[This corrects the article DOI: 10.1371/journal.pone.0322592.].

Atypical haemolytic uraemic syndrome (aHUS) is a rare disease which without treatment is associated with high morbidity and mortality. Eculizumab, a monoclonal complement inhibitor, is an effective treatment but the optimal way to use this high-cost medication has not been determined. The SETS aHUS trial aimed to establish the safety of eculizumab withdrawal and the effectiveness of a monitoring protocol to detect disease relapse and safe reintroduction of treatment if disease relapse occurs. The SETS aHUS multicentre, open label, prospective, single arm trial enrolled participants from 15 UK hospitals with embedded qualitative and health economic analyses. Patients over two years of age with aHUS who were receiving eculizumab therapy for at least six months were eligible to withdraw from treatment, replacing it with monitoring to assess disease activity with re-introduction of treatment if relapse occurred. The primary outcome measure was harm to a participant as a consequence of eculizumab withdrawal during the 2-year trial period. Participants met a primary outcome if there was a permanent reduction in estimated glomerular filtration rate (GFR), requirement for kidney replacement therapy or significant extra-renal manifestation of disease. The Bayes factor single arm binary model was used to monitor and analyse the trial data, applying pre-trial stopping rules. The trial is registered with the European Union Drug Regulating Authority (EudraCT 2017-003916-37). One of 28 participants (3.6%) who withdrew from treatment met a primary outcome. Four participants relapsed, all of whom had pathogenic genetic variants in complement proteins. Only participants with an identified cause of complement dysregulation relapsed. It was possible, by monitoring and rapid participant access, to successfully reintroduce eculizumab treatment. Based on the pre-trial analysis plan, withdrawal from treatment is not associated with a greater risk to patients compared to remaining on treatment. Most patients welcomed the opportunity to withdraw from treatment but identified concerns about monitoring and the risk of relapse, informed by initial experience at presentation. Withdrawing a patient from treatment saves £4.2 million in health care costs. Withdrawal of eculizumab treatment with monitoring of disease activity was not associated with an increased risk of harm compared to continuation of eculizumab. The presence of an identifiable cause of complement dysregulation predicts a higher risk of relapse. This study adds to the growing evidence for time limited periods of anti-complement therapy in patients with aHUS.

Thrombotic microangiopathy (TMA) is a challenging and serious complication of kidney transplantation that significantly affects graft and patient survival, occurring in 0.8%-15% of transplant recipients. TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to endothelial damage and microthrombi formation in small vessels. However, clinical features can range from a renal-limited form, diagnosed only on a kidney biopsy, to full-blown systemic manifestations, which include neurologic, gastrointestinal, and cardiovascular injury. TMA can arise because of genetic or acquired defects such as in complement-mediated TMA or can occur in the context of other conditions like infections, autoimmune diseases, or immunosuppressive drugs, where complement activation may also play a role. Recurrent TMA after kidney transplant is almost always complement-mediated, although complement overactivation may also play a role in de novo post-transplant TMAs associated with ischemia-reperfusion injury, immunosuppressive drugs, antibody-mediated rejection, viral infections, and relapse of autoimmune diseases, such as antiphospholipid antibody syndrome. Differentiating between a complement-mediated process and one triggered by other factors is often challenging but critical to minimize allograft damage because the former is nonresponsive to supportive therapy, needs long-term anticomplement therapy, and has a high risk of recurrence. Given the central role of complement and effect of genetic defects on the risk of recurrence in many forms of post-transplant TMA, genetic testing for complement disorders is key for proper diagnosis and management. Given that complement activation may also play a role in a subset of TMAs associated with other conditions, prompt recognition and timely initiation of anticomplement therapy is equally important. In addition, TMA associated with noncomplement genes, often part of a broader syndromic process with distinct clinical features, has also been described. Early identification and treatment are essential to prevent graft failure and other severe complications. This review explores the pathophysiologic mechanisms underlying various post-transplant TMAs.

Cognitive models hypothesize a role for motivated behaviour in anxiety disorders, with safety behaviours leading to exaggerated threat appraisals and increased anticipatory anxiety. Based on the Affective Imagery Theory of Motivation, we propose that increasing motivation for engagement behaviours will reduce motivation for safety behaviours through competition for limited capacity cognitive resources supporting motivational imagery. We hypothesize that imagining successful engagement will reduce anxiety directly, and through promoting subsequent engagement. We present preliminary evidence that functional imagery training (FIT), an intervention that develops and teaches motivational imagery, reduces anxiety. FIT was delivered to undergraduates with anxiety in one session lasting 40-60 min, with two booster calls over 2 weeks (10-20 min). Qualitative data from study 1a (N = 9) showed that FIT reduced anxiety by strengthening motivation for engagement goals and by the calming and empowering effects of imagery practice. Study 1b (N = 10) replicated these findings. Using a stepped wedge design, study 2 (N = 29) showed that anxiety reduction over 4 weeks was specifically due to FIT rather than generic experimental factors. GAD-7 scores reduced sooner for a group who received FIT immediately after baseline assessments than for a delayed group who received FIT after the week 2 assessments (BF10 = 25 for group × time interaction). Thus, at week 2, GAD-7 scores were lower for the immediate group (M = 7.2, SD = 3.86) than for the delayed group who had not yet received FIT (M = 13.0, SD = 3.80; BF10 = 71). The results provide initial evidence that brief imagery-based motivational support can reduce anxiety.

Perinatal depression is highly prevalent, yet there is a very low rate of treatment uptake and help-seeking. The MumSpace Initiative was funded by the Australian government to invest in digital stepped-care treatments and support for perinatal depression, to improve mental health outcomes and national access. This paper describes the reach of the MumSpace initiative as a one-stop shop offering perinatal depression treatments with a solid evidence base (MumMoodBooster programmes), supported by a prevention programme addressing modifiable risk factors through a smartphone application (MindMum) as well as evidence-based universal prevention programmes. We have brought together multi-skilled teams and a Perinatal Depression Consortium to deliver the programmes and address changing technology. The effectiveness of MumSpace was evaluated through systematic monitoring of consumer reach: data analysis of website traffic and resource uptake. MumSpace has successfully sustained engagement, attracting over 275,000 visits since its launch in 2017, with the number of visitors to the website increasing year on year. The central treatment tools, MumMoodBooster and Mum2BMoodBooster, have reached over 10,000 Australian women, largely through self-referral. Despite the development of a portal for direct clinician referral and monitoring, continuing challenges for implementation involve integrating digital treatments into traditional services and recruiting professionals to directly engage mothers.

Introduction of complement (C) inhibition into clinical practice has revolutionized the treatment of patients with complement-mediated atypical hemolytic syndrome (aHUS). Our C3D1115N mouse model, engineered around a gain of function point mutation in C3, is associated with complement mediated aHUS in man, allowing us to study the clinical disease in a preclinical model. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled further determination of the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on kidney disease. C7 deficiency completely abolished both clinical and histological evidence of disease. Removing C5aR1 (CD88) attenuated the risk of developing clinical disease, but mice still developed thrombotic microangiopathy. Therapeutic inhibition strengthened our genetic findings showing both anti-C7 therapy and an oral C5aR1 antagonist, when used before evidence of significant kidney injury, prevented mice from succumbing to disease. However, there was ongoing histological disease within mice treated with the C5aR1 antagonist. Our data suggest that both C5aR1 and C7 play a role in the development of the conditions required for thrombotic microangiopathy of the kidney. While disrupting the C5a-C5aR1 axis is beneficial, our genetic and therapeutic studies showed that thrombotic microangiopathy of the kidney can still develop and ultimately our data confirm that the membrane attack complex is required to develop thrombotic microangiopathy of the kidney. Overall, our study shows that in addition to requiring alternative pathway dysregulation, local generation of membrane attack complex within the kidney is also critical to drive disease pathology in complement-mediated aHUS.

BACKGROUND:C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway. We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade. METHODS:APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin-angiotensin-aldosterone system (RAAS) inhibitors] and immunosuppression). Adult participants (aged 18-60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries. Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <0·85 × lower limit of the central laboratory normal range]) at screening, urine protein-creatinine ratio (UPCR) of 1·0 g/g or higher at day -75 and day -15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 1·73 m2 or higher at screening and day -15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae. All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no). During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily. The primary endpoint was relative reduction in proteinuria (measured by log-transformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months. The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis. This trial was registered with ClinicalTrials.gov (NCT04817618) and the adult cohort has been completed. FINDINGS:Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36). One participant in the placebo group discontinued treatment during the open-label period. The 24-h UPCR percentage change relative to baseline at 6 months was -30·2% (95% CI -42·8 to -14·8) in the iptacopan group and 7·6% (-11·9 to 31·3) in the placebo group. In the iptacopan group, the geometric mean of 24-h UPCR was 3·33 g/g (95% CI 2·79 to 3·97) at baseline and 2·17 g/g (1·62 to 2·91) at 6 months; in the placebo group, this was 2·58 g/g (2·18 to 3·05) at baseline and 2·80 g/g (2·37 to 3·30) at 6 months. The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 35·1% (13·8 to 51·1; p=0·0014). 30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity. There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections. Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group. INTERPRETATION:Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months. Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy. FUNDING:Novartis Pharma.

BACKGROUND:Psychological comorbidities are common in cardiac surgery patients, however much research on their prevalence, correlates and effects remains subject to methodological inconsistencies, with screening and interventions to address the problem not being systematically applied. More information about patient preferences for support and formative contextual knowledge is needed to improve screening program design, uptake, and benefits. AIMS:This study aims to estimate the prevalence and relationship of psychosocial comorbidity with cardiac surgery post-operative health outcomes and explore patients' support interests and preferences in the public hospital acute surgical setting. These findings will generate contextualised knowledge for subsequent development and implementation of a psychosocial screening and support program. METHODS:A sample of 260 patients will be screened using a pragmatic informatics platform of pre-operatively self-reported psychometric instruments including for depression, anxiety, PTSD, perceived stress, and personality traits. Post-operative outcomes and medical covariates will be linked from routinely collected clinical data as well as post-operative psychometric surveys. Prevalence of exposures of interest will be ascertained, and multivariable regression will assess associations with the primary outcome of Days Alive and Out of Hospital to 30 days (DAOH), controlling for patient-level covariates. Secondary outcomes will include measures of post-operative morbidity, Quality of Life and resource utilisation to 1 year of follow-up. Simultaneously, mixed methods will be used to elucidate patient interests and preferences for available support options including online eMental Health resources in blended care, via a post-operative preferences survey and a nested subsample of semi-structured interviews. CONCLUSION:Inconsistent evidence on screening program implementation and patient benefit necessitates a re-evaluation of locally contextualised evidence. This formative research study design will provide a contextual evidence-base including patient perspectives. This can be used to underpin the collaborative co-design of a multidisciplinary, blended model of care leveraging efficient and cost-effective care services suited to patient preferences.

The purpose of this study was to evaluate the efficacy of the RAW Wellbeing program in vocational schools. This 6-week program aims to improve the mental distress and wellbeing of adolescents at-risk of not being in education, employment, or training (NEET). Participants were 57 senior students (23 females; mean age 16.19 years, SD = 0.89) attending two vocational schools in Queensland, Australia. Students completed two baseline surveys (week 0, week 4) before receiving the RAW Wellbeing program and two follow-up surveys (week 13, week 17). An interrupted time-series design evaluated the outcomes of the RAW program. Results revealed significant reductions in mental distress at 4 weeks follow-up and a significant increase in mental wellbeing post-intervention. No improvements in resilience, self-esteem, sense of belongingness, or functioning were found. A randomized controlled trial is now required to confirm the efficacy of the program on mental health, school, and NEET outcomes in a larger sample.

Aims: The final year of high school is a challenging phase, during which substance use is common. We conducted longitudinal and cohort comparisons on the levels of alcohol and cannabis use among final year (Year 12) high school students compared to the previous year. Design: Longitudinal and cohort analyses of self-reported survey data. Setting: Ten independent schools across South-East Queensland, Australia. Participants: Year 12 students in 2020 (n = 1024) were compared (a) longitudinally with themselves in Year 11; and (b) to the 2019 Year 12 cohort (n = 632). Measures: Self-reported alcohol and cannabis use. Analyses adjusted for socio-demographic, parental, and schooling variables. Findings: Longitudinally, Year 12 students of 2020 had higher odds of having six or more drinks per occasion, monthly or more often, and reporting lifetime cannabis use, compared to themselves in 2019. However, they were not more likely to drink alcohol weekly or more often in 2020 versus 2019. Compared to the 2019 cohort, the 2020 cohort had higher odds of drinking weekly or more often, having six or more drinks per occasion monthly, and reporting lifetime cannabis use. Conclusions: The 2020 cohort of Year 12 adolescents were more likely to engage in heavy drinking and cannabis use, compared to themselves the previous year, and compared to the previous cohort. Greater alcohol consumption and likelihood of cannabis use among the 2020 cohort might be explained by increased age and impacts of the COVID-19 pandemic. Future research to monitor if this is a continuing trend is warranted.

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.

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 C5ina & iuml;ve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-na & iuml;ve 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-na & iuml;ve 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 eff i cacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-na & iuml;ve adults and pediatric patients, respectively. The median increase in estimated glomerular fi ltration rate from baseline was maintained over 2 years in C5i-na & iuml;ve adults (35 mL/min/ 1.73 m 2 ) and pediatric patients (82.5 mL/min/ 1.73 m 2 ). Most adverse events and serious adverse events occurred during the fi rst 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.

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.

Background Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, 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 facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with 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 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 173 or more to first eGFR of less than 30 mL/min per 173 m 2 (the therapeutic trial window). Findings Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up from diagnosis was 96 years (IQR 59-167). RaDaR participants had significantly higher 5 -year cumulative incidence of kidney failure than 281 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<00001), but better survival rates (standardised mortality ratio 042 [95% CI 032-052]; p<00001). Median age at failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, therapeutic trial window all varied substantially between rare diseases. Interpretation Patients with rare kidney diseases differ from the general population of individuals with chronic disease: they have higher 5 -year rates of kidney failure but higher survival than other patients with chronic 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 term kidney replacement therapy demand.