Alternative pathway activation in pregnancy, a measured amount "complements" a successful pregnancy, too much results in adverse events.

During pregnancy, the maternal host must adapt in order to enable growth of the fetus. These changes affect all organ systems and are designed both to protect the fetus and to minimize risk to the mother. One of the most prominent adaptations involves the immune system. The semi-allogenic fetoplacental unit has non-self components and must be protected against attack from the host. This requires both attenuation of adaptive immunity and protection from innate immune defense mechanisms. One of the key innate immune players is complement, and it is important that the fetoplacental unit is not identified as non-self and subjected to complement attack. Adaptation of the complement response must, however, be managed in such a way that maternal protection against infection is not compromised. As the complement system also plays a significant facilitating role in many of the stages of a normal pregnancy, it is also important that any necessary adaptation to accommodate the semi-allogenic aspects of the fetoplacental unit does not compromise this. In this review, both the physiological role of the alternative pathway of complement in facilitating a normal pregnancy, and its detrimental participation in pregnancy-specific disorders, are discussed.

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.

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.

Plasminogen activator-coated nanobubbles targeting cellbound ß2-glycoprotein I as a novel thrombus-specific thrombolytic strategy.

ß2-glycoprotein I (ß2-GPI) is a serum protein widely recognized as the main target of antibodies present in patients with antiphospholipid syndrome (APS). ß2-GPI binds to activated endothelial cells, platelets and leukocytes, key players in thrombus formation. We developed a new targeted thrombolytic agent consisting of nanobubbles (NB) coated with recombinant tissue plasminogen activator (rtPA) and a recombinant antibody specific for cell-bound ß2-GPI. The therapeutic efficacy of targeted NB was evaluated in vitro, using platelet-rich blood clots, and in vivo in three different animal models: i) thrombosis developed in a rat model of APS; ii) ferric chloride-induced mesenteric thrombosis in rats, and iii) thrombotic microangiopathy in a mouse model of atypical hemolytic uremic syndrome (C3-gain-of-function mice). Targeted NB bound preferentially to platelets and leukocytes within thrombi and to endothelial cells through ß2-GPI expressed on activated cells. In vitro, rtPA-targeted NB (rtPA-tNB) induced greater lysis of platelet-rich blood clots than untargeted NB. In a rat model of APS, administration of rtPA-tNB caused rapid dissolution of thrombi and, unlike soluble rtPA that induced transient thrombolysis, prevented new thrombus formation. In a rat model of ferric chloride triggered thrombosis, rtPA-tNB, but not untargeted NB and free rtPA, induced rapid and persistent recanalization of occluded vessels. Finally, treatment of C3-gain-of-function mice with rtPA-tNB, that target ß2-GPI deposited in kidney glomeruli, decreased fibrin deposition, and improved urinalysis data with a greater efficiency than untargeted NB. Our findings suggest that targeting cell-bound ß2-GPI may represent an efficient and thrombus-specific thrombolytic strategy in both APS-related and APS-unrelated thrombotic conditions.

Behavioral flexibility is associated with changes in structure and function distributed across a frontal cortical network in macaques.

One of the most influential accounts of central orbitofrontal cortex-that it mediates behavioral flexibility-has been challenged by the finding that discrimination reversal in macaques, the classic test of behavioral flexibility, is unaffected when lesions are made by excitotoxin injection rather than aspiration. This suggests that the critical brain circuit mediating behavioral flexibility in reversal tasks lies beyond the central orbitofrontal cortex. To determine its identity, a group of nine macaques were taught discrimination reversal learning tasks, and its impact on gray matter was measured. Magnetic resonance imaging scans were taken before and after learning and compared with scans from two control groups, each comprising 10 animals. One control group learned discrimination tasks that were similar but lacked any reversal component, and the other control group engaged in no learning. Gray matter changes were prominent in posterior orbitofrontal cortex/anterior insula but were also found in three other frontal cortical regions: lateral orbitofrontal cortex (orbital part of area 12 [12o]), cingulate cortex, and lateral prefrontal cortex. In a second analysis, neural activity in posterior orbitofrontal cortex/anterior insula was measured at rest, and its pattern of coupling with the other frontal cortical regions was assessed. Activity coupling increased significantly in the reversal learning group in comparison with controls. In a final set of experiments, we used similar structural imaging procedures and analyses to demonstrate that aspiration lesion of central orbitofrontal cortex, of the type known to affect discrimination learning, affected structure and activity in the same frontal cortical circuit. The results identify a distributed frontal cortical circuit associated with behavioral flexibility.

