Search

Trypsin is an ancient protease best known as a digestive enzyme in animals, and traditionally believed to be absent in plants and protists. However, our recent studies have revealed its wide presence and important roles in marine phytoplankton. Here, to gain a better understanding on the importance of trypsin in phytoplankton, we further surveyed the distribution, diversity, evolution and potential ecological roles of trypsin in global ocean phytoplankton. Our analysis indicated that trypsin is widely distributed both taxonomically and geographically in marine phytoplankton. Furthermore, by systematic comparative analyses we found that algal trypsin could be classified into two subfamilies (trypsin I and trypsin II) and exhibited highly duplicated and diversified during evolution. We also observed markedly different domain sequences and organizations between and within the subfamilies, suggesting potential neofunctionalization. Diatoms contain both subfamilies of trypsin, with higher numbers of genes and more environment-responsive expression of trypsin than other lineages. The duplication and subsequent neofunctionalization of the trypsin family may be important in diatoms for adapting to dynamical environmental conditions, contributing to diatoms' dominance in the coastal oceans. This work advances our knowledge on the distribution and neofunctionalization of this ancient enzyme and creates a new window of research on phytoplankton biology.

Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin, and standard of care in cancer-associated VTE. Tinzaparin has the highest molecular weight of all LMWH, and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20ml/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20ml/min and in cancer-associated VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50ml/min with an indication for anticoagulation. Tinzaparin anti-Xa levels were tested at days 2, 7 and 14 (+/- one day) and transition to oral anticoagulants were allowed at clinician discretion. No accumulation of tinzaparin was seen into day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor), and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and BSA-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on day 2, and this effect was lost when patients with CrCl >50ml/min were excluded. Data from our cohort confirms previous pharmacokinetic studies using therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50ml/min with no signs of accumulation. Bleeding and death outcomes were also comparable to other trials using tinzaparin in cancer-associated VTE. Tinzaparin is an attractive alternative anticoagulant with once-daily administration in a range of potential indications. This article is protected by copyright. All rights reserved.

To assess the prevalence and potential risk factors for polypharmacy and prescribing of the potentially inappropriate medications, opioids and benzodiazepines/Z-drugs, in older adults with systemic lupus erythematosus (SLE).The study population comprised adults age ≥50 years meeting American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria followed at a tertiary care rheumatology clinic. Information on prescriptions filled in the 4 months preceding chart review was obtained from the Manitoba Drug Program Information Network. Clinical data, including age, sex, Charlson Comorbidity Index (CCI) score, Systemic Lupus Erythematosus Disease Activity Index 2000 score, prednisone use, SLE duration, and rural residence were abstracted from electronic medical records. Logistic regression analyses were performed to assess any association between polypharmacy (using 2 definitions: ≥5 and ≥10 medications), potentially inappropriate medication use, and clinical features.A total of 206 patients (mean age 62 years, 91% female, 36% rural) were included: 148 (72%) filled ≥5 medications, 71 (35%) filled ≥10 medications, 63 (31%) used benzodiazepines/Z-drugs, and 50 (24%) used opioids. Among the 77 patients age ≥65 years, 57 (74%) filled ≥5 medications, and 26 (34%) filled ≥10 medications, compared to 30% and 4%, respectively, of Manitobans age ≥65 years (National Prescription Drug Utilization Information System, 2016). The odds of polypharmacy were greater with prednisone use (adjusted odds ratio [OR] 3.70 [95% confidence interval (95% CI) 1.40-9.79] for ≥5 medications), CCI score (adjusted OR 1.62 [95% CI 1.20-2.17]), and rural residence (adjusted OR 2.05 [95% CI 1.01-4.18]). Odds of benzodiazepine/Z-drug use were increased with polypharmacy (adjusted OR 4.35 [95% CI 1.69-11.22]), and odds of opioid use were increased with polypharmacy (adjusted OR 6.75 [95% CI 1.93-23.69]) and CCI score (adjusted OR 1.29 [95% CI 1.08-1.54]).The prevalence of polypharmacy in this SLE cohort was higher than in the general Manitoban population. Polypharmacy is a strong marker for use of prescription benzodiazepines/Z-drugs and opioids.

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared to aggressive B-cell lymphomas. However, such outcomes are heavily dependent upon subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment for most aggressive PTCLs, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to better understand the pathogenesis of PTCLs to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice. This article is protected by copyright. All rights reserved.

BACKGROUND Warfarin for the prevention of non-valvular atrial fibrillation related thromboembolic stroke in patients on maintenance haemodialysis is controversial. Despite the exclusion of haemodialysis patients in randomised control trials, the American Heart Association/American College of Cardiology has recommended warfarin in high-risk AF patients. AIM We retrospectively examined the utility of warfarin anticoagulation therapy in our prevalent haemodialysis patients over 10 years of follow-up. METHODS Eligible patients were retrospectively identified and stratified to two cohorts based on whether warfarin was prescribed. The outcomes of interest were ischaemic stroke, haemorrhagic stroke and death from any cause. Rate ratio and cox proportional hazard regression model were compare the differences in outcome between the two cohorts. The Kaplan-Meier method was used to analyse survival. RESULTS Three ischaemic strokes and four haemorrhagic strokes occurred in the unexposed group of 166 patients over 484.44 patient-years follow-up. One ischaemic stroke and no cases of haemorrhagic stroke occurred in the exposed warfarin group of 16 patients over 39.32 patient-years of follow-up. 87% of patients in both groups were indigenous. More than 90% of each cohort was had CHA2DS2VaSc score ≥2. 101 deaths occurred in the follow-up period, ninety in the unexposed group and eleven in the warfarin group. A non-statistically significant trend towards increasing mortality was observed in the warfarin group (Hazard ratio =1.63, p=0.13). CONCLUSION This retrospective study of prevalent haemodialysis patients with co-existing history of non-valvular AF failed to demonstrate sufficient evidence for the routine use of warfarin for prophylaxis of thromboembolic stroke. This article is protected by copyright. All rights reserved.

Optimal strategies for managing lupus medications after end-stage renal disease (ESRD) have not been addressed. The objective was to identify the current US-wide prescribing patterns of hydroxychloroquine (HCQ) and oral glucocorticoids (GS) among systemic lupus erythematosus (SLE) patients with incident ESRD enrolled in the US Renal Data System (USRDS) registry.We identified incident ESRD patients age ≥18 years with SLE as a primary cause of ESRD between January 2006 and June 2013. Patients who were started on dialysis at ESRD onset and enrolled in Medicare Part D within 93 days as required by Medicare were included.Among the 2,654 new-onset ESRD patients with Part D, the median duration of follow-up was 761 days (interquartile range [IQR] 374-1,375). At baseline, 1,076 patients (41%) were not receiving HCQ or GS, 220 (8%) were prescribed HCQ alone, 509 (19%) were prescribed both HCQ and GS, and 849 (32%) were prescribed GS alone. Of the 1,983 patients who either never received or discontinued HCQ after ESRD onset, 667 (34%) continued GS to the end of the follow-up period. The median GS dose was lower for patients taking HCQ (14 mg [IQR 9-21]) compared to patients who were never prescribed HCQ (15 mg [IQR 9-27]) or patients who discontinued HCQ after ESRD (17 mg [IQR 10-27]; P = 0.001).Approximately one-third of patients with lupus nephritis and new-onset ESRD received GS monotherapy at high doses. As GS-related complications contribute to hospitalizations and deaths in SLE ESRD, changing these prescribing practices may improve morbidity and mortality outcomes.

