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BackgroundTyrosine kinase 2 (TYK2) mediates signaling of Type I interferons, IL-23, and IL-12, key cytokines involved in lupus pathogenesis. Deucravacitinib (DEUC) is an oral, selective, allosteric TYK2 inhibitor with a unique mechanism of action, distinct from Janus kinase (JAK) 1/2/3 inhibitors, and has shown efficacy in psoriasis and psoriatic arthritis.ObjectivesAssess efficacy and safety of DEUC in patients with active systemic lupus erythematosus (SLE).MethodsThis was a 48-week (wk), randomized, double-blind, placebo (PBO)-controlled, phase 2 trial (NCT03252587). Eligible patients met SLICC criteria, were seropositive (ANA/anti-dsDNA/anti-Sm), and had a SLEDAI-2K score ≥6 and ≥1 BILAG index A or >2 BILAG B manifestations from the musculoskeletal or mucocutaneous domain. Patients on standard background medications were randomized 1:1:1:1 to PBO or DEUC (3 mg BID, 6 mg BID, 12 mg QD). Oral corticosteroid tapering to 7.5 mg/day was required from wks 8-20; further tapering was optional from wks 32-40. The primary endpoint was the proportion of patients achieving SRI(4) at wk 32. Key secondary endpoints at wk 48 included SRI(4), BICLA, LLDAS, CLASI-50, and change from baseline in active (tender and swollen) joint count.ResultsA total of 363 patients were randomized, with baseline demographic and disease characteristics similar across treatment groups. Of randomized patients, 275 (76%) completed 48 wks of treatment. The primary endpoint at wk 32 was met, with significantly greater proportion of patients in DEUC 3 mg BID and 6 mg BID groups vs PBO achieving SRI(4) responses (PBO: 34.4%; DEUC 3 mg BID: 58.2%, P=0.0006; DEUC 6 mg BID: 49.5%, P=0.021; DEUC 12 mg QD: 44.9%, P=0.078). SRI(4) response was sustained across all DEUC groups up to 48 wks (Figure 1). At wk 48, the DEUC 3 mg BID group demonstrated statistical significance in BICLA, LLDAS, CLASI-50, and active joint count, and the two other DEUC groups demonstrated clinically meaningful differences vs PBO (Figure 1). Rates of adverse events (AEs), serious AEs, and AEs of interest were similar between DEUC and PBO groups (Table 1). Most common AEs (≥10%) with DEUC were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major cardiac events, thrombotic events, systemic opportunistic infections, or active tuberculosis occurred. Malignancies were rare with similar rates across all groups. No meaningful abnormalities in mean levels of hematology and chemistry laboratory parameters were observed.Table 1.Summary of Adverse Events Through Week 48AE, na(%)Placebo n = 90DEUC 3 mg BID n = 91DEUC 6 mg BID n = 93DEUC 12 mg QD n = 89AE79 (87.8)85 (93.4)81 (87.1)75 (84.3)SAE11 (12.2)7 (7.7)8 (8.6)7 (7.9)AEs leading to treatment discontinuation3 (3.3)8 (8.8)6 (6.5)11 (12.4)Skin-related AEsb12 (13.3)15 (16.5)32 (34.4)30 (33.7)Overall infections/infestations48 (53.3)60 (65.9)60 (64.5)45 (50.6)Serious infections/infestations1 (1.1)1 (1.1)2 (2.2)1 (1.1)Infections of interest Tuberculosis0000 Herpes zosterc4 (4.4)3 (3.3)3 (3.2)2 (2.2) Influenza1 (1.1)3 (3.3)1 (1.1)3 (3.4) COVID-193 (3.3)3 (3.3)5 (5.4)3 (3.4)Malignancy events1 (1.1)d1 (1.1)e01 (1.1)fMACE0000Thrombotic events0000an is the number of patients who experienced an event. bIncludes (≤8.6% in any arm) acne, rash, dermatitis acneiform, pruritus, skin lesion, urticaria. cIncludes herpes zoster, herpes ophthalmic, genital herpes zoster. dBasal cell carcinoma. eBreast carcinoma. fVaginal squamous cell carcinoma.AE, adverse event; COVID-19, coronavirus disease 2019; DEUC, deucravacitinib; MACE, major adverse cardiac events; SAE, serious adverse event.ConclusionIn patients with active SLE, DEUC showed statistically significant and sustained clinical efficacy in SRI(4), improvement across multiple composite and organ-specific measures up to 48 wks, and was well tolerated. DEUC shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials.AcknowledgementsThis study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Julianne Hatfield, PhD at Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Bristol Myers Squibb. The authors acknowledge Christina Crater, MD, who was employed by Bristol Myers Squibb at the time the study was conducted, for contributions to study conduct.Disclosure of InterestsEric Morand Consultant of: AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, Servier, and Novartis , Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, Janssen, and UCB , Marilyn Pike Consultant of: AstraZeneca, Bristol Myers Squibb, and Pfizer, Joan T. Merrill Consultant of: UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Amgen, Janssen, Lilly, Genentech, Aurinia, Astellas, Alexion, Sanofi, Zenas, and Provention , Grant/research support from: GlaxoSmithKline and AstraZeneca , Ronald van Vollenhoven Consultant of: UCB, Pfizer, AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Galapagos, Gilead, Janssen, Servier, Paid instructor for: Roche, Pfizer, Speakers bureau: UCB, Pfizer, AbbVie, Galapagos, Janssen, Grant/research support from: Bristol Myers Squibb, GlaxoSmithKline, Eli Lilly, UCB, , Victoria P. Werth Consultant of: Celgene, Medimmune, Resolve, Genentech, Idera, Janssen, Lilly, Biogen, Bristol Myers Squibb, Gilead, Amgen, Medscape, Nektar, Incyte, EMD Serono, CSL Behring, Principia, Crisalis, Viela Bio, Argenx, Kirin, AstraZeneca, AbbVie, GSK, AstraZeneca, Cugene, UCB, Corcept, Beacon Bioscience , Grant/research support from: Celgene, Janssen, Biogen, Gilead, AstraZeneca, Viela, Amgen, Lupus Research Alliance/BMS , Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vaishali Shah Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Brian Sharkey Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Thomas Wegman Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ian Catlett Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shalabh Singhal Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