The longitudinal interplay between insecure attachment behaviors and psychosocial strengths among children in child welfare services.

Children who have experienced maltreatment are more likely to have disrupted attachments, fewer psychosocial strengths, and poorer long-term psychosocial outcomes. However, few studies have examined the interplay between attachment security and psychosocial strengths among children involved in therapeutic services in the context of the child welfare system. The present longitudinal study examines the insecure attachment behaviors and psychosocial strengths of 555 children referred to the Therapeutic Family Care program (TFCP) in Cobourg, Ontario between 2000 and 2019. The children were assessed by their caregivers on a regular basis using the Assessment Checklist for Children (ACC) and the complementary strengths-focused ACC+ measure. Average age of children at baseline was 9.57 years (SD = 3.51) and 229 (41.26%) were female. We conducted growth curve and random intercepts cross-lagged panel models to test the longitudinal interplay between insecure attachment behaviors and strengths. Results suggest that females' attachment security improved, males' attachment security worsened, and both males and females developed strengths over time. Further, analyses revealed a directional effect, whereby fewer insecure attachment behaviors predicted more psychosocial strengths approximately 6 months later. Implications for attachment-oriented and strengths-based services in the context of child welfare are discussed.

Correlated structure of neuronal firing in macaque visual cortex limits information for binocular depth discrimination.

Variability in cortical neural activity potentially limits sensory discriminations. Theoretical work shows that information required to discriminate two similar stimuli is limited by the correlation structure of cortical variability. We investigated these information-limiting correlations by recording simultaneously from visual cortical areas primary visual cortex (V1) and extrastriate area V4 in macaque monkeys performing a binocular, stereo depth discrimination task. Within both areas, noise correlations on a rapid temporal scale (20-30 ms) were stronger for neuron pairs with similar selectivity for binocular depth, meaning that these correlations potentially limit information for making the discrimination. Between-area correlations (V1 to V4) were different, being weaker for neuron pairs with similar tuning and having a slower temporal scale (100+ ms). Fluctuations in these information-limiting correlations just prior to the detection event were associated with changes in behavioral accuracy. Although these correlations limit the recovery of information about sensory targets, their impact may be curtailed by integrative processing of signals across multiple brain areas.NEW & NOTEWORTHY Correlated noise reduces the stimulus information in visual cortical neurons during experimental performance of binocular depth discriminations. The temporal scale of these correlations is important. Rapid (20-30 ms) correlations reduce information within and between areas V1 and V4, whereas slow (>100 ms) correlations between areas do not. Separate cortical areas appear to act together to maintain signal fidelity. Rapid correlations reduce the neuronal signal difference between stimuli and adversely affect perceptual discrimination.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

The Magnitude, But Not the Sign, of MT Single-Trial Spike-Time Correlations Predicts Motion Detection Performance.

Spike-time correlations capture the short timescale covariance between the activity of neurons on a single trial. These correlations can significantly vary in magnitude and sign from trial to trial, and have been proposed to contribute to information encoding in visual cortex. While monkeys performed a motion-pulse detection task, we examined the behavioral impact of both the magnitude and sign of single-trial spike-time correlations between two nonoverlapping pools of middle temporal (MT) neurons. We applied three single-trial measures of spike-time correlation between our multiunit MT spike trains (Pearson's, absolute value of Pearson's, and mutual information), and examined the degree to which they predicted a subject's performance on a trial-by-trial basis. We found that on each trial, positive and negative spike-time correlations were almost equally likely, and, once the correlational sign was accounted for, all three measures were similarly predictive of behavior. Importantly, just before the behaviorally relevant motion pulse occurred, single-trial spike-time correlations were as predictive of the performance of the animal as single-trial firing rates. While firing rates were positively associated with behavioral outcomes, the presence of either strong positive or negative correlations had a detrimental effect on behavior. These correlations occurred on short timescales, and the strongest positive and negative correlations modulated behavioral performance by ∼9%, compared with trials with no correlations. We suggest a model where spike-time correlations are associated with a common noise source for the two MT pools, which in turn decreases the signal-to-noise ratio of the integrated signals that drive motion detection.SIGNIFICANCE STATEMENT Previous work has shown that spike-time correlations occurring on short timescales can affect the encoding of visual inputs. Although spike-time correlations significantly vary in both magnitude and sign across trials, their impact on trial-by-trial behavior is not fully understood. Using neural recordings from area MT (middle temporal) in monkeys performing a motion-detection task using a brief stimulus, we found that both positive and negative spike-time correlations predicted behavioral responses as well as firing rate on a trial-by-trial basis. We propose that strong positive and negative spike-time correlations decreased behavioral performance by reducing the signal-to-noise ratio of integrated MT neural signals.