Background Internationally, clinical and economic advantages of low-risk penicillin delabeling have been explored, supporting changes to healthcare delivery systems where penicillin delabeling is embedded into inpatient usual care. Aim To determine if economic advantages of low-risk inpatient penicillin delabeling, described in the international literature, are realised in the Australian context. Methods This explorative economic evaluation had prospective patient data collection between January and August 2019, across two Australian health services. Part-1: Determine the cost per effectively delabeled patient for Penicillin Allergy Delabeling Program inpatients (PADP cohort) compared to Outpatient Antibiotic Allergy Testing Service outpatients (OAATS cohort). Part-2: A cost analysis to compare hospital costs for inpatients with low-risk penicillin allergy who did (PADP cohort) and did not (usual care cohort) undergo PADP delabeling. Results Part-1: The PADP (n=350) and OAATS (n=27 patients, n=36 individual visits) cohorts were comparable. In PADP, costs/proportion delabeled was $20.10/0.98, equating to $20.51 per effectively delabeled patient; in OAATS, it was $181.24/0.50, equating to $362. Compared to OAATS, PADP was associated with savings of $341.97 per effectively delabeled patient; indicating the outpatient testing was the dominated strategy, being more costly and less effective. Part-2: The PADP (n=218) and usual care (n=32) cohorts were comparable. Significantly favouring the delabeled PADP cohort, mean difference per patient was -4.41 days (95%CI -7.64, -1.18) and -$9,467.72 (95%CI -$15,419.98, -$3,515.46). Conclusions Consistent with international literature, delabeling low-risk penicillin allergies in the inpatient setting had economic advantages in the Australian context. Fully powered economic evaluations are urgently required to consolidate these findings. This article is protected by copyright. All rights reserved.

Background HAE leads to significant morbidity and mortality from unpredictable intermittent peripheral, abdominal and laryngeal swelling. Access to appropriate healthcare and effective therapies which can prevent and treat attacks, reduce the suffering and greatly improve quality of life. Although treatments such as C1 inhibitor (Berinert®), and Icatibant® are available in New Zealand (Aotearoa), there is no published data available on their use. Aims This study presents a national audit of Hereditary Angioedema (HAE) and Acquired Angioedema (AAE) in 2019. Results The total number of known adult (48) and children (3) HAE and Acquired Angioedema (3) patients is 54. Of these, 41/ 54 (75%) of HAE and AAE patients were recruited to the audit. Icatibant® has been available for treatment of acute HAE attacks since 2016, and is now used in 73% of HAE patients. Icatibant® is also used by patients for laryngeal attacks in the community, who may not then present to hospital. Androgens are used in half of the patients as prophylaxis but 33% of the latter were identified as not having regular liver ultrasound screening. Tranexamic acid is used as prophylaxis in one fifth of patients. Participants have had 40 children, half of whom may be affected. Three have been diagnosed with HAE, suggesting that the majority have not yet been tested. Conclusions Corrective actions arising from this audit will improve our capacity to provide long term care for HAE patients and their families. This article is protected by copyright. All rights reserved.

Systemic lupus erythematosus (SLE) patients have more pregnancy complications than healthy patients. Data regarding pregnancy outcomes in women with undifferentiated connective tissue disease (UCTD) are more limited, and existing studies are concentrated in Italy and predominantly in patients with a new diagnosis. Our objective was to compare pregnancy outcomes for UCTD and SLE patients with established disease.Between 2008 and 2017, patients with UCTD and SLE at an academic medical center were recruited to a prospective pregnancy registry. UCTD was defined as a positive autoantibody plus connective tissue disease symptoms not meeting criteria for another rheumatic diagnosis. SLE was defined by American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria or by physician diagnosis. Data were collected throughout pregnancy and postpartum. Comparator groups included UCTD, low-activity SLE, and high-activity SLE.A total of 150 SLE and 51 UCTD pregnancies were analyzed. Disease activity was low in most patients, although more patients with SLE had severe activity during pregnancy (12% versus 2%; P = 0.05). The frequencies of prematurity and preeclampsia were significantly lower in UCTD than in high-activity SLE patients (preterm 17% versus 45% [P = 0.004] and preeclampsia 6% versus 34% [P = 0.0008]), although similar to low-activity SLE patients. More infants who were small for gestational age were born to SLE than UCTD patients (33% versus 7% [P = 0.0005]), regardless of disease activity level.Pregnancies in women with UCTD managed by a rheumatologist have a high rate of pregnancy success and fewer risks than those in women with active SLE.

The quality of care for patients admitted with a primary diagnosis of gout, both before and after admission, has not been systematically examined.To understand national trends in hospital admission for a primary diagnosis of gout in Aotearoa New Zealand over the past 10 years and the quality of care for gout received by these patients before and after the admission.Data from the Aotearoa New Zealand National Collections from 1 January 2007 to 31 December 2019 were analysed to determine rates of hospital admission for a primary diagnosis of gout. Admission data include cost-weight analysis, as well as quality of care data including gout-specific medication dispensing in the year prior and year after admission.There were 13 721 admissions with a primary diagnosis of gout over the analysis period, with an average cost per admission in 2019 of NZ$4301. The rate of admission per 100 000 population was highest in Pacific peoples followed by Māori. Although dispensing of any allopurinol increased in the year after admission, rates of regular allopurinol dispensing remained low; 38.1% for admissions in 2018. Patients who were younger (especially 20-44 years), not enrolled in a primary health organisation before admission and female had lower rate of regular allopurinol after admission.In this nationwide study, rates of admission for gout were highest in Pacific peoples and in Māori. Rates of regular allopurinol dispensing were low even after admission for a primary diagnosis of gout. These findings highlight the need for improvements in gout management in Aotearoa New Zealand, including in post-discharge planning from secondary care inpatient services.