Women with systemic lupus erythematosus (SLE) carry a substantially higher risk for pre-eclampsia compared with the general population.1 Aspirin reduces the risk of pre-eclampsia in high-risk pregnancies by more than half2 and thus is recommended in SLE.3–5 The European League Against Rheumatism recommends aspirin in SLE pregnancies, particularly in those with nephritis or positive antiphospholipid antibodies (aPL).5 Despite this, little is known about current practice. Therefore, we assessed the prevalence of aspirin use in SLE pregnancies within the Systemic Lupus International Collaborating Clinics inception cohort, which has been described elsewhere.6 SLE women aged 18–45 with a pregnancy documented at one or more annual study visits (spanning 2000–2017) were included. For each pregnant visit, aspirin use, traditional pre-eclampsia risk factors (hypertension, chronic kidney disease, diabetes, nulliparity, body mass index ≥35, age >40), aPL and active lupus nephritis were assessed (see variable definitions in online supplementary material). Aspirin use was compared among those with and without each/any risk factor, and over time. We identified 475 pregnancies among 300 women. Mean SLE duration at the time of pregnancy was 5.6 years (SD 3.1). Half (51%) of pregnancies had ≥1 traditional pre-eclampsia risk factor, 34/104 (33%) had positive aPL and 53/475 (11%) had …

Background The metabolic syndrome (MetS) may contribute to increased cardiovascular risk in systemic lupus erythematosus (SLE). We aimed to examine the association of demographic factors, lupus phenotype and therapy exposure with the presence of MetS. Methods The Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis inception cohort enrolled recently diagnosed (

ObjectiveNeuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events.MethodsPatients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression.ResultsDisease duration at enrolment was 5.4±4.2 months, follow-up was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events.ConclusionIn a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

ObjectiveTo examine change in health-related quality of life in association with clinical outcomes of neuropsychiatric events in systemic lupus erythematosus (SLE).MethodsAn international study evaluated newly diagnosed SLE patients for neuropsychiatric events attributed to SLE and non-SLE causes. The outcome of events was determined by a physician-completed seven-point scale and compared with patient-completed Short Form 36 (SF-36) health survey questionnaires. Statistical analysis used linear mixed-effects regression models with patient-specific random effects.Results274 patients (92% female; 68% Caucasian), from a cohort of 1400, had one or more neuropsychiatric event in which the interval between assessments was 12.3±2 months. The overall difference in change between visits in mental component summary (MCS) scores of the SF-36 was significant (pConclusionChanges in SF-36 summary and subscale scores, in particular those related to mental health, are strongly associated with the clinical outcome of neuropsychiatric events in SLE patients.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.” The LFA proposes this definition for lupus flare on the basis of its high face validity.