An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy.

Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of complement activation, and treatment options for C3G remain limited. Complement factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1-5 linked to repeats 18-20 (FH1-5^18-20), that was effective in experimental C3G. However, the serum t1/2 of FH1-5^18-20 was significantly shorter than that of serum-purified FH.Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1-2) at the carboxy or amino terminus of human FH1-5^18-20 to generate two homodimeric mini-FH constructs (FHR1-2^1-5^18-20 and FH1-5^18-20^R1-2, respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh-/- mice.Results FHR1-2^1-5^18-20 and FH1-5^18-20^R1-2 homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FHR1-2^1-5^18-20 Each construct was >10-fold more effective than FH at inhibiting cell surface complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH1-5^18-20 FH1-5^18-20^R1-2 had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t1/2 compared with that of FH1-5^18-20, and significantly better retention in the kidney than FH or FH1-5^18-20Conclusions FH1-5^18-20^R1-2 may have utility as a treatment option for C3G or other complement-mediated diseases.

Unsettling the Settlers: Principles of a Decolonial Approach to Creating Safe(r) Spaces in Post-secondary Education.

In this paper we discuss the ongoing colonial relationship between Indigenous and non-Indigenous peoples in Canada with a consideration of how to align the principles and core values of community psychology in relation to Indigenous rights, decolonization, and social justice. In working with Community Psychology values to address issues of social justice it is necessary to recognize that empowerment alone is only one half of the solution. While our discipline focuses on oppression and the empowerment of vulnerable and disenfranchised populations we generally fail to consider the relational aspects of power and justice. Specifically, in recognizing power inequities the focus is often placed on empowerment among vulnerable or subjugated communities while neglecting the requisite counterbalance of consciousness-raising and de-powerment of dominant populations. The authors provide three personal accounts from a non-Indigenous faculty member, an Indigenous doctoral student, and a recently graduated non-Indigenous Masters student. We share our experiences of conscientization and decolonization within the post-secondary and graduate education systems. We describe an educational context, a pedagogical praxis, and our efforts to bridge the theories of Settler colonialism and community psychology. From our individual and collective reflections of engagement with decolonization in the education system we present an emergent framework that highlights four principles for decolonization. In implementing these principles we discuss the co-creation of safe(r), decolonized spaces within post-secondary institutions through deconstructing dominant narratives and illuminating Indigenous narratives of self-determination with attention to the de-powerment of non-Indigenous faculty and students.

Eculizumab in children with hemolytic uremic syndrome.

Greenbaum et al. report the first prospective trial of eculizumab in pediatric atypical hemolytic uremic syndrome. As in adult trials, eculizumab appears effective and no serious safety signals were reported. There is the first suggestion of a dichotomy in response to treatment with a trend toward poorer outcome in those without complement abnormalities. This group, however, had worse renal function at presentation, and it remains to be seen whether this represents true non-response or merely late presentation.

Dynamics of the functional link between area MT LFPs and motion detection.

The evolution of a visually guided perceptual decision results from multiple neural processes, and recent work suggests that signals with different neural origins are reflected in separate frequency bands of the cortical local field potential (LFP). Spike activity and LFPs in the middle temporal area (MT) have a functional link with the perception of motion stimuli (referred to as neural-behavioral correlation). To cast light on the different neural origins that underlie this functional link, we compared the temporal dynamics of the neural-behavioral correlations of MT spikes and LFPs. Wide-band activity was simultaneously recorded from two locations of MT from monkeys performing a threshold, two-stimuli, motion pulse detection task. Shortly after the motion pulse occurred, we found that high-gamma (100-200 Hz) LFPs had a fast, positive correlation with detection performance that was similar to that of the spike response. Beta (10-30 Hz) LFPs were negatively correlated with detection performance, but their dynamics were much slower, peaked late, and did not depend on stimulus configuration or reaction time. A late change in the correlation of all LFPs across the two recording electrodes suggests that a common input arrived at both MT locations prior to the behavioral response. Our results support a framework in which early high-gamma LFPs likely reflected fast, bottom-up, sensory processing that was causally linked to perception of the motion pulse. In comparison, late-arriving beta and high-gamma LFPs likely reflected slower, top-down, sources of neural-behavioral correlation that originated after the perception of the motion pulse.