Glioblastoma multiforme (GBM) is a fatal central nervous system tumor without effective treatment. Chemotherapeutic agents are mainstays in the treatment of glioblastoma. However, the effectiveness of these is seriously hindered by poor blood-brain-barrier (BBB) penetrance and tumor targeting, together with short biological half-life. Improved chemotherapy is thus urgently needed for GBM. Multifunctional nanoparticle delivery systems offer much promise in overcoming current limitations. Accordingly, a multifunctional biomimetic nanomedicine is developed by functionalizing the surface of red blood cell membranes (RBCms) with angiopep-2 and loading pH-sensitive nanoparticles (polymer, doxorubicin (Dox), and lexiscan (Lex)) using the functionalized cell membrane to generate the novel nanomedicine, Ang-RBCm@NM-(Dox/Lex). The studies toward orthotopic U87MG human glioblastoma tumor-bearing nude mice show that the Ang-RBCm@NM-(Dox/Lex) nanomedicine has much improved blood circulation time, superb BBB penetration, superior tumor accumulation and retention. Moreover, effective suppression of tumor growth and significantly improved medium survival time are also observed after Ang-RBCm@NM-(Dox/Lex) treatment. The results show that this biomimetic nanoplatform can serve as a flexible and powerful system for GBM treatment which can be readily adapted for the treatment of other central nervous system (CNS) disorders.

OBJECTIVE Little is known about body composition in patients with PsA. We compared body composition parameters in PsA patients and healthy controls, and then investigated the effects of ustekinumab (UST) on body composition in patients with PsA. METHODS At baseline, 30 PsA patients were compared cross-sectionnally with 60 non-PsA healthy controls matched for age, sex, menopausal status and body mass index. Thirty active PsA patients treated with UST were included in a 6-month open follow-up study. Body composition parameters were measured at baseline and 6 months of treatment. RESULTS Body composition parameters were different in PsA patients compared to healthy controls: in PsA patients, total and appendicular lean mass were lower (p=0.013 and p=0.010 respectively), whereas total fat mass was higher (p

Background and objective Low-dose long-term azithromycin is recommended in clinical practice guidelines for obstructive airway diseases (OADs), however, an optimal therapeutic regimen is not yet established. This study aimed to understand the patterns of azithromycin use in OADs, characterise the patients who received it, and evaluate its safety and efficacy using real-world data. METHODS: We audited 91 patients who had received azithromycin for at least 4 weeks for the management of asthma, chronic obstructive pulmonary disease (COPD) or non-cystic fibrosis bronchiectasis. RESULTS: The mean age was 65±18 years, 60% were female, and 48% were ex-smokers. The majority had asthma (75%) either alone (50%) or in combination with COPD (12%) or bronchiectasis (13%). Most (64%) reported cough or sputum at baseline. The most common treatment regimen was azithromycin 250mg daily (73%) for more than 1 year (57%), with only seven adverse events. There was a significant reduction in the proportions of patients requiring emergency department visits (48% versus 32%; p

Background Splenectomy is an effective intervention in primary immune thrombocytopenia (ITP). Attempts to define pre-clinical predictors of platelet response to splenectomy are inconsistent. Based on international studies defining the likelihood of platelet response using platelet sequestration, patients with relapsed/refractory ITP being considered for splenectomy at a regional Australian hospital were assessed with 111 Indium-labelled autologous platelet sequestration (ILAPS) studies. Aims To audit the use of ILAPS in an Australian setting and define its role in predicting response to splenectomy. Methods A retrospective review of all patients referred for an ILAPS study at a regional hospital was performed. Results for each patient were expressed as an "R" value (spleen/ liver uptake ratio) to quantify the platelet sequestration pattern and outcome post splenectomy, based on platelet counts. Results A total of 45 patients were identified, 13 underwent splenectomy and 32 were medically managed. Patients with favourable ILAPS scans (pure or predominant splenic sequestration) demonstrated a superior response post splenectomy (100% overall response rate (ORR), 83.5% complete remission (CR)) compared to those with unfavourable ILAPS scans (mixed or pure hepatic sequestration) (71.4% ORR, 57.1% CR) over 12 months. Conclusions The use of ILAPS in the Australian setting is feasible and this experience confirms larger international studies demonstrating its utility as a predictor of response to splenectomy in ITP. An unfavourable ILAPS scan could be considered a negative predictor of response prompting consideration for other emerging ITP treatments such as thrombopoietin-receptor agonists (TPO-RAs) or B-cell depleting therapy such as Rituximab. This article is protected by copyright. All rights reserved.

New Zealand has a low burden of tuberculosis; however, multidrug-resistant tuberculosis (MDR-TB) still represents a challenge for clinicians. This is the first description of clinical aspects of MDR-TB in New Zealand.To evaluate the treatment and outcomes of patients with MDR-TB disease in Auckland. Secondary aims were to review the incidence and clinical characteristics of MDR-TB disease.Clinical data were obtained for patients treated for MDR-TB at Auckland District Health Board (ADHB).There were 60 patients nationally with MDR-TB between 1989 and 2018; 41 (69%) of 60 patients received care at ADHB. Pulmonary infection was present in 36 (88%) of 41 patients, with 19 (46%) of 41 patients with smear-positive sputum (smear 1-2+ in 6/41, 15%; smear 3-4+ in 13/41, 32%). The median duration of treatment was 22 months (range 7.5-26) for 18 (44%) of 41 patients who completed MDR-TB treatment by August 2018. The median duration of amikacin treatment was 6 months (range 2-12) for the 23 (61%) of 38 patients in whom these data were available. All 38 patients who received treatment for MDR-TB experienced adverse effects, most commonly gastrointestinal (66%), neurological (50%), ototoxicity (47%) and psychiatric (37%). Complications of intravenous access were experienced by 10 (27%) of 37 patients. Of the 19 (46%) of 41 patients who completed treatment, 18 (95%) achieved cure. There was one case who had recurrence because of inadequate treatment, and one case who had spontaneous resolution without treatment. Seventeen (41%) patients left Auckland prior to completion of treatment, mostly to return to their country of origin (15/17, 88%).MDR-TB is uncommon in New Zealand. Treatment is frequently associated with adverse events; however, rates of cure for people completing treatment in New Zealand are high.

BACKGROUND The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1mg/kg/day. However, recent studies reported non-inferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30mg/day or ≥40mg/day. PATIENTS-METHODS Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30mg/day) and high prednisone groups (≥40mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria

BACKGROUND Since the turn of the century, the prevalence of diabetes mellitus in Australia has increased, primarily due to rising rates of type 2 diabetes. Simultaneously, the landscape of diabetes medications has evolved significantly. The change in prescribing trends and public spending on diabetes medications within Australia during this period are not well defined. AIMS We sought to establish the frequency and cost of dispensed diabetes medications in the Australian public healthcare system between 2003 and 2019. METHODS We performed a longitudinal nationwide observational study using data obtained from the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule websites, which contain information on frequency and spending of diabetes medications dispensed in Australia. RESULTS The total number of PBS-subsidised prescriptions dispensed for diabetes increased from 5,218,690 in 2003 to 12,188,568 in 2019, and spending increased from $117,241,031 to $598,904,983. Of the non-insulin agents, metformin was consistently the most frequently dispensed agent, with a rapid growth in metformin combination tablets. Dispensation of sulphonylureas and thiazolidinediones have declined, with a simultaneous increase in DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. CONCLUSIONS Our data show a large growth in the use of diabetes medications between 2003 and 2019. The rapid growth in dispensing of drugs with proven cardiovascular and renal benefits reflect the evolving approach of diabetes treatment, from a historical approach targeting glycaemic control alone, to a modern individualised approach targeting specific co-morbidities. This article is protected by copyright. All rights reserved.

