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The Improved Kidney Risk Score in ANCA-Associated Vasculitis for Clinical Practice and Trials.
Bate, S, McGovern, D, Costigliolo, F, Tan, PG, Kratky, V, Scott, J, Chapman, GB, Brown, N, Floyd, L, Brilland, B, et al
Journal of the American Society of Nephrology : JASN. 2024;(3):335-346
Abstract
SIGNIFICANCE STATEMENT Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 µ mol/L=0, K1: 250-450 µ mol/L=4, K2: >450 µ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821). CONCLUSIONS The updated score optimizes clinicopathologic prognostication for clinical practice and trials.
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Blastocyst quality and reproductive and perinatal outcomes: a multinational multicentre observational study.
Zou, H, Kemper, JM, Hammond, ER, Xu, F, Liu, G, Xue, L, Bai, X, Liao, H, Xue, S, Zhao, S, et al
Human reproduction (Oxford, England). 2023;(12):2391-2399
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Abstract
STUDY QUESTION Does the transfer of single low-grade blastocysts result in acceptable reproductive and perinatal outcomes compared to the transfer of single good-grade blastocysts? SUMMARY ANSWER The transfer of single low-grade blastocysts resulted in a reduced live birth rate of around 30% (14% for very low-grade blastocysts) compared to 44% for single good-grade blastocysts, but does not lead to more adverse perinatal outcomes. WHAT IS KNOWN ALREADY It is known that low-grade blastocysts can result in live births. However, the current studies are limited by relatively small sample sizes and single-centre designs. Furthermore, evidence on perinatal outcomes after transferring low-grade blastocysts is limited. STUDY DESIGN, SIZE, DURATION We conducted a multi-centre, multi-national retrospective cohort study of 10 018 women undergoing 10 964 single blastocyst transfer cycles between 2009 and 2020 from 14 clinics across Australia, China, and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS Blastocysts were graded individually based on assessment of the morphology and development of the inner cell mass (ICM) and trophectoderm (TE), and were grouped into three quality categories: good- (AB, AB, or BA), moderate- (BB), and low-grade (grade C for ICM or TE) blastocysts. CC blastocysts were individually grouped as very low-grade blastocysts. Logistic regression with generalized estimating equation was used to analyse the association between blastocyst quality and live birth as well as other reproductive outcomes. Binomial, multinomial logistic, or linear regression was used to investigate the association between blastocyst quality and perinatal outcomes. Odds ratio (OR), adjusted OR (aOR), adjusted regression coefficient, and their 95% CIs are presented. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE There were 4386 good-grade blastocysts, 3735 moderate-grade blastocysts, and 2843 low-grade blastocysts were included in the analysis, for which the live birth rates were 44.4%, 38.6%, and 30.2%, respectively. Compared to good-grade blastocysts, the live birth rate of low-grade blastocysts was significantly lower (aOR of 0.48 (0.41-0.55)). Very low-grade blastocysts were associated with an even lower live birth rate (aOR 0.30 (0.18-0.52)) and their absolute live birth rate was 13.7%. There were 4132 singleton live births included in the analysis of perinatal outcomes. Compared with good-grade blastocysts, low-grade blastocysts had comparable preterm birth rates (<37 weeks, aOR 1.00 (0.65-1.54)), birthweight Z-scores (adjusted regression coefficient 0.02 (0.09-0.14)), and rates of very low birth weight (<1500 g, aOR 0.84 (0.22-3.25)), low birth weight (1500-2500 g, aOR 0.96 (0.56-1.65)), high birth weight (>4500 g, aOR 0.93 (0.37-2.32)), small for gestational age (aOR 1.63 (0.91-2.93)), and large for gestational age (aOR 1.28 (0.97-1.70)). LIMITATIONS, REASONS FOR CAUTION Due to the nature of the retrospective design, residual confounding could not be excluded. In addition, the number of events for some perinatal outcomes was small. Between-operator and between-laboratory variations in blastocyst assessment were difficult to control. WIDER IMPLICATIONS OF THE FINDINGS Patients undergoing IVF should be informed that low-grade blastocysts result in a lower live birth rate, however they do not increase the risk of adverse perinatal outcomes. Further research should focus on the criteria for embryos that should not be transferred and on the follow-up of long-term outcomes of offspring. STUDY FUNDING/COMPETING INTEREST(S): H.Z. is supported by a Monash Research Scholarship. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). R.W. is supported by an NHMRC Emerging Leadership Investigator grant (2009767). B.W.J.M. reports consultancy, travel support, and research funding from Merck. The other authors do not have competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.
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Service user perspectives on social prescribing services for mental health in the UK: a systematic review.