Aims To compare the British Isles Lupus Assessment Group (BILAG) 2004, the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and physician9s global assessment (PGA) in assessing flares of disease activity in patients with systemic lupus erythematosus (SLE). Methods Sixteen patients with active SLE were assessed by a panel of 16 rheumatologists. The order in which the patients were seen was randomised using a 4×4 Latin square design. Each patient9s flare status was determined at each assessment using the BILAG 2004 activity index; the SFI and a PGA. A group of five specialists designated each patient into severe, moderate, mild or no flare categories. Results The rate of complete agreement (95% CI) of the four individual examining physicians for any flare versus no flare was 81% (55% to 94%), 75% (49% to 90%) and 75% (49% to 90%) for the BILAG 2004 index, SELENA flare instrument and PGA, respectively. The overall agreement between flare defined by BILAG 2004 and the SFI was 81% and when type of flare was considered was 52%. Intraclass correlation coefficients (95% CI), as a measure of internal reliability, were 0.54 (0.32 to 0.78) for BILAG 2004 flare compared with 0.21 (0.08 to 0.48) for SELENA flare and 0.18 (0.06 to 0.45) for PGA. Severe flare was associated with good agreement between the indices but mild/moderate flare was much less consistent. Conclusions The assessment of flare in patients with SLE is challenging. No flare and severe flare are identifiable but further work is needed to optimise the accurate ‘capture’ of mild and moderate flares.

ObjectivesTo determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of patients with systemic lupus erythematosus (SLE).MethodsThe study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the American College of Rheumatology case definitions, and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient-perceived impact determined by the SF-36.Results1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years were included in the study. The mean disease duration at enrolment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years, 486/1206 (40.3%) patients had ≥1 NP events, which were attributed to SLE in 13.0–23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE, especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study.ConclusionsNP events in patients with SLE are of variable frequency, most commonly present early in the disease course and adversely impact patients' quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome.

The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL).Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed.A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n = 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab.Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

Objective. To describe the prevalence, characteristics, attribution, and clinical significance of neuropsychiatric (NP) events in an international inception cohort of systemic lupus erythematosus (SLE) patients. Methods. The study was conducted by the Systemic Lupus International Collaborating Clinics (SLICC). Patients were enrolled within 15 months of fulfilling the American College of Rheumatology (ACR) SLE classification criteria. All NP events within a predefined enrollment window were identified using the ACR case definitions of 19 NP syndromes. Decision rules were derived to determine the proportion of NP disease attributable to SLE. Clinical significance was determined using the Short Form 36 (SF-36) Health Survey and the SLICC/ACR Damage Index (SDI). Results. A total of 572 patients (88% female) were recruited, with a mean +/- SD age of 35 +/- 14 years. The mean +/- SD disease duration was 5.2 +/- 4.2 months. Within the enrollment window, 158 of 572 patients (28%) had at least 1 NP event. In total, there were 242 NP events that encompassed 15 of 19 NP syndromes. The proportion of NP events attributed to SLE varied from 19% to 38% using alternate attribution models and occurred in 6.1-11.7% of patients. Those with NP events, regardless of attribution, had lower scores on the SF-36 and higher SDI scores compared with patients with no NP events. Conclusion. Twenty-eight percent of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE. Regardless of attribution, the occurrence of NP events was associated with reduced quality of life and increased organ damage. (Less)

Atmospheric chemistry programs often make use of retrospective back trajectories to determine the source regions of substances sampled at a particular site. Isentropic trajectories, which depict motion on hypothetical surfaces of constant potential temperature, have been used as part of the Atmosphere/Ocean Chemistry Experiment to understand the sources of aerosols and gases sampled over the North Atlantic Ocean. However, isentropic trajectories typically do not adequately describe the transport of mineral aerosol, for example, from the Sahara Desert to Barbados. Boundary layer trajectories indicated that northern Africa was the source region for 12% of the samples with significant aluminum (Al) concentrations (> 1.0 µg m−3). Upper-level isentropic trajectories (310 and 315 K) indicated transport from northern Africa for approximately half of the samples with Al concentrations greater than 1.0 µg m−3. However, at the location of the sampling site, the upper-level trajectories were well above the boundary layer, where the mineral aerosol samples were collected. Stokes's law was used in the calculation of nonisentropic trajectories that incorporated the gravitational settling of aerosol particles. These trajectories, which began in the boundary layer, were calculated from a combination of lower-level and upper-level wind fields, and more accurately represented the wind fields that transported Saharan dust to Barbados. The Stokes's law trajectories for 4-µm aerosol particles reached a maximum in transport from northern Africa during the summer, which was also when the highest Al concentrations were observed. The Stokes's law trajectories for 4-µm aerosol particles indicated northern Africa as the source region for 55% of the high Al samples, while the equivalent value was only 9% for the 2-µm aerosols trajectories. Dust samples collected at Barbados have a smaller mean radius than the calculation required, indicating that other vertical motions are important during transport in addition to gravitational settling. However, up to 20% of the dust sampled at Barbados is in the size range used (4 µm).

Continuous measurements of atmospheric222Rn were made for the past three years by the Environmental Measurements Laboratory (EML) at the Atmosphere/Ocean Chemistry Experiment site located at Tudor Hill, Bermuda and at the National Oceanic and Atmospheric Administration/Climate Monitoring and Diagnostics Laboratory Mauna Loa Observatory. The222Rn analyzer is based on the two-filter tube method. At the Bermuda site, monthly median222Rn concentration range from ∼50 to 700 mBq m−3, and the concentrations vary seasonally, with a maximum in the winter and a minimum in the summer. The concentrations are significantly elevated when local winds traverse the island. At MLO, monthly median222Rn concentrations range from ∼ 100 mBq m−3 during the fall months to ∼ 400 mBq m−3 during the spring months. The springtime maximum values correspond to periods of rapid transport in the free troposphere from the Asian continent, corroborated by backward air mass trajectories. The222Rn data are also used to help decipher local daily upslope/downslope conditions present at MLO. This study illustrates the value of atmospheric222Rn monitoring, when screened through the filter of local meteorology, in studying the transport of continental air to the oceans, as well as the dynamics of local meteorological effects.

We demonstrate universal quantum control over chains of ions in a surface-electrode ion trap, including all the fundamental operations necessary to perform algorithms in a one-dimensional, nearest-neighbor quantum computing architecture. We realize both single-qubit operations and nearest-neighbor entangling gates with Raman laser beams, and we interleave the two gate types. We report average single-qubit gate fidelities as high as 0.970(1) for two-, three-, and four-ion chains, characterized with randomized benchmarking. We generate Bell states between the nearest-neighbor pairs of a three-ion chain, with fidelity up to 0.84(2). We combine one- and two-qubit gates to perform quantum process tomography of a CNOT gate in a two-ion chain, and we report an overall fidelity of 0.76(3)., Comment: 17 pages, 7 figures. Corrected pulse sequence label to PB1

The aim of this study was to describe the frequency, attribution, outcome and predictors of seizures in systemic lupus erythematosus (SLE).The Systemic Lupus International Collaborating Clinics, or SLICC, performed a prospective inception cohort study. Demographic variables, global SLE disease activity (SLE Disease Activity Index 2000), cumulative organ damage (SLICC/American College of Rheumatology Damage Index (SDI)) and neuropsychiatric events were recorded at enrolment and annually. Lupus anticoagulant, anticardiolipin, anti-β(2) glycoprotein-I, antiribosomal P and anti-NR2 glutamate receptor antibodies were measured at enrolment. Physician outcomes of seizures were recorded. Patient outcomes were derived from the SF-36 (36-Item Short Form Health Survey) mental component summary and physical component summary scores. Statistical analyses included Cox and linear regressions.The cohort was 89.4% female with a mean follow-up of 3.5±2.9 years. Of 1631 patients, 75 (4.6%) had ≥1 seizure, the majority around the time of SLE diagnosis. Multivariate analysis indicated a higher risk of seizures with African race/ethnicity (HR (CI): 1.97 (1.07 to 3.63); p=0.03) and lower education status (1.97 (1.21 to 3.19); p0.01). Higher damage scores (without neuropsychiatric variables) were associated with an increased risk of subsequent seizures (SDI=1:3.93 (1.46 to 10.55); SDI=2 or 3:1.57 (0.32 to 7.65); SDI≥4:7.86 (0.89 to 69.06); p=0.03). There was an association with disease activity but not with autoantibodies. Seizures attributed to SLE frequently resolved (59/78 (76%)) in the absence of antiseizure drugs. There was no significant impact on the mental component summary or physical component summary scores. Antimalarial drugs in the absence of immunosuppressive agents were associated with reduced seizure risk (0.07 (0.01 to 0.66); p=0.03).Seizures occurred close to SLE diagnosis, in patients with African race/ethnicity, lower educational status and cumulative organ damage. Most seizures resolved without a negative impact on health-related quality of life. Antimalarial drugs were associated with a protective effect.