To develop a claims-based model to predict persistent high-dose opioid use among patients undergoing total knee replacement (TKR).Using Medicare claims (2010-2014), we identified patients ages ≥65 years who underwent TKR with no history of high-dose opioid use (mean 25 morphine milligram equivalents [MMEs]/day) in the year prior to TKR. We used group-based trajectory modeling to identify distinct opioid use patterns. The primary outcome was persistent high-dose opioid use in the year after TKR. We split the data into training (2010-2013) and test (2014) sets and used logistic regression with least absolute shrinkage and selection operator regularization, utilizing a total of 83 preoperative patient characteristics as candidate predictors. A reduced model with 10 prespecified variables, which included demographic characteristics, opioid use, and medication history was also considered.The final study cohort included 142,089 patients who underwent TKR. The group-based trajectory model identified 4 distinct trajectories of opioid use (group 1: short-term, low-dose; group 2: moderate-duration, low-dose; group 3: moderate-duration, high-dose; and group 4: persistent high-dose). The model predicting persistent high-dose opioid use achieved high discrimination (receiver operating characteristic area under the curve [AUC] 0.85 [95% confidence interval (95% CI) 0.84-0.86]) in the test set. The reduced model with 10 predictors performed equally well (AUC 0.84 [95% CI 0.84-0.85]).In this cohort of older patients, 10.6% became persistent high-dose (mean 22.4 MME/day) opioid users after TKR. Our model with 10 readily available clinical factors may help identify patients at high risk of future adverse outcomes from persistent opioid use after TKR.

We aimed at determining the predictors of osteonecrosis (ON) in a longitudinal lupus cohort.Data were reviewed from the initiation of the cohort in 1987 until October 2019. In total, 2,428 patients were included in the analysis based on 224,295 person-months of follow-up. We used pooled logistic regression to assess the relationship between risk factors and rates of ON events. After identifying a set of variables related to ON incidence, we fit a final multivariable model to identify the most important risk factors for incident ON.In 18,691 person-years of follow-up after cohort entry, 122 incident ON events were observed (rate = 6.5/1,000 person-years). In the multivariable analysis, African American patients were at twice the risk for ON compared to White patients. Male patients and smokers had an increased risk for ON of ~80% and 50% compared to female patients and nonsmokers, respectively. For every 10-year increase in the age at diagnosis, there was a 20% reduced risk for ON. Patients diagnosed after the 1990s had a 50% reduced risk of ON compared to those diagnosed before the 1990s. A highest daily dosage of prednisone of 40 mg or higher, even when administered for a month or less, significantly increased the risk of ON. Use of pulse methylprednisolone or intramuscular triamcinolone was not associated with an increased risk of ON.African American patients with systemic lupus erythematosus are at double the risk of experiencing ON compared to White patients. Oral prednisone at 20-39 mg for more than 1 month, or 40 mg daily for even 1 month, at any point in the disease course, remained the most important glucocorticoid predictor of ON.

This review will summarize clinical, genetic and pathophysiologic characteristics that are shared between children with enthesitis related arthritis (ERA) with axial involvement and adults with non-radiographic, and in some cases radiographic, axial spondyloarthritis (SpA); and between children with ERA and primarily peripheral disease manifestations and adults with peripheral SpA. Due to the differences in classification criteria for children with ERA and adults with axial and peripheral SpA, the FDA granted automatic full waivers of studies in children for new medications for "axial spondyloarthropathies including ankylosing spondylitis" up until July 2020. Thus, although current juvenile idiopathic arthritis (JIA) treatment guidelines recommend the use of biologic disease modifying anti-rheumatic drugs (DMARDs) as part of the early treatment for patients with ERA, none of the FDA-approved therapies for peripheral SpA or non-radiographic axial SpA (certolizumab pegol, ixekizumab, and secukinumab) have been studied or are labelled for use in children with ERA. Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis and clinical manifestations summarized in this review, medications approved for axial SpA or peripheral SpA should also be studied in children with active ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children. Considering the current lack of effective FDA-approved therapies for ERA, the FDA should also consider requiring pediatric studies for medications that have already been approved for the treatment of adults with SpA.

OBJECTIVE Developmental and epileptic encephalopathy (DEE) is characterized by refractory seizures, developmental delay or intellectual disability, which may be caused by gene mutation. In this study, we explored the clinical phenotype and long-term outcome in children with genetic early-infantile-onset DEEs. METHODS Next-generation sequencing was performed on 470 patients diagnosed with early-infantile-onset DEE between 2010 and 2020. The genetic variation in all cases was classified and evaluated to identify pathogenic variants. The identified variants were further verified by Sanger sequencing. RESULTS A total of 118 and 10 patients were found to have putative disease-causing gene mutations and copy number variations, respectively. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. In patients with early-infantile-onset DEE with burst suppression, KCNQ2 mutation was found in six patients, and the remaining mutations were reported in SCN2A (n=2) and STXBP1 (n=1). Seven patients with dyskinesia were described. In patients with non-syndromic genetic early-infantile-onset DEEs, we detected possible rare pathogenic variants in SETBP1, DPYD, CSNK2B, and H3F3A. With regards to inheritance pattern, de novo heterozygous mutations accounted for the majority (104/118; 88.1%). Three patients with SMC1A mutations responded well to ketogenic diet add-on therapy. Addition of valproic acid showed good therapeutic effects against KCNB1 and PACS2 encephalopathy. SIGNIFICANCE We detected four possible rare pathogenic gene variants as non-syndromic genetic causes of early-infantile-onset DEEs. Although early-infantile-onset DEEs responded poorly to antiseizure medication treatment, we found that specific antiseizure medications showed good therapeutic effects in some patients with early-infantile-onset DEEs harbouring gene variants.

Alzheimer’s disease is a neurodegenerative disorder characterized clinically by cognitive decline and pathologically by amyloid deposition and neurofibrillary changes. These neuropathological hallmarks are accompanied by reactive events including microglial activation and astrogliosis. The inflammatory response in Alzheimer’s disease brains is distinguished by a pro-inflammatory signature involving amyloid peptides1, inflammasome signaling2 and disrupted blood brain barrier3. Inflammatory changes are observed also in the cerebrospinal fluid in Alzheimer’s disease4,5. It remains unknown, however, whether the choroid plexus which produces cerebrospinal fluid and guards the brain from peripheral inflammatory insults6,7, contributes to the inflammation and pathogenesis of Alzheimer’s disease. Here we show that the choroid plexus in Alzheimer’s disease exhibits a pro-inflammatory signature with aberrant protein accumulations, which contribute to the age-dependent inflammatory changes observed in the cerebrospinal fluid. Magnetic resonance imaging reveals that the choroid plexus in patients with Alzheimer’s disease displays pathological signal and increased volume, which inversely correlates with cognitive decline. Our findings suggest that the choroid plexus, being unable to efficiently resolve inflammatory insults over the lifetime, eventually ignites and drives the aberrant inflammatory response observed in Alzheimer’s disease. These findings advance our understanding of the pathogenesis and open new vistas in the diagnostics and therapeutics of Alzheimer’s disease.

Objectives Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with differences in prevalence and severity among ancestral groups. This study aims to identify novel genetic components either shared or distinct between Asian and European populations. Methods Both trans-ancestral and ancestry-specific meta-analyses of genome-wide association studies (GWAS) for SLE were performed, involving 30,604 participants of European, Chinese or Thai origin. Using public epigenomic data and expression quantitative trait loci, fine-mapping analyses were conducted to identify putative causal variants and genes for the newly identified loci. Performance of polygenic risk scores (PRS) for the Thai cohort was evaluated comparing different training data. Results We identified ten novel SLE susceptibility loci, four of which were found by Asian-specific meta-analyses. A 1bp deletion upstream of IFNLR1 was found associated with SLE, with the risk allele correlated with increased expression of IFNLR1. This gene encodes interferon lambda receptor 1, pointing to the role of type III interferon signaling in SLE. An intronic variant in SLC29A3 was found associated with SLE only in Asians. The putative risk variant may modulate SLC29A3 expression in a monocyte-specific manner. SLC29A3 encodes a lysosomal nucleoside transporter, and subsequent analyses suggest reduced lysosomal function and phagocytosis might be the mechanism underlying this association. In addition, trans-ancestral meta-analysis was proved to be valuable in risk prediction for individuals without ancestry-matched data. Conclusion Multi-ancestral GWAS identified both shared and Asian-specific loci for SLE, and functional annotation pointed to the involvement of increased type III interferon signaling and reduced lysosomal function in SLE.

Background Up to 3% of methotrexate (MTX)-treated rheumatoid arthritis (RA) patients may develop liver fibrosis or cirrhosis, requiring effective screening algorithms. Aims To assess the utility of non-invasive liver fibrosis assessment in RA patients on MTX. Methods 56 patients were recruited from rheumatology outpatient clinics in a public tertiary centre from July 2017 to October 2018. Clinical data was collected. Screening for hepatic fibrosis was performed utilising transient elastography (TE), aminoaspartate transaminase to platelet ratio index (APRI), Hepascore, and Fibrosis-4 index (FIB-4). Those with suspected significant liver fibrosis based on these screening tests were assessed by a hepatologist. Results 27 patients were suspected to have liver fibrosis on screening, including 10/56 (18%) by TE, 20/56 (36%) by Hepascore, 2/56 by APRI (4%) and 1/56 by FIB-4 (2%). Of these 27 patients, 11 were reviewed by a hepatologist and 1 diagnosed with significant liver fibrosis. TE, but not APRI, Hepascore or FIB-4, was found to have 100% sensitivity and 84% specificity (p=0.029) for hepatologist-diagnosed liver fibrosis. Conclusion Liver fibrosis develops in a minority of MTX-treated RA patients. This study suggests that TE is a more sensitive screening test than APRI, FIB-4 or Hepascore in the identification of people with RA at risk of hepatic fibrosis. This article is protected by copyright. All rights reserved.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by skin fibrosis, vasculopathy, and dysimmunity. Data regarding osteitis in SSc are scarce.We performed a nationwide multicenter, retrospective, case-control study including patients with SSc, according to the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification, with a diagnosis of osteitis. The objectives of the study were to describe, to characterize, and to identify associated factors for osteitis in patients with SSc.Forty-eight patients were included. Twenty-six patients (54.1%) had osteitis beneath digital tip ulcers. Physical symptoms included pain (36 of 48, 75%), erythema (35 of 48, 73%), and local warmth (35 of 48, 73%). Thirty-one (65%) patients had median (interquartile range) C-reactive protein levels2 mg/liter of 8 (2.7-44.3) mg/liter. On radiography, computed tomography, or magnetic resonance imaging, osteitis was characterized by swelling or abscess of soft tissues, with acro-osteolysis or lysis in 28 patients (58%). Microbiological sampling was performed in 45 (94%) patients. Most pathogens were Staphylococcus aureus (43.8%), anaerobes and Enterobacteriaceae (29.1%), and Pseudomonas aeruginosa (10.4%). Management comprised antibiotics in 37 (77.1%) patients and/or surgery in 26 (54.2%). Fluoroquinolones were used in 22 (45.8%) patients, and amoxicillin plus β-lactamase inhibitor in 7 (14.6%). Six (12.6%) patients relapsed, 6 (12.6%) patients had osteitis recurrence, 15 (32%) sequelae, and 2 patients had septic shock and died.This study confirmed digital tip ulcers as an associated factor for osteitis and revealed a high rate of functional sequelae. Antimicrobial therapy with oral fluoroquinolone or intravenous amoxicillin and β-lactamase inhibitor are used as first-line antibiotic therapy in SSc patients with osteitis.

Findings from previous small studies have been reassuring regarding the safety of treatment with hydroxychloroquine (HCQ) during pregnancy. In one recent study, it was demonstrated that the frequency of major birth defects was increased in women who had received HCQ at a dose of ≥400 mg/day during pregnancy. This study was undertaken to examine pregnancy outcomes among women following the use of HCQ.The study cohort comprised pregnant women who were prospectively enrolled in the MotherToBaby/Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Study and were receiving treatment with HCQ. For the control groups, disease-matched women without HCQ exposure and healthy women were randomly selected from the same source, with subject matching using a 1:1 ratio. Data were collected through interviews, medical records, and dysmorphology examinations. Pregnancy outcome measures included the presence or absence of major and minor birth defects, rates of spontaneous abortion, rates of preterm delivery, and infant growth measures.Between 2004 and 2018, 837 pregnant women met the criteria for study inclusion, including 279 women exposed to HCQ during pregnancy and 279 women in each unexposed control group. Sixty pregnant women (7.2%) were lost to follow-up. Among the women with live births, major birth defects occurred as a pregnancy outcome in 20 (8.6%) of 232 women with HCQ exposure in the first trimester, compared to 19 (7.4%) of 256 disease-matched unexposed controls (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.61-2.26) and 13 (5.4%) of 239 healthy controls (adjusted OR 0.76, 95% CI 0.28-2.05). Risks did not differ in women who were receiving an HCQ dose of ≥400 mg/day. No pattern of birth defects was identified. There were no differences in the rates of spontaneous abortion or preterm delivery between groups. Occurrence of infant growth deficiencies did not differ in the HCQ-exposed group compared to the disease-matched unexposed control group, except in the infant's head circumference at birth (adjusted OR 1.85, 95% CI 1.07-3.20).In this study, there was no evidence of an increased risk of structural birth defects or other adverse outcomes among women receiving HCQ during pregnancy, with the exception of infant head circumference at birth. For pregnant women being treated with HCQ, these findings are reassuring.

