Otsuka (United Kingdom)

significant differences in autoantibody profiles were detected between deceased and non-deceased patients. We observed a bimodal distribution of causes of death, with SLE, malignancy and infection more likely to cause early deaths, and cardiovascular disease more likely to cause later deaths. Across the whole cohort, patients lived longer than was expected. However, a third of patients still died early, suggesting future work should focus on addressing these highest risk patients. Across the cohort proportionally more male than female patients died. This may reflect known differences in life expectancy between genders, but highlights male patients as a group with persisting poorer mortality outcomes. No significant differences in autoantibody profiles were observed between patients that died versus those that survived. This may be because the entire cohort is enriched for positive serology, perhaps making it less likely that differences will be identified. REFERENCE:

BackgroundLupus nephritis (LN) is a severe renal manifestation of the autoimmune disease lupus. Tests for renal function, such as estimated glomerular filtration rate (eGFR), should be standard in the diagnosis and monitoring of patients with renal disease as recommended by the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease (CKD) Working Group [1]. These tests are important to identify renal function decline and prompt interventions to prevent further disease progression. It has been found that use of eGFR is low in Italy for CKD patients [2] but data on real-world testing in other countries is limited.ObjectivesTo understand renal function test use by nephrologists in the diagnosis and monitoring of LN patients in Europe in a real-world clinical setting.MethodsData were sourced from the Adelphi Lupus IV Disease Specific Programme™, a point-in-time survey of nephrologists and their LN patients conducted in France, Germany, Italy, Spain and the United Kingdom in April – October 2021. Nephrologists completed patient record forms covering each patient’s management, including tests and assessments used for diagnosis and monitoring.The data was analysed descriptively.Results72 nephrologists provided data for 376 LN patients. Overall, 20% of LN patients in the sample did not have a Glomerular Filtration Rate (GFR) or eGFR test documented to diagnose their condition. The use of these tests at diagnosis was lower in Germany and Italy (≤72%) compared to the other countries where use was over 80%. Of all the patients without GFR/eGFR at diagnosis, only 43% had an alternative renal test completed (e.g. urine protein, creatinine clearance (CrCl), albumin-to-creatinine ratio (ACR) or ‘other urinalysis test’ (including urine protein creatinine ratio)).Across Europe, the use of GFR/eGFR to monitor patients with LN was 85% or above, apart from Italy where 31% of patients did not have either test.In patients without GFR/eGFR for monitoring, the use of alternative renal tests was higher than at diagnosis (60% vs. 43%). However, 40% of those patients received no other renal test (e.g. urine protein, CrCl or ACR) to monitor their condition.Table 1.Renal test use in EuropeOverallFranceGermanyItalySpainUKRenal tests used at LN diagnosis, n (%)Samplen=376n=63n=75n=75n=81n=82GFR133 (35)31 (49)27 (36)31 (41)35 (43)9 (11)eGFR220 (59)25 (40)37 (49)33 (44)59 (73)66 (80)GFR and/or eGFR302 (80)56 (89)54 (72)53 (71)71 (88)68 (83)Neither GFR nor eGFR74 (20)7 (11)21 (28)22 (29)10 (12)14 (17)Of patients without GFR/eGFR at diagnosis – Other renal tests to diagnose, n (%)Samplen=74At least one renal test other than eGFR/GFR32 (43)Renal tests used in monitoring of LN*, n (%)Samplen=368n=62n=73n=74n=78n=81GFR129 (35)28 (45)29 (40)29 (39)32 (41)11 (14)eGFR225 (61)25 (40)43 (59)34 (46)53 (68)70 (86)GFR and/or eGFR311 (85)53 (85)62 (85)51 (69)70 (90)75 (93)Neither GFR nor eGFR57 (15)9 (15)11 (15)23 (31)8 (10)6 (7)Of patients without GFR/eGFR for monitoring – Other renal tests to monitor, n (%)Samplen=57At least one renal test other than eGFR/GFR34 (60)*Patients with available data,Abbreviations: eGFR, Estimated Glomerular Filtration Rate; GFR, Glomerular Filtration Rate; LN, Lupus Nephritis; UK, United KingdomConclusionGFR/eGFR are key markers of renal function as discussed in the KDIGO recommendations [1], but this analysis observed lower-than-expected use of GFR/eGFR among nephrologists. This was especially apparent in Germany and Italy. There may be even less use of these tests among non-nephrology specialities. Lower-than-expected use of these recommended tests indicates a need for improvement in the diagnosis and monitoring of LN patients in Europe. This suboptimal management may be affecting patient outcomes, but further research is needed to assess this. Results are subject to recall bias which was minimised by asking survey respondents to use patient medical records for the completion of forms.

