Ravulizumab in Atypical Hemolytic Uremic Syndrome: An Analysis of 2-Year Efficacy and Safety Outcomes in 2 Phase 3 Trials.

Rationale & Objective: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS. Study Design: This analysis reports 2-year data from 2 phase 3, single-arm studies. Setting & Participants: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219). Exposure: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight. Outcomes: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart. Analytical Approach: All analyses used descriptive statistics. No formal statistical comparisons were performed. Results: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m2) and pediatric patients (82.5 mL/min/1.73 m2). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years. Limitations: Limitations were the small sample of pediatric switch patients and limited availability of genetic data. Conclusions: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.

This research tested a drug called ravulizumab for the treatment of atypical hemolytic uremic syndrome (aHUS). aHUS is a rare disease that causes clots in tiny blood vessels. This can damage the kidneys and other organs. We analyzed data from 2 clinical trials in which children and adults with aHUS received ravulizumab through a tube placed in a vein (intravenous line). They received ravulizumab every 4-8 weeks depending on their weight. We found that treating patients for 2 years with ravulizumab was associated with improved blood health, kidney function, and quality of life and was well tolerated. These results support ravulizumab as a long-term treatment for people with aHUS.

Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort.

Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR. Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered). We assessed ethnicity and socioeconomic status in the following: (i) prevalent RaDaR patients receiving KRT compared with patients with eligible rare disease diagnoses receiving KRT in the UKRR, (ii) patients recruited to RaDaR compared with all eligible unrecruited patients at 2 renal centers, and (iii) the age-stratified ethnicity distribution of RaDaR patients with autosomal dominant polycystic kidney disease (ADPKD) was compared to that of the English census. Results: We found evidence of disparities in ethnicity and social deprivation in recruitment to RaDaR; however, these were not consistent across comparisons. Compared with either adults recruited to RaDaR or the English population, children recruited to RaDaR were more likely to be of Asian ethnicity (17.3% vs. 7.5%, P-value < 0.0001) and live in more socially deprived areas (30.3% vs. 17.3% in the most deprived Index of Multiple Deprivation (IMD) quintile, P-value < 0.0001). Conclusion: We observed no evidence of systematic biases in recruitment of patients into RaDaR; however, the data provide empirical evidence of negative economic and social consequences (across all ethnicities) experienced by families with children affected by rare kidney diseases.

Kidney Transplantation in Patients With aHUS: A Comparison of Eculizumab Prophylaxis Versus Rescue Therapy.

BACKGROUND: Guidelines advise eculizumab prophylaxis for most kidney transplant recipients with atypical hemolytic uremic syndrome (aHUS). However, recurrence rates may be overestimated, and starting eculizumab at relapse ("rescue therapy") may prevent graft loss. Randomized controlled trials have not compared the efficacy, safety, and costs of different treatment strategies. We performed a comparative study, including a previously described Dutch cohort treated with rescue therapy and a UK cohort using eculizumab prophylaxis. METHODS: In the Netherlands, we selected all adult patients with aHUS who received a kidney transplant between 2010 and 2021 in the Radboud University Medical Center (n = 30) and enriched this cohort with 8 patients who received rescue therapy in other centers. The UK cohort included all adult patients with aHUS at moderate or high risk of recurrence, transplanted between 2013 and 2017 with prophylactic eculizumab. RESULTS: We included 38 Dutch patients and 35 UK patients. Characteristics were comparable, although the UK cohort included more patients with a complement factor H SCR20 mutation or hybrid gene (31% versus 5%; P < 0.01), and more Dutch patients received living donor kidneys (66% versus 20%; P < 0.001). Follow-up was comparable (the Dutch patients 70.8 mo, range, 10-134; UK patients 55.4 mo, range, 2-95). Eighteen (47%) Dutch patients received rescue therapy. Death-censored graft survival was not significantly different (the Dutch patients 1 y, 3 y, and 6 y: 97.4%, 91.2%, and 87.1%, respectively; UK patients 1 y, 3 y, and 6 y: 97.1%, 88.2%, and 65.6%, respectively, log-rank P = 0.189). CONCLUSIONS: In a population characterized by low prevalence of "very high risk" genes, who were predominantly transplanted using an endothelial protective regime, death-censored graft survival with eculizumab rescue therapy was not inferior to prophylaxis.