To date, the only study that has assessed the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 mRNA) vaccine in systemic lupus erythematosus (SLE) observed a moderate response, but the sample size precluded an accurate analysis of the effect of individual drugs. Therefore, we evaluated the immunogenicity of an inactivated SARS-CoV-2 vaccine (Sinovac-CoronaVac) and the influence of different medications in SLE. Safety was also assessed.We conducted a prospective controlled study of 232 SARS-CoV-2-naive SLE patients and 58 SARS-CoV-2-naive controls who were vaccinated with 2 doses of Sinovac-CoronaVac with a 28-day interval (day 0/day 28 [D0/D28]). Immunogenicity analysis at D0/D28 and D69 included anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralizing antibodies (NAb) positivity. The influence of individual drugs on immune response and safety was assessed.Patients and controls were well balanced for age (P = 0.771). At D69, SLE patients showed a moderate SC (70.2% versus 98.1%; P 0.001) and moderate frequency of NAb positivity (61.5% versus 84.6%; P = 0.002), although both frequencies were lower than in controls. Factors associated with lower SC in univariate analysis at D69 were prednisone use (odds ratio [OR] 0.215 [95% confidence interval (95% CI) 0.108-0.427], P 0.001) and mycophenolate mofetil (MMF) use (OR 0.201 [95% CI 0.107-0.378], P 0.001), whereas hydroxychloroquine (HCQ) use led to a 2.5 increase in SC (P = 0.011). SLE patients who were receiving HCQ monotherapy had similar SC to controls at D69 (100% versus 98.1%; P = 1.000). In multivariate analysis, prednisone and MMF use were independently associated with lower SC (P 0.001) and NAb positivity (P 0.001). Safety analysis revealed no moderate/severe adverse events.Sinovac-CoronaVac has a moderate immunogenicity in SARS-CoV-2-naive SLE patients with an excellent safety profile. We further demonstrate that HCQ may improve SC, whereas prednisone and MMF had a major deleterious effect in vaccine response, reinforcing the need to investigate the role of temporary MMF withdrawal or a vaccine-booster dose (ClinicalTrials.gov identifier: NCT04754698).

ZFP91 positively regulates IL-1β production in macrophages and may be a potential therapeutic target to treat inflammatory-related diseases. We investigated whether this process is modulated by convallatoxin, which is a cardiac glycoside isolated from the traditional Chinese medicinal plant Adonis amurensis Regel et Radde.In vitro, the mechanisms by which convallatoxin inhibits ZFP91-regulated IL-1β expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence and immunoprecipitation assays.In vivo, mice liver injury was induced by an intraperitoneal injection of D-GalN and LPS, colitis was induced by oral administration of dextran sulfate sodium (DSS) in drinking water and peritonitis was induced by an intraperitoneal injection of alum.We confirmed that convallatoxin inhibited the release of IL-1β by down-regulating ZFP91. Importantly, we found that convallatoxin significantly reduced K63-linked polyubiquitination of pro-IL-1β regulated by ZFP91 and decreased the efficacy of pro-IL-1β cleavage. Moreover, convallatoxin suppressed ZFP91-mediated activation of the non-canonical cysteine-requiring aspartate protease-8 (caspase-8) inflammasome and MAPK signalling pathways in macrophages. Furthermore, we showed that ZFP91 promoted the assembly of the caspase-8 inflammasome complex, whereas convallatoxin treatment reversed this result. Mice in vivo studies further demonstrated that convallatoxin ameliorated D-GalN/LPS-induced liver injury, DSS-induced colitis and alum-induced peritonitis by down-regulating ZFP91.We show for the first time that convallatoxin-mediated inhibition of ZFP91 is an important regulatory event that prevents inappropriate inflammatory responses to maintain immune homeostasis. This mechanism provides new insight for the development of convallatoxin as a novel anti-inflammatory drug targeting ZFP91.This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

To identify predictors of response to immunosuppressive therapy after 1 year, with a focus on autoantibodies, in patients newly diagnosed with idiopathic inflammatory myopathies (IIM) followed longitudinally in an electronic registry.We assessed the association between autoantibody-defined groups and improvement according to American College of Rheumatology/European Alliance of Associations for Rheumatology 2016 response criteria.We identified 156 patients; of those, 111 (71%) were positive for any autoantibody tested, 90% received glucocorticoid treatment at baseline, and 78% received immunosuppressive drugs at some follow-up point. After 1 year from the index date, the overall median improvement score was 27.5 (interquartile range 10-51). No differences were observed in the total improvement score between the autoantibody-defined groups. Overall, 62% of patients (n = 96) showed a minimal response, 38% (n = 60) achieved a moderate response, and 19% (n = 30) achieved a major response. Regarding the different levels of response, dermatomyositis-specific autoantibodies were associated with a moderate response versus the seronegative group (reference), odds ratio 4.12 (95% confidence interval 1.2-16.5). In addition, dysphagia, time from symptom onset to diagnosis, and initial glucocorticoid dose were significant predictors of response after 1 year of follow-up.Patients with DM-specific autoantibodies achieved better levels of response compared to other autoantibody-defined groups. Dysphagia, a shorter time span from symptom onset to diagnosis, and intensive initial immunosuppressive treatment were associated with a higher response rate after 1 year of pharmacologic treatment from the index date, regardless of autoantibody status.

Background and purpose Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviors. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signaling pathway of GS, especially at the peripheral sensory neuronal levels. Experimental approach Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behavior tests were also performed with wild-type and Trpv4 knockout mice. Key results GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor), and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviors were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behavior was also significantly decreased in Trpv4 knockout mice. Conclusion and implications Overall, the present study provides evidence for a novel molecular signaling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.

Brilacidin, a mimetic of host defense peptides (HDPs), is currently in Phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inactivating the virus. In this study, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on the host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, an HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on the host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.

Aims Therapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non-invasive gentamicin TDM strategy using saliva was investigated. Methods This was a multicentre, prospective, observational cohort study including 54 neonates. Any neonate treated with intravenous gentamicin was eligible for the study. Up to eight saliva samples were collected per patient at different time-points. Gentamicin levels in saliva were determined with liquid chromatography tandem mass-spectrometry (LC-MS/MS). A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects modelling (NONMEM) to describe the relation between gentamicin concentrations in saliva and plasma. Monte Carlo simulations with a representative virtual cohort (n = 3000) were performed to evaluate the probability of target attainment with saliva versus plasma TDM. Results Plasma PK was adequately described with an earlier published model. An additional saliva compartment describing the salivary gentamicin concentrations was appended to the model with first-order input (k(13) 0.023 h(-1)) and first-order elimination (k(30) 0.169 h(-1)). Inter-individual variability of k(30) was 38%. Postmenstrual age (PMA) correlated negatively with both k(13) and k(30). Simulations demonstrated that TDM with four saliva samples was accurate in 81% of the simulated cases versus 94% when performed with two plasma samples and 87% when performed with one plasma sample. Conclusion TDM of gentamicin using saliva is feasible and the difference in precision between saliva and plasma TDM may not be clinically relevant, especially for premature neonates.

Drug, alcohol and tobacco use disorders are a global burden affecting millions of people. Despite decades of research, treatment options are sparse or missing, and relapse rates are high. Glucagon-like peptide 1 (GLP-1) is released in the small intestine, promotes blood glucose homeostasis, slows gastric emptying and reduces appetite. GLP-1 receptor agonists approved for treating Type 2 diabetes mellitus and obesity have received attention as a potential anti-addiction treatment. Studies in rodents and non-human primates have demonstrated a reduction in intake of alcohol and drugs of abuse, and clinical trials have been initiated to investigate whether the preclinical findings can be translated to patients. This review will give an overview of current findings and discuss the possible mechanisms of action. We suggest that effects of GLP-1 in alcohol and substance use disorders is mediated centrally, at least partly through dopamine signalling, but precise mechanisms are still to be uncovered. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Aims: Although diabetes mellitus (DM) is a common co-morbidity in chronic heart failure (HF) patients, European data on concurrent HF and DM treatment are lacking. Therefore, we have studied the HF treatment of patients with and without DM. Additionally, with the recent breakthrough of sodium–glucose cotransporter 2 (SGLT2) inhibitors in the field of HF, we studied the potential impact of this new drug in a large cohort of HF patients. Methods and results: A total of 7488 patients with chronic HF with a left ventricular ejection fraction 2, P Conclusions: In this large real-world HF registry, a high prevalence of DM was observed and diabetics more often received guideline-recommended target doses. Based on current evidence, the majority of patients would fulfil the enrichment criteria of SGLT2 trials in HF and the impact of this new drug class will be large.

Capsid allosteric modulators (CAMs) inhibit the encapsidation of hepatitis B virus (HBV) pregenomic RNA (pgRNA), which contains a pathogen-associated molecular pattern motif. However, the effect of CAMs on the innate immune response of HBV-infected hepatocytes remains unclear, and we examined this effect in this study. Administration of a CAM compound, BAY41-4109 (BAY41), to HBV-infected primary human hepatocytes (PHHs) did not change the total cytoplasmic pgRNA levels but significantly reduced intracapsid pgRNA levels, suggesting that BAY41 increased extracapsid pgRNA levels in the cytoplasm. BAY41 alone did not change the intracellular interferon (IFN)-stimulated gene (ISG) expression levels. However, BAY41 enhanced antiviral ISG induction by IFN-α in HBV-infected PHHs but did not change ISG induction by IFN-α in uninfected PHHs. Compared with BAY41 or IFN-α alone, coadministration of BAY41 and IFN-α significantly suppressed extracellular HBV-DNA levels. HBV-infected human liver-chimeric mice were treated with vehicle, BAY41, pegylated IFN-α (pegIFN-α), or BAY41 and pegIFN-α together. Compared with the vehicle control, pegIFN-α highly up-regulated intrahepatic ISG expression levels, but BAY41 alone did not change these levels. The combination of BAY41 and pegIFN-α further enhanced intrahepatic antiviral ISG expression, which was up-regulated by pegIFNα. The serum HBV-DNA levels in mice treated with the combination of BAY41 and pegIFN-α were the lowest observed in all the groups. Conclusion: CAMs enhance the host IFN response when combined with exogenous IFN-α, likely due to increased cytoplasmic extracapsid pgRNA.

BACKGROUND P2Y12 inhibitor therapy is recommended for 12 months in patients hospitalised for acute myocardial infarction (AMI) unless bleeding risk is high. AIMS To describe real-world use of P2Y12 inhibitor therapy following AMI hospitalisation. METHODS We used population-level linked hospital data to identify all patients discharged from a public hospital with a primary diagnosis of AMI between July 2011-June 2013 in New South Wales and Victoria, Australia. We used dispensing claims to examine dispensing of a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) within 30 days of discharge, and multilevel models to identify predictors of post-discharge dispensing and persistence of therapy to one year. RESULTS We identified 31 848 patients hospitalised for AMI, of whom 56.8% were dispensed a P2Y12 inhibitor within 30 days of discharge. The proportion of patients with a post-discharge dispensing varied between hospitals (interquartile range: 25.0%-56.5%), and significant between-hospital variation remained after adjusting for patient characteristics. Patients factors associated with the lowest likelihood of post-discharge dispensing were having undergone coronary artery bypass grafting (OR:0.17, 95% CIs:0.15-0.20), having oral anticoagulants dispensed 180 days before or 30 days after discharge (OR:0.39, 95% CIs:0.35-0.44), major bleeding (OR:0.68, 95% CIs:0.61-0.76) or being aged ≥85 (OR:0.68, 95% CIs:0.62-0.75). 26.8% of patients who were dispensed a P2Y12 inhibitor post-discharge discontinued therapy within one year. CONCLUSION Post-hospitalisation use of P2Y12 inhibitor therapy in AMI patients is low, and varies substantially by hospital of discharge. Our findings suggest strategies addressing both health system (hospital and physician) and patient factors are needed to close this evidence-practice gap. This article is protected by copyright. All rights reserved.

Vitamin D is used to reduce cancer risk and improve the outcome of cancer patients, but the vitamin D receptor (VDR; also known as the calcitriol receptor) pathway needs to be functionally intact to ensure the biological effects of circulating calcitriol, the active form of vitamin D. Besides estrogen receptor alpha (ERα), estrogen-related receptor alpha (ERRα) has also been shown to interfere with the VDR pathway, but its role in the antitumor and transactivation activity of calcitriol is completely unknown in breast cancer (BC). We observed that ERRα functionally supported the proliferation of BC cell lines and acted as a calcitriol-induced regulator of VDR. As such, ERRα deregulated the calcitriol-VDR transcription by enhancing the expression of CYP24A1 as well as of both ERα and aromatase (CYP19A1) in calcitriol-treated cells. ERRα knockdown limited the effect of calcitriol by reducing calcitriol-induced G0/G1 phase cell cycle arrest and by affecting the expression of cyclin D1 and p21/Waf. The interactome analysis suggested that Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α (PGC-1α) and Proline-, glutamic acid-, and leucine-rich protein 1 (PELP-1) are key players in the genomic actions of the calcitriol-VDR-ERRα axis. Evaluation of patient outcomes in the The Cancer Genome Atlas (TCGA) dataset showed the translational significance of the biological effects of the VDR-ERRα axis, highlighting that VDR, CYP24A1 and ERRα overexpression correlates with poor prognosis in basal-like BC.