C receptor CR3 (iC3b-receptor, CD11b/CD18) plays an essential role in several phagocytic and adhesive neutrophil functions. Recent evidence suggests that stimulus-induced phosphorylation of the CR3 beta-chain, CD18, may mediate certain neutrophil functions by transiently converting the molecule to an activated state. Staurosporine, a protein kinase C inhibitor that blocks PMA-induced CD18 phosphorylation, was used to study the functional relevance of this event. Neutrophils adhered to glass were assayed for binding and phagocytosis of iC3b-opsonized sheep E (EC3bi) in the presence or absence of PMA and/or staurosporine. Binding of EC3bi was markedly increased, not only by PMA, but also by staurosporine and by a combination of both agents (three- to sevenfold). The enhancement of rosetting by staurosporine was likely caused by increased surface expression of CR3 via exocytosis of specific granular contents. In contrast, staurosporine alone did not stimulate phagocytosis of EC3bi and markedly inhibited PMA-induced phagocytosis. Staurosporine also inhibited phagocytosis of yeast beta glucan particles, a CR3 ligand that, in contrast to EC3bi, is bound and ingested without additional prior treatment with PMA. beta glucan phagocytosis was associated with a low level of CD18 phosphorylation. Staurosporine did not block phagocytosis in general, because this agent had relatively little effect on FcR-mediated phagocytosis. These data demonstrate that phagocytosis mediated by CR3 requires activation of CR3 via a staurosporine-sensitive pathway. Increased binding of EC3bi, a function of increased surface expression of CR3, does not require activation of CR3 by such a pathway, confirming previous evidence for the independence of these two phenomena. A direct role for CD18 phosphorylation in the activation of CR3 for phagocytosis is consistent with these data.

A 19-year-old woman with systemic lupus erythematosus (SLE) developed Guillain-Barre like ascending motor paralysis with sensory neuropathy and was subsequently documented to have "necrotizing vasculitis" by sural nerve biopsy. After 1 month of aggressive treatment with high-dose corticosteroids, plasmapheresis, i.v. gamma globulin and cyclophosphamide, there was limited improvement in her neurologic examination. The patient was discharged with bilateral foot-drop and complete sensory loss in the lower legs. There was no improvement in her neurologic status for several months until she had two separate accidental burn injuries, first in the right leg then in the left, after which the motor and sensory function in each leg began to rapidly recover. This case not only illustrates an unusual pattern of neuropathy in SLE but also allows us to postulate that thermal injury may effect the function of stunned nerves by impairing immune function.

Objective. To determine the short-term outcome of neuropsychiatric (NP) events upon enrollment into an international inception cohort of patients with systemic lupus erythematosus (SLE). Methods. The study was performed by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis and NP events were characterized using the American College of Rheumatology case definitions. Decision rules were derived to identify NP events attributable to SLE. Physician outcome scores of NP events and patient-derived mental component summary (MCS) and physical component summary (PCS) scores of the Short Form 36 were recorded. Results. There were 890 patients (88.7% female) with a mean +/- SD age of 33.8 +/- 13.4 years and mean disease duration of 5.3 +/- 4.2 months. Within the enrollment window, 271 (33.5%) of 890 patients had at least 1 NP event encompassing 15 NP syndromes. NP events attributed to SLE varied from 16.5% to 33.9% using alternate attribution models and occurred in 6.0-11.5% of patients. Outcome scores for NP events attributed to SLE were significantly better than for NP events due to non-SLE causes. Higher global disease activity was associated with worse outcomes. MCS scores were lower in patients with NP events, regardless of attribution, and were also lower in patients with diffuse and central NP events. There was a significant association between physician outcome scores and patient MCS scores only for NP events attributed to SLE. Conclusion. In SLE patients, the short-term outcome of NP events is determined by both the characteristics and attribution of the events. Conclusion. In SLE patients, the short-term outcome of NP events is determined by both the characteristics and attribution of the events. (Less)

Chemical data derived from air and precipitation samples collected during the Global Change Expedition/Coordinated Air-Sea Experiment/ Western Atlantic Ocean Experiment (GCE/CASE/WATOX) over the North Atlantic Ocean (NAO) are interpreted using simple box models. Estimated total sulfur (S) deposition fluxes from air masses with tropical oceanic, African, clean North American, and polluted North American origins are 4.4, 16, 33, and 70 μmol m−2 day−1, respectively, with associated uncertainties of at least factors of 2 to 3. Crude estimates of the fractions of deposition attributable to marine biogenic versus anthropogenic S sources suggest that the latter may be enhancing the natural NAO atmospheric S cycle by a factor of 0.5 to 0.8. Combination with similar estimates for the North Pacific region [Savoie and Prospero, 1989] yields an overall, area-weighted enhancement factor of approximately 0.3 for northern hemisphere ocean areas, consistent with estimates by Wigley [1989] based on climate modeling studies.