Cooper, M, Flynn, D, Avery, L, Ashley, K, Jordan, C, Errington, L, Scott, J
Perspectives in public health. 2023;(3):135-144
Abstract
AIM: To thematically synthesise adult service users' perspectives on how UK-based social prescribing services support them with their mental health management. METHODS Nine databases were systematically searched up to March 2022. Eligible studies were qualitative or mixed methods studies involving participants aged ⩾ 18 years accessing social prescribing services primarily for mental health reasons. Thematic synthesis was applied to qualitative data to create descriptive and analytical themes. RESULTS 51,965 articles were identified from electronic searches. Six studies were included in the review (n = 220 participants) with good methodological quality. Five studies utilised a link worker referral model, and one study a direct referral model. Modal reasons for referral were social isolation and/or loneliness (n = 4 studies). Two analytical themes were formulated from seven descriptive themes: (1) person-centred care was key to delivery and (2) creating an environment for personal change and development. CONCLUSIONS This review provides a synthesis of the qualitative evidence on service users' experiences of accessing and using social prescribing services to support their mental health management. Adherence to principles of person-centred care and addressing the holistic needs of service users (including devoting attention to the quality of the therapeutic environment) are important for design and delivery of social prescribing services. This will optimise service user satisfaction and other outcomes that matter to them.
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The role of methionine synthases in fungal metabolism and virulence.
Scott, J, Amich, J
Essays in biochemistry. 2023;(5):853-863
Abstract
Methionine synthases (MetH) catalyse the methylation of homocysteine (Hcy) with 5-methyl-tetrahydrofolate (5, methyl-THF) acting as methyl donor, to form methionine (Met) and tetrahydrofolate (THF). This function is performed by two unrelated classes of enzymes that differ significantly in both their structures and mechanisms of action. The genomes of plants and many fungi exclusively encode cobalamin-independent enzymes (EC.2.1.1.14), while some fungi also possess proteins from the cobalamin-dependent (EC.2.1.1.13) family utilised by humans. Methionine synthase's function connects the methionine and folate cycles, making it a crucial node in primary metabolism, with impacts on important cellular processes such as anabolism, growth and synthesis of proteins, polyamines, nucleotides and lipids. As a result, MetHs are vital for the viability or virulence of numerous prominent human and plant pathogenic fungi and have been proposed as promising broad-spectrum antifungal drug targets. This review provides a summary of the relevance of methionine synthases to fungal metabolism, their potential as antifungal drug targets and insights into the structures of both classes of MetH.
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Effectiveness and active ingredients of social prescribing interventions targeting mental health: a systematic review.
Cooper, M, Avery, L, Scott, J, Ashley, K, Jordan, C, Errington, L, Flynn, D
BMJ open. 2022;(7):e060214
Abstract
OBJECTIVE This study aims to establish the effectiveness and active ingredients of UK-based social prescribing interventions targeting mental health and well-being outcomes. DESIGN Systematic review adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analysies guidelines and a published protocol. DATA SOURCES Nine databases were systematically searched up to March 2022. ELIGIBILITY CRITERIA Social prescribing interventions in the UK involving adults aged ≥18 years, which reported on mental health outcomes. DATA EXTRACTION AND SYNTHESIS Two reviewers extracted data on study characteristics; outcomes; referral pathways; treatment fidelity strategies; person-centredness; intervention development processes and theory-linked behaviour change techniques (BCTs). Data were narratively synthesised. RESULTS 52 074 records were retrieved by the search, 13 interventions reported across 17 studies were included in this review (N=5036 participants at post-intervention). Fifteen studies were uncontrolled before-and-after designs, one a randomised controlled trial and one a matched groups design. The most frequently reported referral pathway was the link worker model (n=12), followed by direct referrals from community services (n=3). Participants were predominantly working age adults, and were referred for anxiety, depression, social isolation and loneliness. 16 out of 17 studies reported statistically significant improvements in outcomes (mental health, mental well-being, general health, or quality of life). Strategies to enhance treatment fidelity were suboptimal across studies. Only two studies used a specific theoretical framework. A few studies reported engaging service users in codesign (n=2) or usability and/or feasibility testing (n=4). Overall, 22 BCTs were coded across 13 interventions. The most frequently coded BCTs were social support-unspecified (n=11), credible source (n=7) and social support-practical (n=6). CONCLUSIONS Robust conclusions on the effectiveness of social prescribing for mental health-related outcomes cannot be made. Future research would benefit from comprehensive intervention developmental processes, with reference to appropriate theory, alongside long-term follow-up outcome assessment, using treatment fidelity strategies and a focus on principle of person-centred care. PROSPERO REGISTRATION NUMBER CRD42020167887.
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Vitreous cytokine levels following the administration of a single 0.19 mg fluocinolone acetonide (ILUVIEN®) implant in patients with refractory diabetic macular edema (DME)-results from the ILUVIT study.
