0.42, 0.34-0.51; 1 January 2021 onwards: 0.52, 0.41-0.67; vs time period until 15 June 2020), a diagnosis of PsO (without arthritis) (0.49, 0.37-0.65; vs PsA), and exposure to TNFi (0.58, 0.45-0.75; vs no DMARDs), IL17i (0.63, 0.45-0.88; vs no DMARDs), IL-23/IL-12 + 23i (0.68, 0.46-0.997; vs no DMARDs) and NSAIDs (0.77, 0.60-0.98; vs no NSAIDs).ConclusionMore severe COVID-19 outcomes in PsO, PsA and axSpA are largely driven by demographic factors (age, sex), comorbidities, and active disease. None of the DMARDs typically used in PsO, PsA and axSpA, were associated with severe COVID-19 outcomes, including IL-17i, IL-23/IL-12 + 23i, JAKi and apremilast.AcknowledgementsWe thank all the contributors to the COVID-19 PsoProtect, GRA and EULAR Registries.Disclosure of InterestsNone declared

BackgroundThere is a paucity of data in the literature about the outcome of patients with idiopathic inflammatory myopathy (IIM) who have been infected with SARS-CoV-2.ObjectivesTo investigate factors associated with severe COVID-19 outcomes in patients with IIM.MethodsData on demographics, number of comorbidities, region, COVID-19 time period, physician-reported disease activity, anti-rheumatic medication exposure at the clinical onset of COVID-19, and COVID-19 outcomes of IIM patients were obtained from the voluntary COVID-19 Global Rheumatology Alliance physician-reported registry of adults with rheumatic disease (from 17 March 2020 to 27 August 2021). An ordinal COVID-19 severity scale was used as primary outcome of interest, with each outcome category being mutually exclusive from the other:a) no hospitalization, b) hospitalization (and no death), or c) death. Odds ratios (OR) were estimated using multivariable ordinal logistic regression. In ordinal logistic regression, the effect size of a categorical predictor can be interpreted as the odds of being one level higher on the ordinal COVID-19 severity scale than the reference category.ResultsComplete hospitalization and death outcome data was available in 348 IIM cases. Mean age was 53 years, and 223 (64.1%) were female. Overall, 167/348 (48.0%) people were not hospitalized, 136/348 (39.1%) were hospitalized (and did not die), and 45/348 (12.9%) died. Older age (OR=1.59 per decade of life, 95%CI 1.32-1.93), male sex (OR=1.63, 95%CI 1.004-2.64; versus female), high disease activity (OR=4.05, 95%CI 1.29-12.76; versus remission), presence of two or more comorbidities (OR=2.39, 95%CI 1.22-4.68; versus none), prednisolone-equivalent dose >7.5 mg/day (OR=2.37, 95%CI 1.27-4.44; versus no glucocorticoid intake), and exposure to rituximab (OR=2.60, 95%CI 1.23-5.47; versus csDMARDs only) were associated with worse COVID-19 outcomes (Table 1).Table 1.Multivariable logistic regression analysis of factors associated with the ordinal COVID-19 severity outcomes. AZA, azathioprine; CI, confidence interval; combo, combination; CSA, ciclosporin; CYC, cyclophosphamide; DMARD, disease-modifying anti-rheumatic drug; b/tsDMARD, biologic/targeted synthetic DMARD, csDMARD, conventional synthetic DMARD; HCQ, hydroxychloroquine; IVIg, intravenous immunoglobulin; LEF, leflunomide; MMF, mycophenolate mofetil; mono, monotherapy; MTX, methotrexate; OR, odds ratio; Ref, reference; RTX, rituximab; SSZ, sulfasalazine; TAC, tacrolimus.VariableOR (95%CI)P-valueVariableOR (95%CI)P-valueAge (per decade)1.59 (1.32-1.93)ComorbiditiesMale sex1.63 (1.004-2.64)0.048NoneRefNAPrednisolone-equivalent doseOne1.46 (0.79-2.72)0.228NoneRefNATwo or more2.39 (1.22-4.68)0.011>0 to 7.5mg/day1.10 (0.57-2.11)0.779Physician-reported disease activity>7.5mg/day2.37 (1.27-4.44)0.007RemissionRefNAIVIg0.41 (0.15-1.16)0.093Low/moderate1.23 (0.67-2.28)0.504DMARDsHigh4.05 (1.29-12.76)0.018csDMARD only (mono or combi - HCQ, MTX, LEF, SSZ)RefNARegionNo DMARD1.84 (0.90-3.75)0.094EuropeRefNAb/tsDMARD mono or combi (except RTX)1.60 (0.49-5.26)0.435North America0.89 (0.49-1.61)0.694CSA/CYC/TAC mono or combi (except RTX or b/tsDMARDs)1.55 (0.52-4.58)0.429Other4.25 (2.21-8.16)AZA mono1.70 (0.69-4.19)0.249Time periodMMF mono1.22 (0.53-2.82)0.634Before 15 June 2020RefNAAZA/MMF combi (except RTX or b/tsDMARDs)0.71 (0.25-2.00)0.51716 June - 30 September 20200.58 (0.26-1.27)0.171RTX mono or combi2.60 (1.23-5.47)0.012After 1 October 20200.58 (0.35-0.95)0.032ConclusionThese are the first global registry data on the impact of COVID-19 on IIM patients. Older age, male gender, higher comorbidity burden, higher disease activity, higher glucocorticoid intake and rituximab exposure were associated with worse outcomes. These findings will inform risk stratification and management decisions for IIM patients.ReferencesNoneDisclosure of InterestsSu-Ann Yeoh: None declared, Milena Gianfrancesco: None declared, Saskia Lawson-Tovey: None declared, Kimme Hyrich Speakers bureau: AbbVie unrelated to this work, Grant/research support from: Pfizer, BMS, both unrelated to this work, Anja Strangfeld Speakers bureau: AbbVie, Celltrion, MSD, Janssen, Lilly, Roche, BMS, Pfizer, all unrelated to this work, Laure Gossec Consultant of: AbbVie, Amgen, BMS, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, UCB, all unrelated to this work, Grant/research support from: Amgen, Galapagos, Lilly, Pfizer, Sandoz, all unrelated to this work, Loreto Carmona: None declared, Elsa Mateus Consultant of: Boehringer Ingelheim Portugal, not related to this work, Martin Schaefer: None declared, Christophe Richez Speakers bureau: Abbvie, Amgen, Astra Zeneca, Biogen, BMS, Celltrion, Eli Lilly, Galapagos, GSK, MSD, Novartis, and Pfizer, all unrelated to this abstract, Consultant of: Abbvie, Amgen, Astra Zeneca, Biogen, BMS, Celltrion, Eli Lilly, Galapagos, GSK, MSD, Novartis, and Pfizer, all unrelated to this abstract, Eric Hachulla Speakers bureau: Johnson & Johnson, GlaxoSmithKline, Roche-Chugai, all unrelated to this work, Consultant of: Bayer, Boehringer Ingelheim, GlaxoSmithKline, Johnson & Johnson, Roche-Chugai, Sanofi-Genzyme, all unrelated to this work, Grant/research support from: CSL Behring, GlaxoSmithKline, Johnson & Johnson, Roche-Chugai, Sanofi-Genzyme, all unrelated to this work, Marie Holmqvist: None declared, Carlo Alberto Scirè Grant/research support from: AbbVie, Lilly, both unrelated to this work, Rebecca Hasseli: None declared, Arundathi Jayatilleke: None declared, Tiffany Hsu: None declared, Kristin D’Silva: None declared, Victor Pimentel-Quiroz: None declared, Monica Vasquez del Mercado: None declared, Samuel Katsuyuki Shinjo: None declared, Edgard Reis Neto: None declared, Laurindo Rocha Jr: None declared, Ana Carolina de Oliveira e Silva Montandon Speakers bureau: GSK, not related to this work, Paula Jordan: None declared, Emily Sirotich: None declared, Jonathan Hausmann Speakers bureau: Novartis, Biogen, Pfizer, not related to this work, Consultant of: Novartis, Biogen, Pfizer, not related to this work, Jean Liew Grant/research support from: Pfizer research grant, completed in 2021, not related to this work, Lindsay Jacobsohn: None declared, Monique Gore-Massy Speakers bureau: Aurinia Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, not related to this work, Consultant of: Aurinia Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, not related to this work, Paul Sufka: None declared, Rebecca Grainger Speakers bureau: AbbVie, Janssen, Novartis, Pfizer and Cornerstones, all unrelated to this work, Consultant of: AbbVie, Novartis, both unrelated to this work, Suleman Bhana Shareholder of: Pfizer, Inc, Speakers bureau: AbbVie, Horizon, Novartis, and Pfizer, all unrelated to this work, Consultant of: AbbVie, Horizon, Novartis, and Pfizer, all unrelated to this work, Employee of: Pfizer, Inc, Zachary Wallace: None declared, Philip Robinson Speakers bureau: Abbvie, Janssen, Roche, GSK, Novartis, Lilly, UCB, all unrelated to this work, Paid instructor for: Lilly, unrelated to this work, Consultant of: GSK, Kukdong, Atom Biosciences, UCB, all unrelated to this work, Grant/research support from: Janssen, Pfizer, UCB and Novartis, all unrelated to this work, Jinoos Yazdany Consultant of: Aurinia, Astra Zeneca, Pfizer, all unrelated to this work, Grant/research support from: Astra Zeneca, Gilead, BMS Foundation, all unrelated to this work, Pedro Machado Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this work., Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this work.