The characteristics of homotypic neutrophil aggregation, mediated by the adhesion molecule CD11b/CD18, differ according to whether activation takes place via intracellular protein kinase C(PKC) inducers or chemoattractants. In response to diacylglycerol (DAG) analogues such as PMA and 1,2-dioctanoyl-sn-glycerol, a prolonged cellular aggregation occurs that is associated with intense phosphorylation of the CD18 beta-chain. In response to the chemoattractant FMLP, a more transient aggregation event results that is associated with minimal beta-chain phosphorylation. By using the PKC inhibitor staurosporine, we now show that these differences are likely to reflect two different pathways of activation. Both aggregation and phosphorylation induced by DAG analogues are completely abolished by staurosporine in a parallel dose-dependent manner. Conversely, FMLP-induced aggregation is enhanced and prolonged by staurosporine whereas the associated minimal phosphorylation event is further diminished by staurosporine. Accordingly, activation of neutrophil aggregation by DAG analogues is associated with and presumably due to phosphorylation of the CD18 beta-chain. This intense phosphorylation occurs via a staurosporine-sensitive kinase such as PKC. FMLP, on the other hand, appears to activate CD11b/CD18 by a distinct mechanism. This latter mechanism does not seem to be dependent on what may be a minor PKC-induced phosphorylation of the beta-chain, and indeed is enhanced by inhibition of PKC. Of note, staurosporine was also found to cause selective release of specific granules with concomitant increase in surface display of CD11b/CD18. These data further support previous observations that up-regulation of this adhesive molecule is not the primary event in the induction of cellular adhesiveness.

During the summer of 1988, a team of scientists aboard the NOAA ship Mt. Mitchell and the NOAA King Air aircraft investigated the spatial distributions of sulfur, nitrogen, and related species and their interactions over the North Atlantic Ocean. In support of these measurements, meteorological data from the National Meteorological Center and from rawinsonde data obtained from the ship were archived and back trajectories were calculated. A summary of the meteorological conditions during the cruise is presented using synoptic maps, soundings, cross sections, and isobaric and isentropic back trajectories. Since day-to-day variability of the synoptic situation was generally small, one representative day was chosen to illustrate the overall meteorology. During the cruise, three synoptic regimes were encountered: (1) north of the polar front, (2) under the Bermuda/Azores high, and (3) under the Intertropical Convergence Zone (ITCZ). Soundings from three different days illustrate these regimes. Boundary layer depth and cloud layers were also estimated from all the soundings. Cross sections of temperature, wind, and relative humidity describing the vertical structure of the atmosphere along the cruise show the general day-to-day uniformity except near the polar front and near the ITCZ boundary. The back trajectories show general air flow patterns and the land mass source regions of air reaching the ship within three days. For parts of the cruise, air reached the ship from North America, Iceland or Greenland, Africa, and South America.

To determine whether members of the highly phosphorylated SR protein family are autoantigens and, if so, to determine the frequency and molecular basis of antigen recognition.Native human SR proteins were purified to homogeneity from HeLa cells, and an enzyme-linked immunosorbent assay (ELISA) was developed. Further studies employed immunoblotting of both phosphorylated and dephosphorylated SR proteins.Anti-SR protein reactivity was frequently detected in the sera of patients with systemic lupus erythematosus (SLE). Sera from 52% of the SLE patients in a group of patients with a variety of autoimmune and other disorders (n = 137) and from 50% of the SLE patients in a separate group (n = 102) were positive in an ELISA. In contrast, sera from patients with other disorders, such as rheumatoid arthritis and primary antiphospholipid syndrome, reacted infrequently. Reactivity with double-stranded DNA (dsDNA), used in the diagnosis of SLE, did not correlate with SR protein reactivity. Anti-SR autoantisera did not bind highly charged unphosphorylated peptides related to the SR domain, which is rich in arginine and phosphoserine residues. Surprisingly, many of the epitopes were influenced by the presence or absence of SR protein phosphorylation. In immunoblots, some patient sera lost reactivity upon SR protein dephosphorylation, while others significantly gained reactivity.We have identified a novel set of autoantigens in SLE, the SR protein family of non-small nuclear RNP pre-messenger RNA splicing factors. Anti-SR autoantibodies are distinct from those which bind dsDNA. The identification of this new set of autoantigens and the observation that the auto-epitope(s) involves posttranslational modification offer new possibilities for understanding autoimmunity and its development.

Sex hormone binding globulin (SHBG) is a transport protein in human plasma which regulates the bioavailability of sex hormones, mediates membrane receptor signaling and may affect inflammatory processes, suggesting a regulatory role for this protein in the prevention of atherosclerosis. The current report summarizes literature implicating several members of the SHBG family in the regulation of hormonal and inflammatory processes which may be pertinent to the accelerated atherosclerosis seen in systemic lupus.