OBJECTIVE The goal of this article is to present the analysis of anti-abatacept antibody data from children with polyarticular-course juvenile idiopathic arthritis (pJIA), treated with abatacept. The data are from 395 participants with pJIA from two abatacept registrational trials. METHODS We analyzed immunogenicity data according to age groups, administration route (intravenous [IV] or subcutaneous [SC]), drug treatment interruption, and co-medications (with or without methotrexate [MTX]) to assess impact on the incidence of anti-abatacept antibodies. RESULTS The overall immunogenicity incidences observed in both JIA trials ranged between 4.7% and 23.3%. There was a slightly higher immunogenicity incidence in the 2-5-year-old participants (15.2%) compared with 6-17-year-old participants (4.7%). In the study with SC dosing, the overall incidence on treatment was 2.3% (3% if co-dosed with MTX), similar to the incidence for Period A of the IV study (similar duration of treatment as the SC study), which was 2.1% (1.4% if co-dosed with MTX). In the IV study, the period following a 6-month interruption in treatment had comparable immunogenicity incidences (22.9% with interruption vs. 18.2% without interruption, both co-dosed with MTX and 0% for both not co-dosed with MTX). In most cases, participants co-dosed with MTX had higher immunogenicity incidences than those on abatacept alone. CONCLUSION Although some trends were noted in terms of incidence according to age and MTX co-dosing, none where conclusive owing to differences in population size. Drug holiday had no impact on immunogenicity incidence once treatment was resumed, and incidences across SC and IV dosing were comparable. There was no impact of immunogenicity on pharmacokinetics, safety, and efficacy.

Introduction Hyperinflammatory state has a role in the pathogenesis of COVID‐19. Anakinra could reduce inflammation and help to combat the condition. In this study, we aimed to assess the safety and efficacy of anakinra (PerkinRA®) in severe COVID‐19. Method The study was an open‐label, randomized, controlled trial conducted in Imam Hossein Medical Center from May to July 2020. Patients with a confirmed diagnosis of COVID‐19 were included in this study. We administered anakinra 100 mg daily intravenously. All patients received COVID‐19 pharmacotherapy based on the represented national guideline. The need for invasive mechanical ventilation is considered the primary outcome. Results Thirty patients were included in this study, and 15 of them received Anakinra. Nineteen patients were male (63.3%), and 11 were female (36.7%). The mean age of patients was 55.77 ± 15.89 years. In the intervention group, the need for invasive mechanical ventilation was significantly reduced compared to the control group (20.0% vs. 66.7%, p = .010). Also, these patients had a significantly lower length of hospital stay (p = .043). No significant higher rate of infection was recorded. Conclusion Anakinra as an immunomodulatory agent has been associated with the reduced need for mechanical ventilation in patients admitted to intensive care units because of severe COVID‐19. The medication reduced the hospital length of stay. Furthermore, no increased risk of infection was observed. Further randomized placebo‐controlled trials with a larger sample size are needed to confirm these findings., Anakinra administration significantly reduces the need for mechanical ventilation. No increased risk of infection was observed because of anakinra use. Reduced hospitalization duration observed in patients who received anakinra.

Oxcarbazepine (OXZ) and levetiracetam (LEV) are two new generation anti‐epileptic drugs, often co‐administered in children with enzyme‐inducing antiepileptic drugs (EIAEDs). The anti‐epileptic effect of OXZ and LEV are linked to the exposure of OXZ’s active metabolite 10‐monohydroxy derivative (MHD) and (the parent) LEV, respectively. However, little is known about the confounding effect of age and EIAEDs on the pharmacokinetics (PKs) of MHD and LEV. To address this knowledge gap, physiologically‐based pharmacokinetic (PBPK) modeling was performed in the PK‐Sim software using literature data from children greater than or equal to 2 years of age. Age‐related changes in clearance (CL) of MHD and LEV were characterized, both in the presence (group 1) and absence (group 2) of concomitant EIAEDs. The drug‐drug interaction effect of EIAEDs was estimated as the difference in CL estimates between groups 1 and 2. PBPK modeling suggests that bodyweight normalized CL (ml/min/kg) is higher in younger children than their older counterparts (i.e., due to an influence of age). Concomitant EIAEDs further increase MHD’s CL to a fixed extent of 25% at any age, but EIAEDs’ effect on LEV’s CL increases with age from 20% (at 2 years) to 30% (at adolescence). Simulations with the maximum recommended doses (MRDs) revealed that children between 2 and 4 years and greater than 4 years, who are not on EIAEDs, are at risk of exceeding the reference exposure range for OXZ and LEV, respectively. This analysis demonstrates the use of PBPK modeling in understanding the confounding effect of age and comedications on PKs in children and adolescents.

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist (MRA) that recently demonstrated its efficacy to delay chronic kidney disease (CKD) progression and reduce cardiovascular events in patients with CKD and type 2 diabetes. Here, we report the development of a physiologically-based pharmacokinetic (PBPK) model for finerenone and its application as a victim drug of cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDI) using the open-source PBPK platform PK-Sim® which has recently been qualified for this application purpose. First, the PBPK model for finerenone was developed using physico-chemical, in vitro and clinical (including mass balance) data. Subsequently, the finerenone model was validated regarding the contribution of CYP3A4 metabolism to total clearance by comparing to observed data from dedicated clinical interaction studies with erythromycin (simulated geometric mean ratios of the area under the plasma concentration-time curve (AUCR) of 3.46 and geometric mean peak plasma concentration ratios (Cmax R) of 2.00 versus observed of 3.48 and 1.88, respectively) and verapamil (simulated AUCR of 2.91 and Cmax R of 1.86 versus observed of 2.70 and 2.22, respectively). Finally, the finerenone model was applied to predict clinically untested DDI studies with various CYP3A4 modulators. An AUCR of 6.31 and a Cmax R of 2.37 was predicted with itraconazole, of 5.28 and 2.25 with clarithromycin, 1.59 and 1.40 with cimetidine, 1.57 and 1.38 with fluvoxamine, 0.19 and 0.32 with efavirenz, and 0.07 and 0.14 with rifampicin. This PBPK analysis provides a quantitative basis to guide the label and clinical use of finerenone with concomitant CYP3A4 modulators.

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin‐based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5‐aza deoxy‐cytosine (5‐aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5‐aza‐resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin‐resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5‐aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5‐aza and 5‐aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5‐aza‐resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin‐resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5‐aza‐resistant cells, the exact opposite changes seen in cisplatin‐resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5‐aza resistance and cisplatin sensitization, and mediated genome‐wide repression of polycomb target gene expression. Finally, genome‐wide analysis revealed that 5‐aza‐resistant, cisplatin‐resistant, and DNMT3B‐knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5‐aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs., Alternative therapies are needed for testicular germ cell tumors (TGCTs) refractory to cisplatin. Recent preclinical and clinical studies suggest that cisplatin refractory TGCTs are distinctly sensitive to hypomethylating agents. The current study suggests a reciprocal relationship between cisplatin and hypomethylation agent sensitivity in TGCTs involving DNMT3B and the polycomb pathway that could lead to biomarkers for future clinical trials.