BackgroundVasculitides are a heterogenous group of diseases characterized by intense vessel wall inflammation, endothelial injury, and systemic inflammation. Several vasculitides are associated with high risk of cardiovascular (CV) disease, an important source of morbidity and mortality in this population. This excess CV risk is attributed both to a high burden of traditional risk factors and to inflammation, but this remains poorly studied. Indeed, inflammation is a known risk factor for CV disease and implicated in coronary microvascular dysfunction (CMD) which may precede obstructive coronary artery disease (CAD).ObjectivesWe sought to assess whether vasculitis is associated with CMD in the absence of obstructive CAD.MethodsWe retrospectively identified subjects with systemic vasculitis who underwent symptom prompted rest/stress myocardial perfusion PET. Patients with an abnormal myocardial perfusion study (summed stress score ≥3) or LVEFResultsWe studied 26 vasculitis cases and 66 matched controls. The most common vasculitides were giant cell arteritis (38%), ANCA-associated vasculitis (31%), and Takayasu’s arteritis (12%). Median (IQR) time between diagnosis and PET was 6.5 (2.9, 14.2) years. Seven (27%) cases had active vascultis at the time of PET. Cases and controls were well-matched on age, sex, and CV risk factors (Table 1). Despite a similar prevalence of CV risk factors, coronary flow reserve (reflected by CMD) was abnormal in 38% of vasculitis cases compared to 15% of controls (p=0.004). The mean [SD] CFR was 19% lower in vasculitis cases vs controls (2.11 [0.5] versus 2.6 [0.7], p=0.003).Table 1.The presence of coronary microvasculature dysfunction in patients with systemic vasculitis without obstructive coronary artery diseaseCohort characteristicsVasculitis (n=26)Control (n=66)P-valueAge at PET, years62 (18)61 (17)0.24Time from Vasculitis Diagnosis to PET, years (median, IQR)6.5 (2.9, 14.2)n/aFemale, n (%)18 (72%)43 (65%)0.99Vasculitis CharacteristicsLarge Vessel (e.g., giant cell arteritis, Takayasu’s), n(%)13 (50%)n/an/aMedium Vessel (e.g., polyarteritis nodosa, Kawasaki’s arteritis), n(%)2 (8%)n/an/aSmall Vessel (e.g., ANCA-associated vasculitis, Henoch-Schonlein Purpura), n(%)11 (42%)n/an/aCardiovascular Risk FactorsAt DiagnosisAt PETAt PETHypertension, n (%)12 (46%)20 (71%)47 (80%)0.47Obesity, n (%)3 (12%)2 (32%)2 (32%)0.84Diabetes, n (%)3 (12%)5 (20%)13 (20%)0.99Dyslipidemia, n (%)4 (15%)15 (58%)40 (61%)0.99Known CAD, n (%)0 (0%)1 (4%)1 (2%)0.48Imaging FindingsRest myocardial blood flow, ml/min/g1.0 (0.3)1.0 (0.3)0.8Stress myocardial blood flow, ml/min/g2.1 (0.6)2.6 (1.0)0.008Coronary Flow Reserve, ml/min/g*2.1 (0.5)2.6 (0.7)0.003Coronary Microvasculature Dysfunction** (CMD), n (%)10 (38%)11 (15%)0.004ConclusionPatients with systemic vasculitis, even in the absence of obstructive CAD, have a high prevalence of CMD compared with non-vasculitis patients. These differences were observed despite matching cases and controls on traditional CV risk factors, highlighting the importance of other factors, such as inflammation and vasculitis treatments on CMD and CV disease in this population. CMD is a known independent risk factor for CV mortality. Future prospective studies are needed to understand the relationship between vasculitis, systemic inflammation, and CMD.Disclosure of InterestsNone declared

In this work, the effect of porphyrin loading and template size is varied systematically to study its impact on the oxygen reduction reaction (ORR) activity and selectivity as followed by rotating ring disc electrode experiments in both acidic and alkaline electrolytes. The structural composition and morphology are investigated by 57 Fe Mössbauer spectroscopy, transmission electron microscopy, Raman spectroscopy and Brunauer–Emmett–Teller analysis. It is shown that with decreasing template size, specifically the ORR performance towards fuel cell application gets improved, while at constant area loading of the iron precursor (here expressed in number of porphyrin layers), the iron signature does not change much. Moreover, it is well illustrated that too large area loadings result in the formation of undesired side phases that also cause a decrease in the performance, specifically in acidic electrolyte. Thus, if the impact of morphology is the focus of research it is important to consider the area loading rather than its weight loading. At constant weight loading, beside morphology the structural composition can also change and impact the catalytic performance. This article is part of the theme issue ‘Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)’.