Deuchler, SK, Schubert, R, Singh, P, Chedid, A, Kenikstul, N, Scott, J, Kohnen, T, Ackermann, H, Koch, F
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2022;(8):2537-2547
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Abstract
PURPOSE To investigate the changes in vitreous inflammatory and angiogenic cytokine levels, primarily interleukin-(IL)-6, following intravitreal injection of the 0.19 mg fluocinolone acetonide (FAc, ILUVIEN®) implant in patients with diabetic macular edema. METHODS A single-center phase IV study involving 12 patients' eyes with diabetic macular edema. Vitreous fluid samples were obtained prior to intravitreal injection of the fluocinolone acetonide implant and then again over a 6-month period. Vitreous samples were examined using a cytometric bead array to measure IL-6, IL-8, IP-10, MCP-1, VEGF, and CD54. PIGF and PEDF were measured using an enzyme-linked immunosorbent assay. Changes in the cytokine and chemokine expression patterns were analyzed. Clinical parameters such as BCVA and center point thickness (CPT) were also examined. RESULTS There were mean reductions in all parameters between baseline and month 6. Significant changes (p < 0.05 versus baseline) were observed in the expression of IL-6, IP-10, MCP-1, and CD54 following the administration of fluocinolone acetonide implant. VEGF and PIGF increased at month 1 before declining at month 6, though this trend was not significant. CPT decreased rapidly between screening and the first follow-up visit, and this decrease was sustained. BCVA remained relatively stable throughout. CONCLUSION This study demonstrated changes in vitreous inflammatory and angiogenic cytokine levels following intravitreal injection of the FAc implant in patients with diabetic macular edema. Data show that the fluocinolone acetonide implant led to rapid and sustained reductions of some inflammatory cytokines with improvement of the overall clinical picture.
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Risk factors for clozapine-induced myocarditis and cardiomyopathy: A systematic review and meta-analysis.
Vickers, M, Ramineni, V, Malacova, E, Eriksson, L, McMahon, K, Moudgil, V, Scott, J, Siskind, D
Acta psychiatrica Scandinavica. 2022;(5):442-455
Abstract
OBJECTIVE Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and meta-analysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy. METHODS A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale. RESULTS Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature. CONCLUSION Concurrent use of sodium valproate increases the odds of clozapine-induced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine.
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Impact of body size and body composition on bladder cancer outcomes: Risk stratification and opportunity for novel interventions.
Sanchez, A, Kissel, S, Coletta, A, Scott, J, Furberg, H
Urologic oncology. 2020;(9):713-718
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Abstract
Body size is emerging as a novel and clinically-relevant patient factor in bladder cancer research. Historically, a patient's body mass index (BMI) has been used as a proxy for obesity but it shows inconsistent associations with risk of developing the disease as well as with most clinical outcomes. More specific body composition features can be derived for patients using a variety of methods. To date, skeletal muscle measurements derived from preoperative computed tomography scans have shown the most consistent associations with clinical outcomes. Importantly, skeletal muscle can potentially be modified through resistance training and/or nutritional interventions. Large scale studies that evaluate the prognostic impact of not only body composition features at baseline but also describe changes in body composition post-treatment are needed to move the field forward to ultimately improve clinical outcomes for bladder cancer patients.
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Protocol update and statistical analysis plan for CADENCE-BZ: a randomized clinical trial to assess the efficacy of sodium benzoate as an adjunctive treatment in early psychosis.
Lim, C, Baker, A, Saha, S, Foley, S, Gordon, A, Ward, D, Burgher, B, Dark, F, Beckmann, M, Stathis, S, et al
Trials. 2019;(1):203
Abstract
BACKGROUND CADENCE-BZ is a multi-centre, parallel-group, double-blind randomized controlled trial designed to examine the clinical efficacy and safety of an accessible food preservative, sodium benzoate, as an add-on treatment for patients with early psychosis. The original study protocol was published in 2017. Here, we describe the updated protocol along with the Statistical Analysis Plan (SAP) for the CADENCE-BZ trial prior to study completion. METHODS AND MATERIALS Two important changes were made to the original protocol: (1) improvements to our statistical analysis plan permitted a reduction in sample size; and (2) a revision in the secondary outcomes with the intent of reducing redundancy and excluding those measures that were not appropriate as outcomes. CONCLUSIONS We provide the updated SAP prior to the completion of the study with the intent of increasing the transparency of the data analyses for CADENCE-BZ. The final participants are currently completing the study and the results will be published in the near future. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ( ACTRN12615000187549 ). Registered on 26th February 2015.
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Lipoprotein apheresis efficacy, challenges and outcomes: A descriptive analysis from the UK Lipoprotein Apheresis Registry, 1989-2017.
Pottle, A, Thompson, G, Barbir, M, Bayly, G, Cegla, J, Cramb, R, Dawson, T, Eatough, R, Kale, V, Neuwirth, C, et al
Atherosclerosis. 2019;:44-51
Abstract
BACKGROUND AND AIMS In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011. METHODS Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients. RESULTS Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA. CONCLUSIONS The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias.