Prevalence, incidence and healthcare burden of eosinophilic granulomatosis with polyangiitis in the UK.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease characterised by the combination of small-to-medium vessel vasculitis, blood and tissue eosinophilia, and asthma and/or sinonasal disease. This study estimated the prevalence and incidence of diagnosed EGPA in the United Kingdom (UK), and described the demographics, clinical characteristics and healthcare resource utilisation (HCRU) of this population. Methods: This retrospective longitudinal study of patients with newly diagnosed EGPA (index) (2005-2019) used the Clinical Practice Research Datalink AURUM and Hospital Episode Statistics databases. The primary outcomes were the annual prevalence (2005-2019) and incidence (2006-2019) of EGPA, and secondary outcomes included patient demographics and clinical characteristics, and HCRU in the year pre- and post-index (diagnosis). Results: Populations of patients with EGPA comprised 940 prevalent cases and 502 incident cases, of which 377 were linked to Hospital Episode Statistics. EGPA prevalence increased from 22.7 to 45.6 cases per 1 000 000 (2005-2019), driven by patients aged ≥18 years. Incidence ranged from 2.3 to 4.0 per 1 000 000 person-years (2006-2019). Pre-index, the most common clinical symptoms were respiratory related, and the most common comorbidities were asthma (80.6%) and nasal polyps (32.1%). Post-index, 19.1% had an EGPA-related inpatient stay (median length of stay 11.0 days) and 38.7% had five or more oral corticosteroid (OCS) prescriptions with a mean OCS possession ratio per patient of 47.0%. Conclusions: Although EGPA incidence in the UK remains relatively stable, prevalence is increasing, and HCRU and OCS use remain frequent, suggesting considerable healthcare burden for patients with EGPA.

Real-world characterisation of patients with chronic rhinosinusitis with nasal polyps with and without surgery in England.

OBJECTIVES: To characterise the real-world burden of chronic rhinosinusitis with nasal polyps (CRSwNP) in the UK, stratified by number of surgeries. DESIGN: Retrospective cohort study. SETTING: UK Clinical Practice Research Datalink Aurum database with Hospital Episodes Statistics linkage (2007-2019). PARTICIPANTS: Adults ≥18 years of age with a first NP diagnosis (index) and 365 days of baseline and ≥180 days of follow-up data. Follow-up continued until disenrollment, death or end of data collection. MAIN OUTCOME MEASURES: Primary: primary care physician prescribed CRSwNP-related treatments, and all-cause healthcare resource utilisation (HCRU) in 90 days post-index, stratified by surgeries during follow-up. Secondary: rate of surgery and CRSwNP point prevalence. Baseline patient demographics, clinical characteristics and comorbidities were also assessed. RESULTS: Of the 33 107 patients included, 23.5% and 2.2% had ≥1 and ≥2 surgeries during follow-up, respectively (mean follow-up: 5.3 years). Patients with more surgeries (≥2/≥1/0) during follow-up were more likely to be male (67.3%/69.0%/58.0%), have asthma (37.8%/28.2%/20.2%) and have baseline blood eosinophil counts ≥300 cells/µL (68.5%/66.0%/51.5%). During the first 90-days post-index as surgery number increased, the proportion of patients using oral corticosteroids (25.8%/20.7%/14.2%) and mean (SD) number of all-cause healthcare visits (5.9 [4.2]/5.4 [4.0]/4.9 [4.2]) increased. Time between surgeries was shorter among patients with more surgeries. CRSwNP prevalence on 31 December 2018 was 476 cases per 100 000 persons. CONCLUSION: A small proportion of patients in the UK required multiple surgeries for CRSwNP and this was associated with increasing comorbidity burden, baseline blood eosinophil counts, CRSwNP-related treatment and HCRU use.

Extending the data collection from a clinical trial: The Extended Salford Lung Study research cohort.

The Extended Salford Lung Study (Ext-SLS) is an extension of the Salford Lung Studies (SLS) in asthma and chronic obstructive pulmonary disease (COPD) through retrospective and prospective collection of patient-level electronic health record (EHR) data. We compared the Ext-SLS cohort with the SLS intention-to-treat populations using descriptive analyses to determine if the strengths (e.g. randomization) of the clinical trial were maintained in the new cohort. Historical and patient-reported outcome data were captured from asthma-/COPD-specific questionnaires (e.g., Asthma Control Test [ACT]/COPD Assessment Test [CAT]). The Ext-SLS included 1147 participants (n = 798, SLS asthma; n = 349, SLS COPD). Of participants answering the ACT, 39% scored <20, suggesting poorly controlled asthma. For COPD, 61% of participants answering the CAT scored ≥21, demonstrating a high disease burden. Demographic/clinical characteristics of the cohorts were similar at SLS baseline. EHR data provided a long-term view of participants' disease, and questionnaires provided information not typically captured. The Ext-SLS cohort is a valuable resource for respiratory research, and ongoing prospective data collection will add further value and ensure the Ext-SLS is an important source of patient-level information on obstructive airways disease.