BackgroundSystemic autoimmune rheumatic disease (SARD) patients may be at risk for disease flare and prolonged symptom duration after COVID-19, perhaps related to DMARD disruption and immune activation.ObjectivesTo describe DMARD disruption and identify differences in SARD activity among patients with and without prolonged COVID-19 symptom duration.MethodsWe identified all SARD patients with confirmed COVID-19 at the Mass General Brigham healthcare system in Boston, USA; prospective recruitment is ongoing. Surveys were used to collect demographics, clinical characteristics, DMARD disruption, COVID-19 course, and SARD disease activity before and after COVID-19. The survey included validated instruments measuring disease activity, pain, fatigue, functional status, and respiratory quality of life. Prolonged symptom duration was defined as COVID-19 symptoms lasting ≥28 days. We compared differences in patient-reported measures between those with and without prolonged symptoms.ResultsWe analyzed survey responses from 174 COVID-19 survivors with SARDs (mean age 52±16 years, 81% female, 80% White). The most common SARDs were RA (40%) and SLE (14%). Fifty-one percent of the 127 respondents on any DMARD reported a disruption to their regimen at COVID-19 onset (Figure 1). Among individual DMARDs, 56-77% were reported to have any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41% of respondents (Table 1). Patient global assessment of SARD activity was worse after COVID-19 (mean 7.6±2.3 before vs. 6.6±2.9 after COVID-19, pTable 1.Acute COVID-19 course, SARD flare/activity, and patient-reported outcomes among COVID-19 survivors with SARDs.All COVID-19 survivors with SARDs (n=174)Prolonged symptom duration ≥28 days (n=78)No prolonged symptom duration/(n=96)p-value (prolonged vs. not)Acute COVID-19 courseCOVID-19 symptom duration, days, median [IQR]14 [9, 29]46 [30, 65]11 [7, 14]Initial symptom count, median [IQR]6 [3, 8]7 [6, 9]4 [2, 7]Hospitalized, n (%)38 (22)22 (28)16 (17)0.001SARD flare/activitySelf-reported SARD flare after COVID-19, n (%)71 (41)38 (49)33 (34)0.15Disease activity by RAPID3, median [IQR]9 [4, 14]11.2 [6, 16]7 [3, 13]0.0067RAPID3 categorical score, n (%)0.13Remission (0)11 (7)4 (5)7 (7)Near remission (0.3-1.0)23 (14)5 (7)18 (19)Low severity (1.3-2.0)26 (15)10 (14)16 (17)Moderate severity (2.3-4.0)55 (33)27 (36)28 (29)High severity (4.3-10.0)54 (32)28 (38)26 (27)Patient-reported outcomesPain by SF-MPQ, median [IQR]2 [1, 2]2 [1, 2]1 [0, 2]0.0008Fatigue by FSI, median [IQR]53 [27, 84]66 [31, 91.5]43 [26, 76]0.031mHAQ, median [IQR]0.125 [0, 0.38]0.25 [0, 0.75]0.125 [0, 0.38]0.11Respiratory quality of life by SGRQ, global [IQR]15 [4, 29]16 [4, 36]10 [4, 26]0.49RAPID3, Routine Assessment of Patient Index Data 3; SF-MPQ, Short-form McGill Pain Questionnaire; FSI, Fatigue Symptom Inventory; mHAQ, modified Health Assessment Questionnaire; SGRQ, Saint George’s Respiratory Questionnaire.Figure 1.Frequency of baseline DMARD use and proportion with any disruption at COVID-19 onset.ConclusionDMARD disruption, SARD flare, and prolonged symptoms were common in this prospective study of COVID-19 survivors with SARDs. Those with prolonged COVID-19 symptom duration, defined as ≥28 days, had higher SARD activity, more pain, and more fatigue compared to those without prolonged symptoms. These findings suggest that post-acute sequelae of COVID-19 may have a large impact on underlying SARD activity and quality of life.Disclosure of InterestsMichael Di Iorio: None declared, Claire Cook: None declared, Kathleen Vanni: None declared, Naomi Patel Consultant of: Receives consulting fees from FVC Health unrelated to this work., Kristin D’Silva: None declared, Xiaoqing Fu: None declared, Jiaqi Wang: None declared, Lauren Prisco: None declared, Emily Kowalski: None declared, Alessandra Zaccardelli: None declared, Lily Martin: None declared, Grace Qian: None declared, Tiffany Hsu: None declared, Zachary Wallace Consultant of: Receives consulting fees from Viela Bio, Zenas BioPharma, and MedPace unrelated to this work., Grant/research support from: Receives research support from Bristol-Myers Squibb and Principia/Sanofi., Jeffrey Sparks Consultant of: Receives consultant fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work., Grant/research support from: Receives research support from Bristol Myers Squibb.