Chimeric antigen receptor (CAR)-T cell therapy is a promising therapeutic approach in treating hematological malignancies. However, due to escape of CAR antigens in cancer cells, resistance and relapse occur in some patients after CAR-T cell therapy. Therefore, we investigated whether the combination with an antagonist of inhibitor of apoptosis proteins (IAP), tolinapant, currently being evaluated in a phase 2 study of peripheral T-cell lymphoma and cutaneous T-cell lymphoma, could enhance anti-tumor effect of CAR-T cell therapy. We found that tolinapant enhanced the antitumor effect of CAR-T cell therapy in a TNF-α-dependent manner. TNF-α secreted from CAR-T cells in the presence of tolinapant also induced cell death of antigen-negative cancer cells not in cell-cell contact with CAR-T cells. The significant combined effect was also observed in vivo. Even at ineffective doses of CAR-T cell monotherapy, anti-tumor effect was observed when the combination treatment was used. We propose that this is because tolinapant induced both cancer cell death and CAR-T cell proliferation. In summary, we find that combination therapy with tolinapant improved the efficacy of CAR-T cells by inducing cancer cell death and CAR-T cell proliferation. This combination therapy may overcome the current limitations of CAR-T cell therapy.

Background: To prevent diabetes, it is important to control postprandial glycemic levels. Studies have suggested that consuming black tea decreases the risk of type 2 diabetes; however, only a few studies have examined the effects of black tea on postprandial glycemic control after consuming starch-rich foods. In addition, the mechanism underlying the suppression of postprandial glucose levels remains unclear.Objective: To investigate the effects of black tea on postprandial blood glucose levels in healthy humans and to identify the components of black tea that inhibit digestive enzymes.Methods: The inhibitory activity of black tea on digestive enzymes was measured, and the inhibitory components were fractionated. Healthy Japanese adults ingested 200 ml of black tea, and its effect on postprandial blood glucose and insulin levels were investigated. Results: Black tea dose-dependently inhibited α-glucosidase, sucrase, and α-amylase activity. The major components responsible for this inhibition were high–molecular-weight polyphenols. The galloyl moieties present in these compounds play an important role in their inhibitory activities. Two randomized, double-blind, placebo-controlled, crossover studies of healthy human subjects (total n = 46) were conducted to investigate the effect of black tea on blood glucose and insulin levels. Combined data from the two studies showed that black tea ingestion (200 mL) after cooked rice intake (200 g) significantly reduced the incremental area under the curve of glucose (P =.024) and insulin (P =.014) compared to placebo drink.Conclusions: The high–molecular-weight polyphenols in black tea inhibited α-glucosidase, sucrase, and α-amylase activity in a dose-dependent manner. Furthermore, black tea ingestion after eating cooked rice significantly reduced the incremental area under the curve of glucose and insulin. These effects of black tea could be attributed to the inhibition of digestive enzymes by high–molecular-weight polyphenols containing galloyl groups.Keywords: black tea, blood glucose, α-glucosidase, α-amylase, polyphenol