ROC-based estimates of neural-behavioral covariations using matched filters.

Correlations between responses in visual cortex and perceptual performance help draw a functional link between neural activity and visually guided behavior. These correlations are commonly derived with ROC-based neural-behavioral covariances (referred to as choice or detect probability) using boxcar analysis windows. Although boxcar windows capture the covariation between neural activity and behavior during steady-state stimulus presentations, they are not optimized to capture these correlations during short time-varying visual inputs. In this study, we implemented a matched-filter technique, combined with cross-validation, to improve the estimation of ROC-based neural-behavioral covariance under short and dynamic stimulus conditions. We show that this approach maximizes the area under the ROC curve and converges to the true neural-behavioral covariance using a Poisson spiking model. We also demonstrate that the matched filter, combined with cross-validation, reveals the dynamics of the neural-behavioral covariations of individual MT neurons during the detection of a brief motion stimulus.

Family functioning in the context of current and historical stressors: Exploring the buffering role of social support.

BACKGROUND: Adverse Childhood Experiences (ACEs) can be passed onto future generations through complex biopsychosocial mechanisms. However, social support in caregivers who have experienced adversity may lead to adaptation. Most research on the intergenerational consequences of ACEs has focused on mental health in subsequent generations, while overlooking family functioning as an outcome. OBJECTIVE: This pre-registered study addresses this gap by examining a hypothesized association between caregiver ACEs and caregiver-perceived family functioning, and the moderating role of social support. It was expected that high levels of social support would attenuate the association between caregiver ACEs and family functioning, controlling for contemporaneous stressors in the context of the COVID-19 pandemic. PARTICIPANTS AND SETTING: Data come from a multinational non-clinical sample (n = 310). METHODS: Caregivers completed self-report measures to assess caregiver ACEs, social support, COVID stressors, and family dysfunction. RESULTS: Multiple regression analyses revealed that the ACEs-by-social support interaction was not significant. Exploratory analyses revealed a significant three-way interaction between COVID stressors, ACEs, and social support (b = 0.001, SE < 0.001, p = .008). For lower adversity, social support protected against the association between COVID stressors and family dysfunction; however, for higher adversity, social support was only protective when COVID stressors were low. CONCLUSIONS: Social support is protective against concurrent stressors during the pandemic in relation to family functioning, though this buffering depends on historical levels of adversity. Findings are interpreted through a trauma-informed lens and provide support for family-focused interventions and policies to mitigate the impact of stress on caregivers with high ACEs.

Exploring networks of complex developmental trauma symptomatology among children and adolescents involved in child welfare.

Background: Clinical presentations of child and adolescent psychopathology can vary systematically for boys and girls. While network analysis is increasingly being applied to explore psychopathology in adults, there is a dearth of network studies considering differences in symptoms for boys and girls, particularly in developmental trauma-related symptomatology. Methods: This study involves rural children (n = 375, 39.47% girls) and adolescents (n = 291, 51.20% girls) involved with child protection services in Ontario, Canada. Caregivers completed the Assessment Checklist for Children or Adolescents within the first 6 months of care. Psychometric network analyses were conducted using subscales for boys and girls. Differences were examined via network comparison permutation tests, moderated network models, and independent t-tests. Results: Attachment-related interpersonal difficulties were the most central nodes in the child and adolescent networks for both boys and girls. Emotional dysregulation also had high strength centrality for adolescents. While network comparison tests found the overall network structures and global network strength to be invariant between boys and girls for children and adolescents, moderated network models and independent t-tests revealed several differences with regards to the expression of specific symptoms. Among children, girls exhibited more indiscriminate and pseudomature interpersonal behaviors, whereas boys expressed significantly more non-reciprocal interpersonal behaviors and self-injury. Adolescent girls exhibited more behavioral dysregulation and suicide discourse in the moderated network model; t-tests also indicated higher levels of emotional dysregulation, negative self-image, and other items considered clinically important complex trauma symptoms (e.g., distrust of adults, confused belonging). Discussion: This study supports evidence of differences in the expression of complex trauma symptomatology for boys and girls. Additionally, girls exhibit more symptoms, in general. Consistent with the transdiagnostic conceptualization of the consequences of developmental trauma, findings demonstrate the primacy of attachment-specific difficulties and emotion dysregulation.

Children's activities, parental concerns, and child care service utilization in the early stages of the COVID-19 pandemic.

Introduction: In the early stages of the COVID-19 pandemic, most Canadian provinces and territories enacted public health measures to reduce virus spread, leading most child care centers across the country to limit or halt in-person service delivery. While it is broadly known that the range of activities available to children and youth reduced drastically as a result, research has yet to explore if and how children's activities shifted in relation to changes in child care arrangements. Method: Children's activities during the early months of the pandemic were assessed based on parent-report data (n = 19,959). Activity patterns were extracted via latent profile analysis. Thereafter, differences in child-care related outcomes across profiles were compared via logistic regression models. Results: Latent profile analysis yielded three distinct activity patterns: Screenies (91.5%) were children who engaged in high amounts of screen use relative to all other activities; Analog children (3.1%) exhibited mostly off-screen activities (e.g., reading, physical exercise); and children in the Balanced group (5.4%) appeared to pursue a wide variety of activities. Children were more likely to fall into the Screenies or Balanced profiles when caregivers reported changes in child care arrangements. Moreover, parents of children with Balanced activity profiles were more likely to be planning to use child care when services reopened post-pandemic, compared to parents of children in the Analog group. Discussion: The present findings call attention to heterogeneity in children's activities during COVID-19, which should be considered in the context of pandemic-related child care closures. Implications for children, families, and child care services during and beyond COVID-19 are discussed.

A case study of virtually delivered emotion-focused family therapy.

Clinical psychologists and therapists are increasingly taking advantage of internet and mobile-based technologies to deliver mental health services for individuals and groups since the COVID-19 pandemic. However, there is a dearth of research evaluating the appropriateness of virtual platforms for family interventions. Further, no research has examined the effectiveness of weekly emotion-focused family therapy (EFFT). This case study presents a virtually delivered 8-week EFFT intervention, which supported caregivers to manage child symptoms of depression, anxiety, and anger, facilitate emotion processing, and strengthen relationships. Two parents from one family during a marital separation participated and completed brief measures of therapeutic alliance, family functioning, parental self-efficacy, and parental and child psychological distress at 12 time points as well as a posttreatment semistructured interview. A strong therapeutic alliance was formed, and general family functioning, parental self-efficacy, parent psychopathology, and child depression, anger, and anxiety symptoms improved over the course of therapy.

Parenting and pandemic pressures: Examining nuances in parent, child, and family well-being concerns during COVID-19 in a Canadian sample.

Introduction: The COVID-19 pandemic has caused vast disruptions in family life for Canadian parents since early 2020. While numerous environmental stressors have been identified, including job loss and the demands of balancing work-life conflicts and at-home schooling, relatively less is known about the areas of family life parents are most concerned about and how these worries relate to well-being across the family system. Methods: Canadian parents (n = 29,831, 90.29% mothers, 57.40% Ontario residents) of children aged 0-14 were surveyed about their concerns related to child, parent, and family well-being in June 2020. Structural equation modelling was used to model the relationship between concerns about children, parenting, and the whole family, in association with several sociodemographic variables including child disability status, parent sex and education, job loss during COVID-19, and caregiver employment. Results: Parenting, child, and family concerns were positively correlated. Higher child and family concerns were reported by parents who had not attended university, those who had experienced employment loss or reduced hours, and families with all adults working outside the home. Parents of children with a disability reported higher concerns across all three domains: child, parenting, and family psychosocial well-being. Discussion: These results showcase distinct associations between social determinants of health and the types of worries caregivers exhibited across multiple areas of family life during the first wave of the COVID-19 pandemic in Canada. Findings are interpreted in relation to clinical intervention and public policy targets for families.

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.