BackgroundRA has been associated with poor COVID-19 outcomes, but few studies have investigated outcomes in RA features such as interstitial lung disease.ObjectivesTo assess COVID-19 outcomes in patients with RA overall, and those with and without ILD, compared to general population comparators.MethodsA multicenter, retrospective cohort study was conducted at Mayo Clinic (19 hospitals and affiliated outpatient centers in 4 states) and Mass General Brigham (14 hospitals and affiliated outpatient centers in New England). Consecutive patients with RA meeting ACR/EULAR criteria and a positive COVID-19 test from March 1, 2020 through June 6, 2021 were matched 1:5 on age, sex, race, and COVID-19 test date with general population comparators without RA. RA features assessed included: RA-ILD per Bongartz criteria [1], duration, rheumatoid factor (RF), cyclic citrullinated peptide antibody (CCP), bone erosions, and treatments. The primary outcome was a composite of hospitalization or death following COVID-19 diagnosis. We used multivariable Cox regression to investigate the association of RA, and features such as ILD, with COVID-19 outcomes compared to matched comparators.ResultsWe analyzed 582 patients with RA and 2892 comparators without RA, all with COVID-19. Mean age was 62 years, 51% were female, and 79% were White. Mean RA duration was 11 years, 67% were seropositive (52% RF+ and 54% CCP+), 27% had bone erosions, 28% were on steroids, and 79% were on DMARDs. 50/582 (9%) patients with RA had ILD.The COVID-19 hospitalization or death rate for RA patients was higher than comparators (3.0 per 1,000 days [95% CI 2.5-3.6] vs. 1.9 per 1,000 days [95% CI 1.7-2.1], respectively). Overall, RA patients had a 53% higher risk of hospitalization or death than comparators after adjustment (95% CI 1.20-1.94).Among those with RA-ILD, the hospitalization or death rate was significantly higher than comparators (10.9 [95% CI 6.7-15.2] vs. 2.5 per 1,000 days [1.8-3.2], respectively). RA-ILD was associated with nearly 3-fold higher risk for hospitalization or death than comparators (multivariable HR 2.84 [95% CI 1.64-4.91], Table 1). There was a significant interaction between RA/comparator status and presence/absence of ILD for risk of severe COVID-19 (pTable 1.Frequencies, proportions, and hazard ratios for COVID-19 outcomes, comparing all RA patients, and subgroups with or without RA-ILD, to matched comparators.COVID-19 OutcomesAll RA Patients (n=582)RA-ILD (n=50)RA Patients without ILD (n=532)Comparators (n=2,892)Hospitalization, n (%)121 (21)24 (48)97 (18)402 (14)Unadjusted HR (95% CI)1.58 (1.27, 1.96)2.65 (1.71, 4.09)1.43 (1.12, 1.82)Ref.Adjusted* HR (95% CI)1.45 (1.14, 1.83)2.35 (1.38, 4.00)1.31 (1.00, 1.70)Ref.Death, n (%)26 (4)9 (18)17 (3)63 (2)Unadjusted HR (95% CI)1.72 (0.98, 3.01)5.88 (2.07, 16.71)1.13 (0.56, 2.29)Ref.Adjusted* HR (95% CI)1.24 (0.66, 2.32)13.94 (4.30, 45.18)0.75 (0.35, 1.63)Ref.Hospitalization or death, n (%)126 (22)25 (50)101 (19)419 (14)Unadjusted HR (95% CI)1.66 (1.33, 2.07)3.01 (1.93, 4.70)1.47 (1.14, 1.89)Ref.Adjusted* HR (95% CI)1.53 (1.20, 1.94)2.84 (1.64, 4.91)1.34 (1.02, 1.77)Ref.*Adjusted for age, sex, race, and smokingFigure 1.Multivariable hazard ratios for the composite outcome of hospitalization or death from COVID-19, comparing all RA and subgroups by serostatus, bone erosions, and ILD to matched comparators without RA.ConclusionWe confirmed that RA was associated with severe COVID-19 outcomes compared to the general population. We found evidence that ILD may be an effect modifier for the relationship between RA and severe COVID-19 outcomes, but RA subgroups defined by serostatus and bone erosions had similarly elevated risk. These findings suggest that ILD or its treatment may be a major contributor to severe COVID-19 outcomes in RA.References[1]Bongartz, T, et al, Arthritis Rheum. 2010 Jun;62(6):1583-91.Disclosure of InterestsNone declared

Today, metal-N- as well as metal-S-doped carbon materials are known to catalyze the hydrogen evolution reaction (HER). However, especially N- and S-co-doped catalysts reach highest activity, but it remains unclear if the activity is related to MNx or MSy (M=metal) sites. In this work we apply a simple method for multi-heteroatom doping and investigate the effect of cobalt content on the HER in acidic medium. The CoNx and CoSy sites were evidenced on the basis of structural characterization by Raman, X-ray induced photoelectron spectroscopy, and TEM. The presence of sulfur enables the formation of a larger number of CoNx sites. Structure-performance relationship proves that the HER activity is dominated by CoNx rather than CoSy sites. The most active catalysts also exhibit an excellent stability under galvanostatic conditions making them of interest for electrolyser application.

The influence of high S/Co ratios on the structural composition and oxygen evolution reaction (OER) activity of a group of cobalt-based carbon catalysts was investigated. Catalysts were prepared from polyaniline, cobalt acetate and dicyandiamide as precursors for active site formation and as structure forming agents. The sulphur to cobalt ratio was investigated in a range of S/Co = 10 to 32. On the basis of a comprehensive structural characterisation by XRD, Raman, XPS, TEM and N2 sorption measurements it was possible to show that the S/Co ratio has a significant impact on the carbon morphology. In fact, with increasing S/Co ratio the carbon morphology continuously changes from highly amorphous carbon to carbon-nanotubes, with increasing diameter. Besides the anticipated CoN4 sites and cobalt sulphite species, the catalysts also contained cobalt nanoparticles as well as cobalt hydroxide species. The most active catalyst required 0.37 ± 0.01 V overpotential to reach 10 mA cm−2 and even increased in activity during galvanostatic treatment and cycling-illustrating its very good performance. A faradaic efficiency of >35% was determined. A detailed analysis of the activity and stability in combination with Raman and XPS provides two explanations for observed Tafel slope changes, that might also be coupled to each other, namely a change in the carbon oxidation rate depending on preparation and potential or a variation in the coverage by hydroxide and oxidic species of the metal, whereas hydroxide species seem to enable a higher OER activity.