Renal response at 2 years post biopsy to predict long-term renal survival in lupus nephritis: a retrospective analysis of the Hopkins Lupus Cohort.

OBJECTIVE: This retrospective analysis evaluated the prognostic value of renal response status 2 years after biopsy-proven lupus nephritis (LN) for the prediction of long-term renal outcomes. METHODS: Eligible patients with SLE as per American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria and biopsy-proven class III, IV, V or mixed LN were identified from the Hopkins Lupus Cohort, and categorised into binary renal response categories (modified primary efficacy renal response (mPERR) or no mPERR at 2 years post biopsy). These categories were defined by a modified version of the Belimumab International Lupus Nephritis Study (BLISS-LN) protocol using urine protein:creatinine ratio (≤0.7 g/day) and estimated glomerular filtration rate (≥60 mL/min/1.73 m2 or ≤20% below the baseline value) criteria. Long-term renal survival (defined as survival without end-stage renal disease (ESRD) or death) and chronic renal insufficiency-free survival were assessed in Kaplan-Meier plots with log-rank test and covariate-adjusted Cox proportional hazards models. RESULTS: Of the 173 eligible patients, 91.3% were female; the mean (SD) age at biopsy was 36.2 (11.8) years. At 2 years post biopsy, 114 (65.9%) patients achieved mPERR. These patients showed a lower risk of ESRD/death and chronic renal insufficiency in the follow-up period (HR (95% CI) 0.33 (0.13 to 0.87), p=0.0255; and HR (95% CI) 0.26 (0.14 to 0.47), p<0.0001, respectively). CONCLUSIONS: The 2-year post-biopsy renal response status, defined per 2019-updated BLISS-LN criteria, has prognostic value for long-term renal survival and lower risk of chronic renal insufficiency in patients with LN.

Impact of systemic lupus erythematosus disease activity, hydroxychloroquine and NSAID on the risk of subsequent organ system damage and death: analysis in a single US medical centre.

OBJECTIVE: To assess the impact of mild-moderate systemic lupus erythematosus (SLE) disease activity during a 12-month period on the risk of death or subsequent organ system damage. METHODS: 1168 patients with ≥24 months of follow-up from the Hopkins Lupus Cohort were included. Disease activity in a 12-month observation period was calculated using adjusted mean Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI), defined as the area under the curve divided by the time interval. Damage accrual in the follow-up period was defined as change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score ≥1 among patients without prior damage. Patients visited the clinic quarterly and had SELENA-SLEDAI and SDI assessed at every visit. RESULTS: During follow-up (median 7 years), 39% of patients accrued new damage in any organ system (7% cardiovascular and 3% renal) and 8% died. In adjusted models, an increased SELENA-SLEDAI score increased the risk of death (HR=1.22, 95% CI 1.13 to 1.32, p<0.001), renal damage (HR=1.24, 95% CI 1.08 to 1.42, p=0.003) and cardiovascular damage (HR=1.17, 95% CI 1.07 to 1.29, p<0.001). Hydroxychloroquine use reduced the risk of death (HR=0.46, 95% CI 0.29 to 0.72, p<0.05) and renal damage (HR=0.30, 95% CI 0.13 to 0.68, p<0.05). Non-steroidal anti-inflammatory drug use increased the risk of cardiovascular damage (HR=1.66, 95% CI 1.04 to 2.63, p<0.05). Without prior damage, an increased adjusted mean SELENA-SLEDAI score increased the risk of overall damage accrual (HR=1.09, 95% CI 1.04 to 1.15, p<0.001). CONCLUSIONS: Each one-unit increase in adjusted mean SELENA-SLEDAI during a 12-month observation period was associated with an increased risk of death and developing cardiovascular and renal damage.

Quantifying the burden of steroid-related damage in SLE in the Hopkins Lupus Cohort.