To determine the frequencies at which either a valine or leucine occurs at position 247 in the beta2-glycoprotein I (beta2GPI) gene of normal individuals of the Caucasian, African American, and Asian ethnic groups and to compare these data with those in patients with the antiphospholipid syndrome (APS), with and without anti-beta2GPI antibodies.The DNA segment containing the position-247 polymorphism was amplified by seminested polymerase chain reaction, and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 370 healthy controls of different racial backgrounds were analyzed, and the results were compared with those from 149 APS patients (66 primary; 83 secondary). Allele and genotype frequencies were compared using Fisher's exact test. When significant differences were detected, pairwise comparisons were made using Fisher's exact test with a Bonferroni adjustment.Allele and genotype expression was significantly different (P0.0001 for both) among the 3 races, with the V allele and the VV genotype occurring most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian APS patients than among controls (P = 0.0028 and P = 0.0023, respectively). No significant differences in allele or genotype frequencies were seen in comparisons of the Caucasian or the African American patients with appropriate controls. The differences in allele and genotype frequencies seen in the Asian APS patients were restricted to the anti-beta2GPI-positive patients (P = 0.0018 and P = 0.0005, respectively).In Asian patients with APS, expression of a V at position 247, especially in the homozygous state, is significantly associated with the presence of anti-beta2GPI antibodies and, therefore, can be viewed as a major risk factor in this ethnic group (odds ratio 9.19 and 16.33, respectively).

Thrombosis in the antiphospholipid syndrome has been associated with acquired deficiency of the anticoagulant protein S. We sought evidence that beta2-glycoprotein I, a major target antigen for antiphospholipid antibodies, is involved in regulation of protein S activity. Incubation of purified protein S or plasma with beta2-glycoprotein I reversed functional modulation of protein S by its plasma inhibitor, the C4b-binding protein. In a plasma-free ELISA, beta2-glycoprotein I prevented the binding of protein S and C4b-binding protein when preincubated with immobilized protein S but not when similarly preincubated with C4b-binding protein. beta2-glycoprotein I in fluid phase interfered with precipitation of protein S by sepharose-bound C4b-binding protein. Effects of beta2-glycoprotein I on protein S function were inhibited by one of four monoclonal anti-beta2-glycoprotein 1 antibodies. These data suggest that beta2-glycoprotein I helps maintain adequate plasma levels of circulating free, active protein S. Antiphospholipid (anti-beta2-glycoprotein I) antibodies might cause sporadic thrombosis, at least in part, by impairing this novel regulatory mechanism.

To determine whether antiphospholipid antibodies (aPL) are more prevalent in cardiac patients taking procainamide than in a control population of similar elderly cardiac patients and to determine whether these antibodies react in an ELISA in which the primary antigen is beta 2-glycoprotein I (beta 2-GPI).aPL and antibodies to beta 2-GPI were measured in 66 patients taking procainamide from a Veterans Administration Medical Center population and a control group of 30 similar cardiac patients not taking procainamide.21% of the patients taking procainamide and no control patients were found to have moderate to high aPL. There were similar results in an assay that measured anti-beta 2-GPI in the absence of exogenous phospholipids. aPL were associated with antinuclear antibodies and antihistone antibodies but not with diabetes or clinical manifestations of drug related lupus. There was no increase in cholesterol or past thrombotic history associated with aPL, but there was a frequent history of noncardiac thrombosis in patients taking procainamide (25.7%).The predictive significance of procainamide induced aPL remains unknown but beta 2-GPI dependent aPL may be of some concern in this elderly population already at high risk for thrombosis.

The heterogenous immunoglobulins known as antiphospholipid antibodies (APLA) or . lupus 'anticoagulants' (LA) are prevalent in lupus patients and have been implicated in life-threatening thromboembolic events1-3. Unfortunately, observing the presence of these antibodies in an individual does not predict the likelihood of an event nor does it predict when it may occur4-6. A pathogenic role for these antibodies is supported by the observ ation that high titers and IgG isotype confer an increased risk of thromboembolism7. Addi tionally, numerous reports indicate that isolated patient antibodies interfere with various elements of the coagulation cascade8-15. Nevertheless, attempts to correlate specific anti body characteristics with the future likelihood of a hypercoagulable event in an individual patient16have been unsuccessful to date. Given such uncertainty combined with the poten tial complications of anticoagulant medications, patients are generally not treated until sig nificant morbidity has occurred. Finally, because of the apparent high rate of reoccurrence17most patients must remain on anticoagulant therapy indefinitely, regardless of need.

Trajectory analysis has been used to identify possible sources in both short-and long-range atmospheric transport. Here the focus is on the climatological pathway of airflow to the Atmosphere/Ocean Chemistry Experiment sites, determined by superposition of ensembles of isentropic trajectories. The trajectories are prepared from wind fields on surfaces of constant potential temperature interpolated from the National Meteorological Center global analysis, calculated twice daily for each site for the period from 1986 to 1993. At Bermuda there is a notable seasonal variation, with the months of May–November dominated by flow around the subtropical anticyclone, while flow from the northwest and west is more common in the cooler months of December–April. Flow from the west predominates at Mace Head, Ireland, in the months from April–September, while flow from the east (over Great Britain and western Europe) is of increased importance during October–March. At Izana the flow is most commonly from the west; flow from the east, over Africa and southern Europe, is most common during the months of July–September. The winds at Barbados, West Indies, are much steadier than at the other sites, and there is little seasonal variation in the general pattern of flow. The circulation during precipitation events, evaluated as the airflow weighted by rainfall amount, showed a striking difference from the general pattern of airflow at Mace Head, especially during October–March: in the absence of rain the winds are much more common from the east, over polluted continental areas, than during rain events, when the dominance of flow from the west is greater.

Meteorological data are presented and discussed for the period May 1 to June 4, 1988, in support of the Mauna Loa Observatory Photochemistry Experiment (MLOPEX). Isentropic trajectories were computed to determine air mass origins. Meteorological observations at the Mauna Loa Observatory and radiosonde observations from Hilo, Hawaii, are used to analyze local influences on air mass composition

A new glove-box system that was designed around a high-pressure tritium pump is described. The system incorporates new containment ideas such as ''burpler'' passive pressure controls, valves that can be turned from outside the box, inflatable door seals, ferro-fluidic motor-shaft seals, and rapid box-to-hood conversion during cryostaging. Currently under construction, the system will contain nine separate sections with automatic pressure-balancing and venting systems. 3 refs., 5 figs.

We have investigated the accuracy with which droplets containing cells can be sorted individually onto known and thus relocatable positions. The presence and random arrival of cells and particles in the sorter jet disturbs the orderly production and deflection of droplets, causing a dispersion of sorted droplet trajectories. The magnitude of this dispersion is a function of the phase relationship between the arrival of a cell at the end of the jet and the droplet formation. Using a modified Becton Dickinson Fluorescence-Activated Cell Sorter, we selected for sorting only those droplets that formed with a cell near the center of the droplet. We used this technique to sort Lewis lung tumor cells. The dispersion of droplet positions was reduced from over 3% to about 1% of an average deflection of typically 15 mm for a nozzle with a 50-micron diameter orifice. Sorting onto a surface such as magnetic tape or a microscope slide introduces another uncertainty in position because the cell may be located anywhere within the wetted radius of the droplet on the slide. Sorting onto less-wettable surfaces reduces the wetted radius and thus the variation in cell position.

A cell volume sensing instrument has been built which employs the principle used in the Coulter counter in which a cell changes the impedance of a narrow orifice as it passes through the orifice. An improved transducer utilizes a coaxial flow of the cell suspension inside a sheath of cell‐free solution through the orifice, thereby avoiding some drawbacks of earlier systems. The instrument is described, and the procedure necessary to achieve acceptable operation is discussed. The output for normal human red blood cells is nearly symmetrical with a narrow peak. Abnormal blood samples show various departures from symmetry and narrowness of peak. The output of this instrument is compared with that from a commercially available instrument, and our data show a more accurate representation of the actual distribution of blood volumes. The resolution of this instrument is such that it could be of significant value in a clinical laboratory.

A flow cytometer has been constructed which measures total fluorescence and the distribution of fluorescence along isolated, stained mammalian chromosomes. In this device, chromosomes flow lengthwise at 4 m/sec through a 1-micrometer thick laser beam. The fluorescence from each chromosome is recorded at 10 nsec intervals; the sequence of recorded values represents the distribution of fluorescence along the chromosome and is stored in the memory of a waveform recorder. The total fluorescence of each chromosome is also measured and recorded. Preliminary studies show that doublets of 1.83 micrometers diameter microspheres flow with their long axes parallel to the direction of flow and that the two microspheres are resolved in the slit-scan profile. Ethidium bromide stained Muntjac and Chinese hamster chromosomes have also been slit-scanned. Centromeres were resolved in many of the Nos. 1 and 2 Chinese hamster chromosomes and the Nos. 1 and X + 3 Muntjac chromosomes.

Advantages of a hollow-fiber hemodialyzer have been well described.1–3 The goal of this program was to provide a working model of a noncellulosic hollow fiber artificial kidney with nonthrombogenic blood-contacting surfaces, low blood-priming volume and low pressure drop, a satisfactory rate of urea transport, and high rate of ultrafiltration of water. Also, the reliability and utility of these devices was to be demonstrated through clinical evaluation.