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is considered the most common inherited renal disease. Patient-Reported Outcomes (PROs) and patient experience in ADPKD are difficult to quantify and have not been well studied, particularly in the early stages of the disease. There is evidence to suggest that early-stage ADPKD patients have a lower Health-Related Quality of Life (HRQoL) than the general population due to the signs and symptoms of early-stage ADPKD. However, no research has been carried out on the HRQoL of early-stage ADPKD patients using validated ADPKD-specific PRO measures. Additionally, a new disease progression delaying treatment option has recently emerged for ADPKD. Patient preference for this treatment and unmet treatment needs have not yet been investigated.MethodsThe ACQUIRE study is a prospective, observational study investigating the influence of early-stage ADPKD-related symptoms and treatments on PROs. It aims to collect real-world data on patient demographics, treatment patterns, clinical outcomes, and PROs such as HRQoL, treatment satisfaction and treatment preference in early-stage ADPKD. Adult ADPKD patients in stages 1–3 of chronic kidney disease (CKD) with evidence of rapidly progressing disease are being recruited from seven European countries. At baseline and every 3 months, for a follow-up period of 18 months, general and disease-specific questionnaires are completed remotely to capture patients’ own assessment of their overall and ADPKD-related HRQoL. A Discrete Choice Experiment (DCE) is also used to investigate the value patients place on different attributes of hypothetical treatment options (e.g. treatment outcomes, side effects) and the role each attribute plays in determining overall patient treatment preference.DiscussionThe results of this study will highlight the real-world effects of ADPKD-related challenges on PROs including HRQoL, treatment experience and satisfaction; and help physicians gain greater insight into likely disease outcomes based on early-stage patient symptoms and patients’ experience with treatment. Data captured by the DCE may inform ADPKD treatment decision-making from a patient perspective. The DCE will also provide insights into which patients are more likely to perceive benefit from treatments based on the value and trade-offs they place on specific treatment attributes.Trial registrationNCT02848521.Protocol Number/Version: 156–303-00096/Final

: Objective: To develop a gastroretentive in situ oral gel to improve the bioavailability of the cephalosporin antibiotic drug, Cefuroxime Axetil. Methodology: Sodium alginate and pectin were the ionic dependent gel forming polymer. Calcium chloride was used as complexing agent to increase cross linking along with sodium citrate. Mucoadhesion was enhanced with the help of polymer HPMC K4M. Two factors and three levels factorial design was used for the optimization of formulation using design expert software version 7.1.6. The In situ gel system was evaluated for the content uniformity, pH, gelling capacity, viscosity of gel, in-vitro drug release and mucoadhesion study. Results and Discussion: Optimized formula showed more than 24% Drug release after 1 hour and prolonged release up to 12 hour, Viscosity of gel formed was 6423.9 cps and 3.668 N/cm2. The results revealed that as the concentration of Sodium alginate was directly proportional to mucoadhesion, inversely proportional to drug release while concentration of pectin directly proportional to drug release. Conclusion: The study point to the potential of in situ oral gel in terms of ease of administration, better patient compliance and prolonged gastro-retention.Key words: Gastro-retentive drug delivery system, Mucoadhesive Oral In-situ gel, Cefuroxime Axetil.

SummaryAimsHyponatraemia (HN) is the most common electrolyte balance disorder in clinical practice. Since the 1970s, demeclocycline has been used in some countries to treat chronic HN secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). The precise mechanism of action of demeclocycline is unclear, but has been linked to the induction of nephrogenic diabetes insipidus. Furthermore, the safety profile of demeclocycline is variable with an inconsistent time to onset, and a potential for complications. There has been no systematic evaluation of the use of demeclocycline for the treatment of HN secondary to SIADH to date. A systematic literature review was performed to obtain an insight into the clinical safety and efficacy of demeclocycline for this condition.MethodsEmbase™, MEDLINE®, MEDLINE® In‐Process, and The Cochrane Library were searched on two occasions using MeSH terms combined with free‐text terms. References were screened by two independent reviewers. Relevant publications were then extracted by two independent reviewers, with a third reviewer collating and finalising extractions.ResultsThe searches returned a total of 705 hits. 632 abstracts were screened after the removal of duplicates. Following screening, 35 full‐length publications were reviewed. Of these, 17 were excluded, resulting in 18 studies deemed relevant for data extraction. Two were randomised controlled trials (RCTs), 16 were non‐RCTs, and 10 were case reports.DiscussionAlthough most reports suggest that demeclocycline can address serum sodium levels in specific patients with HN, efficacy is variable, and may depend upon the underlying aetiology. Demeclocycline dose adjustments can be complex, and as its use in clinical practice is not well defined, it can differ between healthcare professionals.ConclusionThere is a lack of clinical and economic evidence supporting the use of demeclocycline for HN secondary to SIADH. Patients receiving demeclocycline for HN secondary to SIADH must be closely monitored.