OBJECTIVE: Corticosteroids are a mainstay of SLE treatment; however, cumulative steroid exposure may lead to organ damage. This study aimed to quantify the risk of new diabetes, hypertension, cataracts, osteoporosis and avascular necrosis that is attributable to cumulative corticosteroid exposure in SLE. METHODS: Using data from the Hopkins Lupus Cohort, a longitudinal study of lupus activity, organ damage and quality of life in patients with SLE, five matched case-control analyses nested within a prospectively enrolled SLE cohort were performed. Two randomly selected controls were matched to each case using incidence-density sampling from defined risk sets. Attributable risk was calculated for steroid exposure (dose and duration, separately). Cumulative steroid dose was modelled as a four-level categorical variable using clinically relevant thresholds: 0 g (no exposure); >0 and <3.65 g (<10 mg/day for a year); ≥3.65 g and <18.25 g (1-5 years at 10 mg/day); and ≥18.25 g (>5 years at 10 mg/day). RESULTS: Eligible cases were identified for diabetes (n=42), hypertension (n=79), cataract (n=132), osteoporosis (n=118) and avascular necrosis (n=38). The unadjusted OR for a one-category increase in cumulative steroid exposure ranged from 1.157 (cataract (0.889 to 1.506); p=0.2779) to 2.183 (avascular necrosis (1.162 to 4.103); p=0.0153). After adjusting for confounding variables, a one-category increase in the cumulative steroid dose was significantly associated with risk of cataract (OR (95% CI) 1.855 (1.190 to 2.892); p=0.0064) and osteoporosis (OR (95% CI) 1.604 (1.067 to 2.412); p=0.0232). ORs for avascular necrosis, diabetes and hypertension suggested a moderately increased risk (not significant). Duration of steroid exposure was not associated with any of the outcomes. The proportion of risk attributable to steroid exposure after adjustment for covariates was 0.711 for cataract and 0.540 for osteoporosis. CONCLUSIONS: Cumulative steroid exposure was associated with an increased risk of cataract and osteoporosis in patients with SLE. TRIAL REGISTRATION NUMBER: NCT01616472.

Renal Remission Status and Longterm Renal Survival in Patients with Lupus Nephritis: A Retrospective Cohort Analysis.

OBJECTIVE: This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy. METHODS: Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death]. RESULTS: In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan-Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082-0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063-0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission. CONCLUSION: Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint.

An assessment of the effect of thiazolidinedione exposure on the risk of myocardial infarction in type 2 diabetic patients.

PURPOSE: To determine the likelihood of myocardial infarction (MI) in type 2 diabetic patients exposed to rosiglitazone and pioglitazone, separately, compared to other antidiabetic therapies. METHODS: A case-control analysis nested within the cohort of type 2 diabetic subjects from the Integrated Healthcare Information Services (IHCIS) claims database. Incident cases of MI were matched to three controls each on age (+/-5 years), gender, and year of first diabetes diagnosis. Subjects were classified according to their antidiabetic drug exposure in the 3, < 6, 6-12, and > 12 months prior to the index date. The adjusted odds ratios of MI were calculated for subjects exposed to rosiglitazone and pioglitazone, separately, compared to other antidiabetic agents. Risk factors adjusted for are age, ACE inhibitors, beta-blockers, diuretics, nitrates, diagnosis of hyperlipidemia, and hypertension and coronary artery disease (CAD). RESULTS: A total of 891 901 diabetic subjects (9870 cases and 29 610 control) identified from 1999 to 2006 were included in the analysis. The mean age was 63 years for the cases and controls. Compared to those treated with other antidiabetic therapies, the adjusted odds ratio of MI was 1.03 [95%CI: 0.93-1.12] for rosiglitazone and 0.92 [95%CI: 0.83-1.01] for pioglitazone in the 3 months prior to the index date. CONCLUSIONS: The results suggest that the risk of MI in subjects exposed to rosiglitazone or pioglitazone for < or = 12 months is not different from those exposed to other antidiabetic agents but exposure for > 12 months is associated with 15 and 13% increased risk of MI, respectively.

[Study on correlation between effective ingredients of dogwood fruit from genuine producing regions and traits].

OBJECTIVE: In order to provide a theoretical foundation for the medically effective ingredient-based selection of elite cultivars in Comnus officinalis, a study has been conducted on the variation in medicinal effective ingredients of the fruit from the genuine producing areas, the correlation among effective medicinal ingredients and the correlation between effective ingredients and fruit shape as well as nutritional indexes. METHOD: The completely mature fruit was collected from the genuine producing areas Chunan county and Lin'an city of Zhejiang province. The contents of colchicine, ursolic acid and oleanolic acid were determined by HPLC, and vertical diameter/transversal diameter of the fruits, soluble solid matter and percentage of fresh flesh to the fruit were also measured. RESULT: (1) Ursolic acid, oleanolic acid, and colchicine in fruits ranged from 0.1010% to 0.4786%, 0.0149% to 0.1274% and 0.59% to 2.30%, respectively, and their RSD were 34.33%, 40.48% and 28.50%, respectively. (2) The correlation between effective ingredients and that between effective ingredients and fruit shape as well as nutritional indexes were as follows: the content of ursolic acid was significantly correlated with that of oleanolic acid with a correlation coefficient of 0.9796; both ursolic acid and oleanolic acid were in significantly negative correlation with soluble solid matter with a correlation coefficient of -0.5544 and -0.5118, respectively; colchicine was significantly associated with soluble solid matter with a correlation coefficient of 0.2412; colchicine, ursolic acid and oleanolic acid were in significantly negative correlation with the percentage of fresh flesh with a correlation coefficient of -0.2507, -0.2443 and -0.2406, respectively; three effective ingredients showed no correlation with the ratio of vertical diameter to transversal diameter of the fruit. CONCLUSION: There is a significant difference in effective ingredients among individual trees, which means that there is a big potential for selection of cultivars. Individual tree-based selection should be mainly adopted when effective ingredients are used as a main index in selection on the basis of the correlation among effective ingredients and that between effective ingredients and fruit shape as well as nutritional indexes, while ursolic acid could be combined with oleanolic acid to be used as an index and a preliminary screen could be conducted using soluble solid matter.

[Photosynthetic acclimation to elevated CO2 in strawberry leaves grown at different levels of nitrogen nutrition].

Photosynthetic characteristics of strawberry (Fragaria ananassa Duch cv. 'Toyonoka') leaves grown in either elevated CO(2) (700 microL/L) or ambient CO(2) (390 microL/L), and at three levels of nitrogen nutrition (12 mmol/L, 4 mmol/L, 0.4 mmol/L) were studied. The results showed that for strawberry grown in 12 mmol/L nitrogen, P(n), maximal carboxylation rate (V(c, max)), maximal linear electron flow through photosystem II (J(max)), electron flow to the photosynthetic carbon reduction cycle (J(c)) and q(P) were all significantly higher in plants grown and measured at elevated CO(2) than for plants grown and measured at ambient CO(2) (Table 1 and 2, Fig. 2), which were due to a significant increase in J(c) exceeding any suppression of electron flow to the photorespiratory carbon oxidation cycle (J(o)). This increase in photochemistrical quenching with decreased non-photochemistrical quenching (q(N) or NPQ) at elevated CO(2) alleviated photoinhibition by high light (Table 2, Fig. 3). For plants grown at 4 mmol/L and 0.4 mmol/L nitrogen, P(n), V(c, max), J(c) and q(P) were all significantly lower in plants grown and measured at elevated CO(2) than for plants grown and measured at ambient CO(2) (Table 1 and 2, Fig. 2). Consistent with decreased photochemistrical quenching and increased non-photochemistrical quenching (q(N) or NPQ), for leaves grown at 4 mmol/L and 0.4 mmol/L nitrogen, the photoinhibition was aggravated by elevated CO(2) (Table 2, Fig. 3). Elevated CO(2) suppressed J(o) in leaves of plants grown at 12 mmol/L, 4 mmol/L and 0.4 mmol/L nitrogen (Fig. 2). The results above suggested that deficient nitrogen (4 mmol/L and 0.4 mmol/L nitrogen) and elevated CO(2) result in an acclimatory decrease of photosynthesis in leaves of plant grown in elevated CO(2).

What do complex spikes signal about limb movements?

Deciphering the information or signals carried by the complex spike discharge of Purkinje cells has proven to be problematic, primarily because of low frequency discharge and lack of adequate analytical techniques. This problem is particularly acute for studies of limb movements. To this end the relationship of cerebellar Purkinje cell complex spike discharge to direction and speed were studied in a manual-tracking task. Two monkeys were trained to pursue track targets moving in one of eight directions and at one of four speeds. An analysis based on Poisson regression modeling fitted the complex spike counts during single movement trials to target direction and/or speed. Using single trial data, the Poisson modeling demonstrated that the complex spike discharge for a majority of the Purkinje cells was significantly fit to tracking direction and speed. A second analysis based on the directional distribution of position and speed errors and a Poisson regression model of complex spike discharge to tracking position and speed errors found little relationship to movement error. Comparison of the preferred direction of the complex spike discharge with that of the simple spike activity revealed a reciprocal relationship for many cells. Thus, the complex spike discharge signals both tracking direction and speed but not movement errors. Furthermore, treating complex spike counts as a Poisson process provides a powerful tool for analyzing these events in single trials, without the need for extensive averaging.