Comprehensive functional characterization of complement factor I rare variant genotypes identified in the SCOPE geographic atrophy cohort.

Rare variants (RVs) in the gene encoding the regulatory enzyme complement factor I (CFI; FI) that reduce protein function or levels increase age-related macular degeneration risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for geographic atrophy secondary to age-related macular degeneration, including CFI sequencing and serum FI measurement. Eleven CFI RV genotypes that were challenging to categorize as type I (low serum level) or type II (normal serum level, reduced enzymatic function) were characterized in the context of pure FI protein in C3b and C4b fluid phase cleavage assays and a novel bead-based functional assay (BBFA) of C3b cleavage. Four variants predicted or previously characterized as benign were analyzed by BBFA for comparison. In all, three variants (W51S, C67R, and I370T) resulted in low expression. Furthermore, four variants (P64L, R339Q, G527V, and P528T) were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased versus the WT protein, while two variants (K476E and R474Q) were ∼1 log reduced in function. Meanwhile, six variants (P50A, T203I, K441R, E548Q, P553S, and S570T) had IC50s similar to WT. Odds ratios and BBFA IC50s were positively correlated (r = 0.76, p < 0.01), while odds ratios versus combined annotation dependent depletion (CADD) scores were not (r = 0.43, p = 0.16). Overall, 15 CFI RVs were functionally characterized which may aid future patient stratification for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

Iptacopan in Idiopathic Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Protocol of the APPARENT Multicenter, Randomized Phase 3 Study.

Introduction: Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultra-rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Dysregulation of the alternative complement pathway is implicated in the pathophysiology of IC-MPGN; and currently, there are no approved targeted treatments. Iptacopan is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the alternative pathway (AP). Methods: This randomized, double-blind, placebo-controlled phase 3 study (APPARENT; NCT05755386) will evaluate the efficacy and safety of iptacopan in patients with idiopathic (primary) IC-MPGN, enrolling up to 68 patients (minimum of 10 adolescents) aged 12 to 60 years with biopsy-confirmed IC-MPGN, proteinuria ≥1 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplant, progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily (bid) or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg bid for all patients for 6 months. The primary objective of the study is to evaluate the efficacy of iptacopan versus placebo in proteinuria reduction measured as urine protein-to-creatinine ratio (UPCR) (24-h urine) at 6 months. Key secondary end points will assess kidney function measured by eGFR, patients who achieve a proteinuria-eGFR composite end point, and patient-reported fatigue. Conclusion: This study will provide evidence toward the efficacy and safety of iptacopan in idiopathic (primary) IC-MPGN.

A Pragmatic Informatics Approach to Develop Knowledge Tools for Supporting Cardiac Surgical Patients' Mental Health Needs.

A pragmatic informatics approach was developed to create knowledge tools for co-design of a new model of mental healthcare in cardiac surgery The real-world evidence generation leverages existing technological platforms and routine data collections plus tailored brief tools, surveys and qualitative data.

Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.

Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0-12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study. Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which is caused by dysregulation of the alternative complement pathway (AP). Complement inhibition is an effective therapeutic strategy in aHUS, though current therapies require intravenous administration and increase the risk of infection by encapsulated organisms, including meningococcal infection. Further studies are required to define the optimal duration of existing therapies, and to identify new agents that are convenient for long-term administration. Iptacopan (LNP023) is an oral, first-in-class, highly potent, proximal AP inhibitor that specifically binds factor B (FB). In phase 2 studies of IgA nephropathy, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathy, iptacopan inhibited the AP, showed clinically relevant benefits, and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with the convenience of oral administration. Methods: Alternative Pathway Phase III to Evaluate LNP023 in aHUS (APPELHUS; NCT04889430) is a multicenter, single-arm, open-label, phase 3 study to evaluate the efficacy and safety of iptacopan in patients (N = 50) with primary complement-mediated aHUS naïve to complement inhibitor therapy (including anti-C5). Eligible patients must have evidence of TMA (platelet count <150 × 109/l, lactate dehydrogenase ≥1.5 × upper limit of normal, hemoglobin ≤ lower limit of normal, serum creatinine ≥ upper limit of normal) and will receive iptacopan 200 mg twice daily. The primary objective is to assess the proportion of patients achieving complete TMA response without the use of plasma exchange or infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. Conclusion: APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.

Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

Cue exposure for alcohol use disorders: A commentary on Kiyak et al. (2023).

While cue exposure therapy (CET) gives similar effects to cognitive-behavior therapies (CBTs) for Alcohol Use Disorder, it does not consistently add to effects of CBT alone. If the non-random trial of Nattala, Murthy, Leung, Rentala and Ramakrishna (2018) is omitted from the systematic review and meta-analysis of Kiyak, Simonetti, Norton and Deluca (2023), even average effects against less stringent controls are not substantial. Some trials have used sub-optimal versions of CET, but effects of CET are also constrained by the fact that many alcohol dependent patients do not exhibit strong craving. In vivo coping skills practice in the presence of powerful alcohol cues remains a viable treatment, especially if a key focus is on skills with wide situational application rather than solely on habituation. Multisensory motivational imagery for alcohol control represents one such strategy.

Assessing the Impact of Prophylactic Eculizumab on Renal Graft Survival in Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare cause of end-stage kidney disease and associated with poor outcomes after kidney transplantation from early disease recurrence. Prophylactic eculizumab treatment at the time of transplantation is used in selected patients with aHUS. We report a retrospective case note review describing transplant outcomes in patients with aHUS transplanted between 1978 and 2017, including those patients treated with eculizumab. METHODS: The National Renal Complement Therapeutics Centre database identified 118 kidney transplants in 86 recipients who had a confirmed diagnosis of aHUS. Thirty-eight kidney transplants were performed in 38 recipients who received prophylactic eculizumab. The cohort not treated with eculizumab comprised 80 transplants in 60 recipients and was refined to produce a comparable cohort of 33 transplants in 32 medium and high-risk recipients implanted since 2002. Complement pathway genetic screening was performed. Graft survival was censored for graft function at last follow-up or patient death. Graft survival without eculizumab treatment is described by complement defect status and by Kidney Disease: Improving Global Outcomes risk stratification. RESULTS: Prophylactic eculizumab treatment improved renal allograft survival ( P = 0.006) in medium and high-risk recipients with 1-y survival of 97% versus 64% in untreated patients. Our data supports the risk stratification advised by Kidney Disease: Improving Global Outcomes. CONCLUSIONS: Prophylactic eculizumab treatment dramatically improves graft survival making transplantation a viable therapeutic option in aHUS.

The economic evaluation of an Internet-based parental wellbeing intervention.

BACKGROUND: Internet-based parental programmes may improve parental wellbeing and mitigate the burden of mental health issues during the perinatal period. However, few studies have explored the cost and clinical impacts of such interventions. In the present study, we sought to evaluate the cost-effectiveness associated with an online cognitive behaviour therapy intervention (Baby Steps Wellbeing) to an information-only programme (Baby Care). METHODS: An alongside-trial cost-effectiveness analysis was undertaken using data from a randomised clinical trial comparing the Baby Steps Wellbeing intervention to Baby Care. Direct healthcare costs, as well as indirect costs attributed to income loss, were considered. The Assessment of Quality of Life-8 Dimensions multi-attribute utility instrument was used to estimate participant utilities, and subsequently calculate quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios were calculated to assess the cost-effectiveness of the intervention. The economic evaluation adopted a societal perspective. RESULTS: In total, 496 parents were randomised to either the Baby Steps Wellbeing intervention or the Baby Care control arm. No significant differences in costs (-$27, 95% confidence interval (CI): -$1189-$1134) or QALYs (0.051, 95% CI: -0.097-0.200) were identified. Bootstrapped results showed that the Baby Steps Wellbeing programme was cost-saving and health improving in 38% of simulations and cost-effective in another 37% of simulations. CONCLUSIONS: The Baby Steps Wellbeing programme was slightly cost-saving with slightly improved health outcomes compared with Baby Care. Bootstrapped results indicate the Baby Steps Wellbeing was cost-effective in 75% of simulations. Overall, the Baby Steps Wellbeing programme is an online programme that is cost-effective. TRIAL REGISTRATION: Australian & New Zealand Clinical Trials Registry: ANZCTR12614001256662.

Retrospective Self-Reports of How Adolescent Substance Use Changed with the COVID-19 Pandemic.