PurposeTo assess the efficacy and safety of aripiprazole once-monthly 400 mg (AOM 400), an extended-release injectable suspension of aripiprazole, in obese and nonobese patients.Patients and methodsThis post hoc analysis of a 38-week randomized, double-blind, active-controlled, noninferiority study (NCT00706654) compared the clinical profile of AOM 400 in obese (body mass index [BMI] ≥30 kg/m2) and nonobese (BMI <30 kg/m2) patients with schizophrenia for ≥3 years. Patients were randomized 2:2:1 to AOM 400, oral aripiprazole 10–30 mg/d, or aripiprazole once-monthly 50 mg (AOM 50 mg) (subtherapeutic dose). Within obese and nonobese patient subgroups, treatment-group differences in Kaplan–Meier estimated relapse rates at week 26 (z-test) and in observed rates of impending relapse through week 38 (chi-square test) were analyzed. Treatment-emergent adverse events (TEAEs) (>10% in any treatment group) were summarized.ResultsAt baseline of the randomized phase, obesity rates were similar among patients randomized to AOM 400 (n=95/265, 36%), oral aripiprazole (n=95/266, 36%), and AOM 50 mg (n=43/131, 33%). In both obese and nonobese patients, relapse rates through week 38 for patients randomized to AOM 400 (obese, 7.4%; nonobese, 8.8%) were similar to those in patients on oral aripiprazole (obese, 8.4%; nonobese, 7.6%), whereas relapse rates were significantly lower with AOM 400 versus AOM 50 mg (obese, 27.9% [P=0.0012]; nonobese, 19.3% [P=0.0153]). The most common TEAEs with AOM 400 in obese and nonobese patients were insomnia (12.6% and 11.2%), headache (12.6% and 8.2%), injection site pain (11.6% and 5.3%), akathisia (10.5% and 10.6%), upper respiratory tract infection (10.5% and 4.7%), weight increase (10.5% and 8.2%), and weight decrease (6.3% and 11.8%). Within the AOM 400 group, 7.6% of patients who were nonobese at baseline became obese, and 17.9% of obese patients became nonobese during randomized treatment.ConclusionThe clinical profile of AOM 400 was similar in obese and nonobese patients.

There have been no randomized trials that have compared peripheral blood (PB) with bone marrow (BM) grafts in the setting of reduced-intensity conditioning (RIC) transplantations for hematologic malignancy. Because immune modulation plays a significant role in sustaining clinical remission after RIC, we hypothesize that higher graft-versus-host disease (GVHD) associated with PB transplantation may offer a survival advantage. The primary outcome evaluated was overall survival. Cox regression models were built to study outcomes after transplantation of PB (n = 887) relative to BM (n = 219) for patients with acute myeloid leukemia, myelodysplastic syndrome, or non-Hodgkin lymphoma, the three most common indications for unrelated RIC transplantation. Transplantations were performed in the United States between 2000 and 2008. Conditioning regimens consisted of an alkylating agent and fludarabine, and GVHD prophylaxis involved a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). After adjusting for age, performance score, donor-recipient HLA-match, disease, and disease status at transplantation (factors associated with overall survival), there were no significant differences in 5-year rates of survival after transplantation of PB compared with BM: 34% versus 38% with CNI-MTX and 27% versus 20% with CNI-MMF GVHD prophylaxis. Survival after transplantation of PB and BM are comparable in the setting of nonirradiation RIC regimens for hematologic malignancy. The effect of GVHD prophylaxis on survival merits further evaluation.