Background:Targeted DMARDs may dampen the inflammatory response in COVID-19, perhaps leading to a less severe clinical course. However, some DMARD targets may impair viral immune defenses. Due to sample size limitations, previous studies of DMARD use and COVID-19 outcomes have combined several heterogeneous rheumatic diseases and medications, investigating a single outcome (e.g., hospitalization).Objectives:To investigate the associations of baseline use of biologic or targeted synthetic (b/ts) DMARDs with a range of poor COVID-19 outcomes in rheumatoid arthritis (RA).Methods:We analyzed voluntarily reported cases of COVID-19 in patients with rheumatic diseases in the COVID-19 Global Rheumatology Alliance physician registry (March 12, 2020 - January 6, 2021). We investigated RA treated with b/tsDMARD at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAK), interleukin-6 inhibitors (IL6i), or tumor necrosis factor inhibitors (TNFi). The outcome was an ordinal scale (1-4) for COVID-19 severity: 1) no hospitalization, 2) hospitalization without oxygen need, 3) hospitalization with any oxygen need or ventilation, or 4) death. Baseline covariates including age, sex, smoking, obesity, comorbidities (e.g., cardiovascular disease, cancer, interstitial lung disease [ILD]), concomitant non-biologic DMARD use, glucocorticoid use/dose, RA disease activity, country, and calendar time were used to estimate propensity scores (PS) for b/tsDMARD. The primary analysis used PS matching to compare each drug class to TNFi. Ordinal logistic regression estimated ORs for the COVID-19 severity outcome. In a sensitivity analysis, we used traditional multivariable ordinal logistic regression adjusting for covariates without matching.Results:Of the 1,673 patients with RA on b/tsDMARDs at the onset of COVID-19, (mean age 56.7 years, 79.6% female) there were n=154 on ABA, n=224 on RTX, n=306 on JAK, n=180 on IL6i, and n=809 on TNFi. Overall, 498 (34.3%) were hospitalized and 112 (6.7%) died. Among all patients, 353 (25.3%) were ever smokers, 197 (11.8%) were obese, 462 (27.6%) were on glucocorticoids, 1,002 (59.8%) were on concomitant DMARDs, and 299 (21.7%) had moderate/high RA disease activity. RTX users were more likely than TNFi users to have ILD (11.6% vs. 1.7%) and history of cancer (7.1% vs. 2.0%); JAK users were more likely than TNFi users to be obese (17.3% vs. 9.0%). After propensity score matching, RTX was strongly associated with greater odds of having a worse outcome compared to TNFi (OR 3.80, 95% CI 2.47, 5.85; Figure). Among RTX users, 42 (18.8%) died compared to 27 (3.3%) of TNFi users (Table). JAK use was also associated with greater odds of having a worse COVID-19 severity (OR 1.52, 95%CI 1.02, 2.28). ABA or IL6i use were not associated with COVID-19 severity compared to TNFi. Results were similar in the sensitivity analysis and after excluding cancer or ILD.Table 1.Frequencies for the ordinal COVID-19 severity outcome for patients with RA on biologic or targeted synthetic DMARDs (n=1673).COVID-19 outcomes by severity scale (n,%)ABAn=154RTXn=224JAKn=306IL6in=180TNFi n=8091)Not hospitalized113 (73.3%)121 (54.0%)220 (71.9%)150 (83.3%)666 (82.3%)2)Hospitalization without oxygenation10 (6.5%)14 (6.2%)11 (3.6%)9 (5.0%)53 (6.5%)3)Hospitalization with any oxygenation or ventilation16 (10.4%)47 (21.0%)52 (17.0%)16 (8.9%)63 (7.8%)4)Death15 (9.7%)42 (18.8%)23 (7.5%)5 (2.8%)27 (3.3%)Conclusion:In this large global registry of patients with RA and COVID-19, baseline use of RTX or JAK was associated with worse severity of COVID-19 compared to TNFi use. The very elevated odds for poor COVID-19 outcomes in RTX users highlights the urgent need for risk-mitigation strategies, such as the optimal timing of vaccination. The novel association of JAK with poor COVID-19 outcomes requires replication.Acknowledgements:The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the ACR, EULAR, the UK National Health Service, the National Institute for Health Research, the UK Department of Health, or any other organization.Disclosure of Interests:Jeffrey Sparks Consultant of: Bristol-Myers Squibb, Gilead, Inova, Janssen, and Optum, unrelated to this work, Grant/research support from: Amgen and Bristol-Myers Squibb, unrelated to this work, Zachary Wallace Consultant of: Viela Bio and MedPace, outside the submitted work., Grant/research support from: Bristol-Myers Squibb and Principia/Sanofi, Andrea Seet: None declared, Milena Gianfrancesco: None declared, Zara Izadi: None declared, Kimme Hyrich Speakers bureau: Abbvie unrelated to this study, Grant/research support from: BMS, UCB, and Pfizer, all unrelated to this study, Anja Strangfeld Paid instructor for: AbbVie, MSD, Roche, BMS, Pfizer, outside the submitted work, Grant/research support from: grants from a consortium of 13 companies (among them AbbVie, BMS, Celltrion, Fresenius Kabi, Lilly, Mylan, Hexal, MSD, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB) supporting the German RABBIT register, outside the submitted work, Laure Gossec Consultant of: Abbvie, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis, UCB, unrelated to this study, Grant/research support from: Lilly, Mylan, Pfizer, all unrelated to this study, Loreto Carmona: None declared, Elsa Mateus Grant/research support from: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal S.A., MSD, Celgene, Medac, Pharmakern, GAfPA; grants and non-financial support from Pfizer, outside the submitted work, Saskia Lawson-Tovey: None declared, Laura Trupin: None declared, Stephanie Rush: None declared, Gabriela Schmajuk: None declared, Patti Katz: None declared, Lindsay Jacobsohn: None declared, Samar Al Emadi: None declared, Leanna Wise: None declared, Emily Gilbert: None declared, Ali Duarte-Garcia: None declared, Maria Valenzuela-Almada: None declared, Tiffany Hsu: None declared, Kristin D’Silva: None declared, Naomi Serling-Boyd: None declared, Philippe Dieudé Consultant of: Boerhinger Ingelheim, Bristol-Myers Squibb, Lilly, Sanofi, Pfizer, Chugai, Roche, Janssen unrelated to this work, Grant/research support from: Bristol-Myers Squibb, Chugaii, Pfizer, unrelated to this work, Elena Nikiphorou: None declared, Vanessa Kronzer: None declared, Namrata Singh: None declared, Manuel F. Ugarte-Gil Grant/research support from: Janssen and Pfizer, Beth Wallace: None declared, Akpabio Akpabio: None declared, Ranjeny Thomas: None declared, Suleman Bhana Consultant of: AbbVie, Horizon, Novartis, and Pfizer (all

Background:Glomerulonephritis and other renal manifestations are common in ANCA-associated vasculitis (AAV). Renal involvement in AAV is associated with adverse outcomes, including end-stage renal disease (ESRD) in up to 25% of patients (1). The United States Renal Data System (USRDS), a national registry of ESRD patients, represents a unique nationwide data source for studying AAV patients with ESRD. Prior research has assessed how often patients with ESRD attributed to AAV have biopsy-proven glomerulonephritis in USRDS (2), but the validity of the diagnosis of AAV as the cause of ESRD in the USRDS remains unknown.Objectives:We aim to validate the diagnosis of AAV as the primary cause of ESRD listed in USRDS.Methods:We identified all patients in the Mass General Brigham (MGB) healthcare system with a billing code for advanced chronic kidney disease or end-stage renal disease or procedure code for dialysis or renal transplantation. We identified all MGB patients fulfilling these criteria to records in the USRDS by name, sex, date of birth, and social security number. From this cohort of patients, we identified those with AAV or related diagnoses listed as the primary disease causing ESRD (ICD9: 446.0, 446.4 or ICD10: M31.3X, M31.7). Two authors reviewed medical records to collect information on whether or not a physician had diagnosed AAV, details of AAV history, renal and non-renal biopsies, and antineutrophil cytoplasmic antibody (ANCA) tests. Discrepancies were resolved through consensus. Details regarding initial ESRD onset date were obtained from the USRDS. To calculate the positive predictive value (PPV) for AAV as the primary cause of ESRD a definite physician diagnosis of AAV (a diagnosis confirmed by two physicians based on available data) in the MGB medical record was used as the gold standard. To calculate sensitivity, we linked the Partners (MGB) AAV Cohort to USRDS records using the same methods. A diagnosis code of AAV as the cause of ESRD was considered a true positive and a diagnosis code for other types of nephritis was considered a false negative.Results:We identified 89 USRDS records linked to MGB medical records in which the primary cause of ESRD was attributed to AAV. Of these, 85 were confirmed to be true cases of AAV after medical record review (PPV=96%) (Table 1). Among the cases classified as AAV, 84 (99%) had a positive ANCA test, which was predominantly MPO/P-ANCA (47, 55%); 36 (42%) had a renal biopsy, all of which were supportive of the diagnosis. The majority of cases were identified as AAV by ICD9 or 10 codes for Wegener’s granulomatosis (446.4 or M313.1). Within the Partners (MGB) AAV cohort linked to USRDS records, 33 (55%) of 60 identified cases had AAV listed as the cause of ESRD; in the remainder, ESRD was attributed to non-specific nephritis codes.Table 1.AAV and non-AAV patients in the USRDS with ESRD due to AAV (N=89)Physician-Diagnosed AAV(N=85)ANCA type n (%)84 (98.8)MPO/P-ANCA+47 (55.3)PR3/C-ANCA+33 (38.8)Renal biopsy n (%)36 (42.4)Pauci-Immune Glomerulonephritis n (%)16 (44%)Non-renal biopsy n (%) Yes10 (11.8) No74 (87.1)Years from AAV diagnosis to ESRD median [IQR]1 [0, 6]Principal diagnosis code (ICD9/ICD10) n (%) Wegener’s granulomatosis (446.4, 446.4B, or M313.1)81 (95.3)Conclusion:We found that the diagnosis of AAV as the primary cause of ESRD in the USRD had a high PPV, suggesting accurate classification of ESRD due to AAV in the USRDS, but that sensitivity was moderate. These findings support the past and future use of the USRDS for research with ESRD attributed to AAV.References:[1]Moiseev S, Novikov P, Jayne D, Mukhin N. End-stage renal disease in ANCA-associated vasculitis. Nephrol Dial Transplant. 2017;32(2):248-53.[2]Layton JB, Hogan SL, Jennette CE, Kenderes B, Krisher J, Jennette JC, et al. Discrepancy between Medical Evidence Form 2728 and renal biopsy for glomerular diseases. Clin J Am Soc Nephrol. 2010;5(11):2046-52.Disclosure of Interests:None declared

In this work a comprehensive study of the activity and stability of a non-precious metal catalyst of type Fe- N- C in acidic media is reported. The catalyst was prepared from polyaniline, dicyandiamide and iron acetate as precursors. Temperature-dependent rotating-disk electrode experiments were performed to determine the activation energy of the catalyst. Besides, load cycle durability tests with and without the addition of methanol show that there is no additional deactivation caused by methanol addition. In a Direct Methanol Fuel Cell (DMFCs) our catalyst performed similarly good in comparison to other Fe-N-C catalysts. Raman and Mossbauer spectroscopy provide valuable information on the structural composition and chemical changes induced by durability and stability testing of the catalyst. While the maximum power density during DMFC operation decreases by 85%, the qualitative distribution of iron sites might indicate the formation of iron and iron oxide clusters as decomposition product associated with the disintegration of FeN4 sites.

In this work the influence of the structure forming agent on the composition, morphology and oxygen reduction reaction (ORR) activity of Fe-N-C catalysts was investigated. As structure forming agent (SFA), dicyandiamide (DCDA) (nitrogen source) or oxalic acid (oxygen source) or mixtures thereof were used. For characterization, cyclic voltammetry and rotating disc electrode (RDE) experiments were performed in 0.1 M H2SO4. In addition to this, N2 sorption measurements and Raman spectroscopy were performed for the structural characterization. The role of metal, nitrogen and carbon sources within the synthesis of Fe-N-C catalysts has been pointed out before. Here, we show that the optimum in terms of ORR activity is achieved if both N- and O-containing SFAs are used in almost similar fractions. All catalysts display a redox couple, whereat its position depends on the fractions of SFAs. The SFA has also a strong impact on the morphology: Catalysts that were prepared with a larger fraction of N-containing SFA revealed a higher order in graphitization, indicated by bands in the 2nd order range of the Raman spectra. Nevertheless, the optimum in terms of ORR activity is obtained for the catalyst with highest D/G band ratio. Therefore, the results indicate that the presence of an additional oxygen-containing SFA is beneficial within the preparation.

Hydrogen evolution on platinum is a key reaction for electrocatalysis and sustainable energy storage, yet its pH-dependent kinetics are not fully understood. Here we present a detailed kinetic study of hydrogen adsorption and evolution on Pt(111) in a wide pH range. Electrochemical measurements show that hydrogen adsorption and hydrogen evolution are both slow in alkaline media, consistent with the observation of a shift in the rate-determining step for hydrogen evolution. Adding nickel to the Pt(111) surface lowers the barrier for hydrogen adsorption in alkaline solutions and thereby enhances the hydrogen evolution rate. We explain these observations with a model that highlights the role of the reorganization of interfacial water to accommodate charge transfer through the electric double layer, the energetics of which are controlled by how strongly water interacts with the interfacial field. The model is supported by laser-induced temperature-jump measurements. Our model sheds light on the origin of the slow kinetics for the hydrogen evolution reaction in alkaline media. Despite its role in electrocatalysis and hydrogen generation, a complete understanding of the hydrogen evolution reaction on platinum remains elusive. Here, a detailed kinetic study of hydrogen adsorption and evolution on Pt(111) highlights the role of interfacial water reorganization in the hydrogen adsorption step.

The title compound, C13H9ClO2, exhibits a non-planar geometry; the furan ring being inclined to the benzene ring by 50.52 (16)°. In the crystal, molecules stack along theaaxis; however, there are no significant intermolecular interactions present.

Background: Evidence-based medicine (EBM) is a framework for critically appraising medical literature and applying it to the care of individual patients. Lack of faculty skilled in practicing and teaching EBM limits the ability to train residents in this area. Description: A 31/2-day interactive course, called Teaching Evidence-Based Medicine, was given in 1996, 1998, and 1999. The goal of the course was to create a cadre of faculty within New York State's internal medicine residency programs educated in EBM knowledge and skills who could integrate EBM into their training program. Thirty (58.8%) of 51 metropolitan New York internal medicine residency programs and three of 12 upstate programs sent participants. Evaluation: The postcourse ratings showed increased self-rated knowledge and a willingness to apply the teaching methods at their home institutions. Conclusions: There is a high demand for the opportunity to learn EBM skills and in turn to implement EBM at home institutions.

Increased morning plasma free cortisol levels have been reported previously in chronic renal failure (CRF) patients. To see whether binding abnormalities of plasma proteins contributed to the increase in morning free cortisol, binding characteristics of corticosteroid-binding globulin (CBG) were studied in pooled plasma from CRF patients and normal subjects. Using an isocolloidosmolar equilibrium dialysis method the unbound, albumin-bound, and CBG-bound fractions of plasma cortisol were measured within the physiologic range of plasma cortisol levels. Cortisol binding to CBG was equal in uremic and nonuremic plasma as determined by the affinity constants and the binding capacities of CBG for cortisol. In addition, the distribution of cortisol binding was identical in uremic and in nonuremic plasma samples at equal total cortisol concentrations. By confirming that cortisol binding properties of CBG are unaltered in CRF patients, these data support the assertion that elevated morning free cortisol levels in CRF patients are probably due to increases of plasma total cortisol.

Adrenomyeloneuropathy is a syndrome comprising spastic paraparesis, polyneuropathy, primary adrenocortical insufficiency and variable hypogonadism. We describe a 32 year old man who presented with contractures, peripheral neuropathy, primary adrenocortical insufficiency adn secondary hypogonadism. Abnormal responses of growth hormone, gonadotropins, prolactin and thyrotropin to provocative stimuli were found, without radiographic evidence of a pituitary or hypothalamic lesion. Almost complete recovery from the neurologic abnormalities occurred with glucocorticoid replacement therapy. The clinical features of this patient support a diagnosis of adrenomyeloneuropathy. The hypothalamic-pituitary dysfunction extends the clinical features of this patient support a diagnosis of adrenomyeloneuropathy. The hypothalamic-pituitary dysfunction extends the clinical spectrum of this disease. Remission of the paraparesis coincident with glucocorticoid replacement has not been reported previously.

1. 1. Two cases of term secondary abdominal pregnancy have been reported. 2. 2. Urinary chorionic gonadotropin assays indicated continuing placental activity for at least 28 and 30 days after removal of the intra-abdominal fetuses in the 2 patients. 3. 3. No clevation of plasma 17-hydroxycorticosteroids, urinary 17-ketosteroids, or urinary 17-hydroxycorticosteroids, or increase in responsiveness to ACTH stimulation was found in either patient during the period of continued placental function.

1. 1. Free plasma hydrocortisone levels are increased in the third trimester of pregnancy. 2. 2. There is an apparent exaggeration of free plasma 17-OH-corticosteroid response to ACTH in the third trimester which disappears by the end of the first week post partum. The excessive response may be partly accounted for by a delay in the clearance of hydrocortisone from plasma in late pregnancy. 3. 3. Free urinary corticoid values are increased in late pregnancy, but the response to ACTH of total urinary corticoids (free plus glucuronides) is no greater than normal. 4. 4. The hypothesis is advanced that there may be in late pregnancy a resistance to the effects of hydrocortisone upon various tissues (e.g., the anterior pituitary), perhaps because some physical factor, as yet unknown, renders a portion of the circulating corticosteroid biologically inert.

1.1. The "cortisone test" has been applied to twenty-six patients with adrenal hyperplasia and ten patients with functioning adrenal tumors including instances of both adrenal virilism and Cushing's syndrome. 2.2. A significant fall in urinary 17-ketosteroids was obtained in all patients with adrenal virilism secondary to adrenal hyperplasia and in most instances of Cushing's syndrome due to this disorder. 3.3. In no instance was a fall in urinary 17-ketosteroids obtained in patients with functioning adrenal neoplasms. 4.4. In view of this experience and the experience reported in the literature, the "cortisone test" appears to be useful in differentiating between adrenal hyperplasia and neoplasia. Criteria for its application and interpretation are presented.

We measured cortisol binding to albumin in uremic plasma during a study to see if increased morning plasma free cortisol values, reported previously in chronic renal failure patients, could be explain

We measured cortisol binding to albumin in uremic plasma during a study to see if increased morning plasma free cortisol values, reported previously in chronic renal failure patients, could be explained by binding abnormalities of plasma proteins. Cortisol binding was measured in plasma from chronic renal failure patients and compared to values in normal controls. The unbound and albumin-bound fractions of plasma cortisol were determined using an isocolloidosmolar equilibrium dialysis method and heat inactivation of corticosteroid-binding globulin. A lower ratio of albumin-bound cortisol to unbound cortisol was seen in uremic than in nonuremic plasma (p less than 0.05). This difference was eliminated when uremic plasma was treated with dextran-activated charcoal. These studies suggest that cortisol binding to albumin is decreased in uremic plasma because of a heat-stable substance which is removed from plasma by charcoal treatment.

• A 37-year-old man with visual loss was found to have hypopituitarism and primary polydipsia associated with sarcoidosis. Neuroradiologic studies demonstrated a dramatic evolution of CNS lesions, including a left thalamic infarct, an enhancing suprasellar mass, and ultimately an empty sella turcica. The patient has been clinically stable in spite of these changes. This case is likely to be the first reported of CNS sarcoidosis with an empty sella turcica documented by computed tomography.

Pituitary-adrenocortical function was studied in patients with chronic renal failure (CRF) and compared with that in normal subjects. All CRF patients were on chronic hemodialysis. The mean morning plasma total and free (nonprotein bound) cortisol levels were higher in patients with CRF. Episodic secretion of cortisol was studied in plasma sampled every 20 min for 24 h. CRF patients demonstrated normal circadian rhythmicity, as evidence by times of peak secretory activity and number of peaks per 24 h. Mean 24-h plasma total cortixol levels were twice the normal levels in CRF patients. Nine of 10 patients with CRF did not suppress plasma total cortisol levels with 1 mg dexamethasone. Four of 10 patients with CRF suppressed with 2 mg dexamethasone orally for 2 days, 5 patients suppressed after 8 mg dexamethasone administration, and 1 patient with CRF resisted suppression. Hemodialysis did not alter mean 24-h cortisol levels or numbers of secretory episodes but produced a shift of secretory activity into the dialysis time period. These studies show alterations in cortisol dynamics in which increased plasma cortisol levels and dexamethasone resistance coexist with normal circadian rhythmicity.

We report a case of a calcified liver tumor in a 23 year old female patient who presented with virilization and a mild degree of Cushing's syndrome. Androgen levels were elevated; there was loss of cortisol circadian rhythm and marked increase in urinary 17-ketogenic and 17-ketosteroids which failed to suppress with administration of dexamethasone. Venous sampling by inferior vena cava catheterization showed that the highest steroid hormone levels were in blood from the right hepatic vein. After death, in vitro studies revealed that the tumor contained testosterone and cortisol as determined by immunofluorescence techniques. The adrenals and ovaries were atrophic. Results of metyrapone testing indicated dyshormonogenesis. To our knowledge, this is the first case of an adrenal rest tumor of the liver proved to be functionally active.

We examined the spectrum of diseases to which medical residents were exposed in a fully integrated residency program comprised of a voluntary and a municipal acute-care hospital. Although circulatory disorders and diseases of the respiratory and nervous systems accounted for the majority of cases, a broad spectrum of diseases was present for residents' training at both institutions. These observations must be considered within the context of the changing nature of medical practice in the United States, with a marked shift from inpatient to outpatient and office medical care.

Twenty-four-hour episodic secretion of cortisol was studied in patients with chronic alcoholic liver disease in order to define how and if feedback inhibition of the hypothalamic-pituitary-adrenocortical axis had occurred. The patients had prolonged disappearance rates of endogenous cortisol and corticosteroid-binding globulin-binding capacity was low. Multiple sampling (every 20 min) for levels of free and total plasma cortisol was carried out. Mean 24-h total and free plasma cortisol levels were not significantly different from normal, although the mean percentage of free cortisol was high. Cortisol secretion was decreased, as judged by urinary free cortisol values and the percentage of time that secretory activity occurred. Circadian rhythmicity of plasma cortisol levels appeared to be normal, but the amplitude of rhythmicity was decreased. Modulation of cortisol secretion in liver disease patients was shown by fewer secretory peaks and decreased secretory time during 24-hr studies. In the subjects studied, the numbers of secretory episodes and the duration of secretory time correlated positively with levels of corticosteroid-binding globulin and negatively with the half-time of cortisol in plasma. These studies suggest that feed-back inhibition modifies bot the frequency and the amplitude of cortisol secretion in patients with liver disease while the underlying circadian rhythm is preserved.

The response to iv dexamehasone was studied in patients with chronic renal failure in whom resistance to suppression of plasma cortisol levels after oral steroid had been reported previously. One milligram of dexamethasone was given iv at 2300 h, and plasma cortisol levels were measured every 20 min between 0500-1000h in patients with renal failure, normal controls, and patients with pituitary-dependent Cushing's syndrome. Normal subjects showed a decrease in mean plasma cortisol levels to less than 3 micrograms/dl; patients with Cushing's syndrome showed no suppression of cortisol secretory activity during the sampling period. In renal failure patients, morning cortisol levels fell to values lower than those achieved when the 1-mg dose was given orally or when the steroid was not given, but did not suppress to the levels seen in normals. Early resumption of cortisol secretion occurred in four of five renal failure patients during the 6-11 h after dexamethasone administration. These studies show that iv dexamethasone is more effective than the oral steroid in suppressing pituitary-adrenocortical activity in renal failure patients. However, the incomplete suppression and early resumption of cortisol secretion which are present in chronic renal failure patients even after iv dexamethasone support the suggestion that they have disordered feedback control of the hypothalamic-pituitary-adrenocortical axis.

We conducted a national survey of medical schools to determine the frequency of the awarding of honors to third-year clinical clerks and fourth-year subinterns in internal medicine. Of 126 schools surveyed, 86.5% responded. Of those responding, 66% award honors to their junior clerks and 47% award honors to their fourth-year students rotating on the internal medicine service. Consistent criteria do not exist among programs and even within some programs for such awards. The number of students receiving the awards or the percentage of the class that is felt to qualify for honors is also highly variable. The attainment of honors is an important criterion for residency selection as well as a positive predictor of future performance of candidates. The writing of the dean's letter, residency selection, and the date of the National Residency Matching Program results announcement are now occurring later in the academic year than previously, thus making the results of the fourth-year medicine rotations available to residency selection committees by the time choices have to be made. We conclude, therefore, that it seems useful for all medical schools to award honors not only to third-year clerks but also to senior students.

Decreased availability of internal medicine residents for inpatient care may result from efforts to contain rising health costs and to decrease funding for graduate medical education. The movement toward increased ambulatory training, reduced work hours for residents, and the declining interest in internal medicine careers will further decrease resident numbers. Hospitals have relied on trainees for an extraordinary range of hospital services, resulting in long duty weeks, assumption of large amounts of ancillary responsibilities, excessive patient loads, and increased house staff stress. Residents must be relieved of time-consuming, nonmedical chores and internal medicine training must be redefined to provide experiences which are important to gain competence. Hospitals must find other resources for providing patient care functions not educationally valid for residents, to allow that training to refocus on the appropriate development of the internist of the future.

Increased morning plasma free cortisol levels have been reported previously in chronic renal failure (CRF) patients. To see whether binding abnormalities of plasma proteins contributed to the increase in morning free cortisol, binding characteristics of corticosteroid-binding globulin (CBG) were studied in pooled plasma from CRF patients and normal subjects. Using an isocolloidosmolar equilibrium dialysis method the unbound, albumin-bound, and CBG-bound fractions of plasma cortisol were measured within the physiologic range of plasma cortisol levels. Cortisol binding to CBG was equal in uremic and nonuremic plasma as determined by the affinity constants and the binding capacities of CBG for cortisol. In addition, the distribution of cortisol binding was identical in uremic and in nonuremic plasma samples at equal total cortisol concentrations. By confirming that cortisol binding properties of CBG are unaltered in CRF patients, these data support the assertion that elevated morning free cortisol levels in CRF patients are probably due to increases of plasma total cortisol.

The finding of a low total thyroxine level in an oligomenorrheic woman uncovered a new family with thyroxine-binding globulin deficiency and oligomenorrhea. Thirteen of 17 family members had the deficiency of thyroxine-binding globulin, with heterozygous female subjects showing overlap of levels with normal subjects. Oligomenorrhea was frequently found but segregated separately from the thyroxine-binding globulin deficiency; of seven women with low levles, three had normal monthly menstrual cycles. Fertility was not impaired.

THE need for practical chemical technics for quantitative estimation of plasma 17-hydroxycorticosteroids has long been recognized, but no clinically feasible methods have been available until the methods of Nelson and Samuels and their co-workers were developed (1, 2). In the relatively short period since their introduction, it has become increasingly apparent that such technics are useful adjuncts to the study of normal and disordered adrenocortical function (3–14). The advantages of procedures applicable to plasma extracts are obvious. They afford a means of assessing adrenocortical function at a given moment and eliminate the inaccuracies of 24-hour urine collections. Evidence has also been obtained suggesting that in certain clinical situations (to be described) plasma values for 17- hydroxycorticosteroid levels are a more accurate reflection of adrenal function than are the urinary values. It has been demonstrated that 17-hydroxycorticosterone is the chief circulating secretory product of the human a...