The final year of high school is a challenging phase of adolescents' lives and substance use can play an important role. We examined changes in the frequency and quantity of alcohol and cannabis use, and demographic correlates among Grade 12 students of 2020. Students (N = 844) from nine schools retrospectively self-reported changes in substance use after the easing of COVID-19 lockdowns (back to school), compared to before the pandemic. Changes in use were examined with age, gender, Aboriginal or Torres Islander, parental and family characteristics, and truancy. Thirty-one percent of students reported that they used alcohol less frequently, and 24% reported that they used it more frequently compared to pre-COVID-19. Most students (46%) reported that they used cannabis less, while a subset reported using more frequently (22%). A history of truancy was associated with an increased frequency (OR = 2.13 [1.18-3.83]) of cannabis use. A substantial minority of adolescents used more alcohol and cannabis after the initial COVID-19 lockdown period. Students in their final year who reported increased use may benefit from increased support to manage their substance use.

Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial.

Introduction: Complement 3 glomerulopathy (C3G) is a rare kidney disease characterized by dysregulation of the alternative pathway (AP) of the complement system. About 50% of patients with C3G progress to kidney failure within 10 years of diagnosis. Currently, there are no approved therapeutic agents for C3G. Iptacopan is an oral, first-in-class, potent, and selective inhibitor of factor B, a key component of the AP. In a Phase II study, treatment with iptacopan was associated with a reduction in proteinuria and C3 deposit scores in C3G patients with native and transplanted kidneys, respectively. Methods: APPEAR-C3G (NCT04817618) is a randomized, double-blind, and placebo-controlled Phase III study to evaluate the efficacy and safety of iptacopan in C3G patients, enrolling 68 adults with biopsy-confirmed C3G, reduced C3 (<77 mg/dl), proteinuria ≥1.0 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplantation, progressive crescentic glomerulonephritis (GN), monoclonal gammopathy of undetermined significance, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg twice daily for all patients for 6 months. The primary objective is to evaluate the efficacy of iptacopan versus placebo on proteinuria reduction urine protein:creatinine ratio (UPCR) (24 h urine). Key secondary endpoints will assess kidney function measured by eGFR, histological disease total activity score, and fatigue. Conclusion: This study aims to demonstrate the clinical benefits of AP inhibition with iptacopan in C3G.

Development of the motivational thought frequency scale for alcohol abstinence (MTF-A).

BACKGROUND AND AIMS: For most treatment-seeking patients with severe Alcohol Use Disorder (AUD), abstinence is the clinically indicated goal. Existing AUD motivation scales are non-specific about treatment consumption goals, which limit their effectiveness. Desires and mental imagery are relevant in the motivation for AUD treatment engagement. The Motivational Thought Frequency Scale for an abstinence goal (MTF-A) was adapted from the MTF for controlled drinking (MTF-CD). This study psychometrically evaluated the MTF-A in an alcohol-dependent sample engaged in treatment with a goal of abstinence. To enhance the clinical utility of the scale, a secondary aim was to evaluate a psychometrically equivalent short version of the MTF-A. METHOD: A sample N of 329 treatment-seeking patients with AUD (mean age of 44.44 years, SD = 11.89 years, 72% male) who were undertaking a cognitive behavioral treatment (CBT) program for abstinence completed the Motivational Thought Frequency Scale for Abstinence (MTF-A) and the Severity of Alcohol Dependence Questionnaire (SADQ). The MTF-A measured motivation for abstinence through four factors: intensity, self-efficacy imagery, incentives imagery, and availability. Confirmatory factor analyses (CFAs) were conducted to examine factor structure and model fit. Cronbach's alpha assessed internal consistency. Predictive validity was determined by logistic regression predicting first-session treatment non-attendance and alcohol consumption between baseline assessment and commencement of treatment, controlling for potential confounds. RESULTS: A four-factor structure provided the best fit for the MTF-A, compared with one- and three-factor models. A shortened 9-item MTF-A scale (S-MTF-A) provided better fit than the 13-item MTF-A scale. Both MTF-A and S-MTF-A displayed good internal consistency. Although both MTF-A and S-MTF-A successfully predicted first-session treatment non-attendance, neither predicted alcohol consumption between the baseline assessment and commencement of treatment. CONCLUSIONS: The model fit of the four-factor, 9-item S-MTF-A was superior to the original 13-item MTF-A. Both scales were predictive of participation of AUD treatment. Desires and mental imagery play an important role in AUD treatment motivation.

Safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome: protocol for a multicentre, open-label, prospective, single-arm study.

INTRODUCTION: Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disease caused by excessive activation of part of the immune system called complement. Eculizumab is an effective treatment, controlling aHUS in 90% of patients. Due to the risk of relapse, lifelong treatment is currently recommended. Eculizumab treatment is not without problems, foremost being the risk of severe meningococcal infection, the burden of biweekly intravenous injections and the high cost.This paper describes the design of the Stopping Eculizumab Treatment Safely in aHUS trial that aims to establish whether a safety monitoring protocol, including the reintroduction of eculizumab for those who relapse, could be a safe, alternative treatment strategy for patients with aHUS. METHODS AND ANALYSIS: This is a multicentre, non-randomised, open-label study of eculizumab withdrawal with continuous monitoring of thrombotic microangiopathy-related serious adverse events using the Bayes factor single-arm design. 30 patients will be recruited to withdraw from eculizumab and have regular blood and urine tests for 24 months, to monitor for disease activity. If relapse occurs, treatment will be restarted within 24 hours of presentation. 20 patients will remain on treatment and complete health economic questionnaires only. An embedded qualitative study will explore the views of participants. ETHICS AND DISSEMINATION: A favourable ethical opinion and approval was obtained from the North East-Tyne & Wear South Research Ethics Committee. Outcomes will be disseminated via peer-reviewed articles and conference presentations. TRIAL REGISTRATION NUMBER: EudraCT number: 2017-003916-37 and ISRCTN number: ISRCTN17503205.

Diagnosis and treatment of thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic haemolytic anaemia and end organ damage. TMAs have varying underlying pathophysiology and can therefore present with an array of clinical presentations. Renal involvement is common as the kidney is particularly susceptible to the endothelial damage and microvascular occlusion. TMAs require rapid assessment, diagnosis, and commencement of appropriate treatment due to the high morbidity and mortality associated with them. Ground-breaking research into the pathogenesis of TMAs over the past 20 years has driven the successful development of targeted therapeutics revolutionizing patient outcomes. This review outlines the clinical presentations, pathogenesis, diagnostic tests and treatments for TMAs.

The stay strong app as a self-management tool for first nations people with chronic kidney disease: a qualitative study.

BACKGROUND: The high burden of chronic kidney disease in First Nations peoples requires urgent attention. Empowering people to self-manage their own condition is key, along with promotion of traditional knowledge and empowerment of First Nations communities. This study explores the potential of a culturally responsive tool, already found to have high acceptability and feasibility among First Nations people, to support self-management for First Nations people with kidney failure. The Stay Strong app is a holistic wellbeing intervention. This study explores the suitability of the Stay Strong app to support self-management as shown by the readiness of participants to engage in goal setting. Data were collected during a clinical trial which followed adaption of research tools and procedures through collaboration between content and language experts, and community members with lived experience of kidney failure. METHODS: First Nations (i.e., Aboriginal and Torres Strait Islander) participants receiving haemodialysis in the Northern Territory (n = 156) entered a three-arm, waitlist, single-blind randomised controlled trial which provided collaborative goal setting using the Stay Strong app at baseline or at 3 months. Qualitative data gathered during delivery of the intervention were examined using both content and thematic analysis. RESULTS: Almost all participants (147, 94%) received a Stay Strong session: of these, 135 (92%) attended at least two sessions, and 83 (56%) set more than one wellbeing goal. Using a deductive approach to manifest content, 13 categories of goals were identified. The three most common were to: 'connect with family or other people', 'go bush/be outdoors' and 'go home/be on country'. Analysis of latent content identified three themes throughout the goals: 'social and emotional wellbeing', 'physical health' and 'cultural connection'. CONCLUSION: This study provides evidence of the suitability of the Stay Strong app for use as a chronic condition self-management tool. Participants set goals that addressed physical as well as social and emotional wellbeing needs, prioritising family, country, and cultural identity. The intervention aligns directly with self-management approaches that are holistic and prioritise individual empowerment. Implementation of self-management strategies into routine care remains a key challenge and further research is needed to establish drivers of success.