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.

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.

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.

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 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.

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.

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.

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.

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.

Influence of Device Geometry and Imperfections on the Interpretation of Transverse Magnetic Focusing Experiments.

Spatially separating electrons of different spins and efficiently generating spin currents are crucial steps towards building practical spintronics devices. Transverse magnetic focusing is a potential technique to accomplish both those tasks. In a material where there is significant Rashba spin-orbit interaction, electrons of different spins will traverse different paths in the presence of an external magnetic field. Experiments have demonstrated the viability of this technique by measuring conductance spectra that indicate the separation of spin-up and spin-down electrons. However the effect that the geometry of the leads has on these measurements is not well understood. By simulating an InGaAs-based transverse magnetic focusing device, we show that the resolution of features in the conductance spectra is affected by the shape, separation and width of the leads. Furthermore, the number of subbands occupied by the electrons in the leads affects the ratio between the amplitudes of the spin-split peaks in the spectra. We simulated devices with random onsite potentials and observed that transverse magnetic focusing devices are sensitive to disorder. Ultimately we show that careful choice and characterisation of device geometry are crucial for correctly interpreting the results of transverse magnetic focusing experiments.

A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration.

Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI's cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain inadequate. Factor H (FH) is a potent regulator of the AP. An in-depth analysis of FH-related protein dimerised minimal (mini)-FH constructs has recently been published. This analysis showed that addition of a dimerisation module to mini-FH not only increased serum half-life but also improved complement regulatory function, thus providing a potential treatment option for C3G. Herein, we describe the production of a murine version of homodimeric mini-FH [mHDM-FH (mFH1-5^18-20^R1-2)], developed to reduce the risk of anti-drug antibody formation during long-term experiments in murine models of C3G and other complement-driven pathologies. Our analysis of mHDM-FH indicates that it binds with higher affinity and avidity to WT mC3b when compared to mouse (m)FH (mHDM-FH KD=505 nM; mFH KD=1370 nM) analogous to what we observed with the respective human proteins. The improved binding avidity resulted in enhanced complement regulatory function in haemolytic assays. Extended interval dosing studies in CFH-/- mice (5mg/kg every 72hrs) were partially effective and bio-distribution analysis in CFH-/- mice, through in vivo imaging technologies, demonstrates that mHDM-FH is preferentially deposited and remains fixed in the kidneys (and liver) for up to 4 days. Extended dosing using an AAV- human HDM-FH (hHDM-FH) construct achieved complete normalisation of C3 levels in CFH-/- mice for 3 months and was associated with a significant reduction in glomerular C3 staining. Our data demonstrate the ability of gene therapy delivery of mini-FH constructs to enhance complement regulation in vivo and support the application of this approach as a novel treatment strategy in diseases such as C3G.

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.

The social and economic cost of sleep disorders.

STUDY OBJECTIVES: To estimate economic cost of common sleep disorders in Australia for 2019-2020. METHODS: Costs were estimated for obstructive sleep apnea (OSA), insomnia, and restless legs syndrome (RLS) using prevalence, financial, and nonfinancial data from national databases. These included: (1) financial costs associated with health care, informal care, productivity losses, non-medical accident costs, deadweight loss from taxation/welfare inefficiencies; and (2) nonfinancial costs associated with loss of well-being. They were expressed in U.S. dollars ($). RESULTS: Estimated overall cost of sleep disorders in Australia in 2019-2020 (population: 25.5 million) was $35.4 billion (OSA $13.1 billion; insomnia $13.3 billion, RLS $9.0 billion). Of this, the financial cost component was $10.0 billion, comprised of: health system costs $0.7 billion; productivity losses $7.7 billion; informal care $0.2 billion; other, mainly non-medical accident costs, $0.4 billion; and deadweight losses $1.0 billion. For moderate to severe OSA syndrome, insomnia unrelated to other conditions and RLS, financial costs represented $16,717, $21,982, and $16,624 per adult with the condition for the year, respectively. The nonfinancial cost was $25.4 billion. CONCLUSIONS: The economic costs associated with sleep disorders are substantial. The financial component of $10.0 billion is equivalent to 0.73% of Australian gross domestic product. The nonfinancial cost of $25.4 billion represents 3.2% of total Australian burden of disease for the year. Health system costs of these disorders are low relative to those associated with their consequences, suggesting greater expenditure on detection, treatment and prevention is warranted.

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.

Family Medicine With Refugee Newcomers During the COVID-19 Pandemic.

Certain members of society are disproportionately affected by the COVID-19 crisis and the added strain being placed on already overextended health care systems. In this article, we focus on refugee newcomers. We outline vulnerabilities refugee newcomers face in the context of COVID-19, including barriers to accessing health care services, disproportionate rates of mental health concerns, financial constraints, racism, and higher likelihoods of living in relatively higher density and multigenerational dwellings. In addition, we describe the response to COVID-19 by a community-based refugee primary health center in Ontario, Canada. This includes how the clinic has initially responded to the crisis as well as recommendations for providing services to refugee newcomers as the COVID-19 crisis evolves. Recommendations include the following actions: (1) consider social determinants of health in the new context of COVID-19; (2) provide services through a trauma-informed lens; (3) increase focus on continuity of health and mental health care; (4) mobilize International Medical Graduates for triaging patients based on COVID-19 symptoms; and (5) diversify communication efforts to educate refugees about COVID-19.

"Is it us or is it me?": Family experiences of connectedness following a reflecting team intervention.

The present study examined family-wide versus individual perceptions of, and changes in, family connectedness in response to a one-time reflecting team (RT) intervention. Seventy-six families (N = 208 individuals), recruited during family therapy, completed family connectedness measures before and after the RT intervention. A subset of adults (n = 26) completed 1-week follow-up measures. Three-level (family, individual, time) multilevel models were used to partition sources of variance in connectedness while permitting different fixed and random effects for adults and minors. Results indicate that family connectedness is a characteristic of whole-families (34% of the variance), individuals (43%), and change over time (23%), including measurement error. Additionally, participants reported higher family connectedness after the RT. This study demonstrates the importance of considering family connectedness as a multilevel relationship construct that potentially changes in response to RT.

Isolated Adrenocorticotropic Hormone Deficiency Secondary to Chronic Opiate Use.

Although opiate use can result in various endocrine disorders, isolated adrenocorticotropic hormone (ACTH) deficiency resulting in secondary adrenal insufficiency remains uncommon. We present a case of a 54-year-old woman with a history of chronic opiate use who presented with a four-month history of worsening fatigue and syncopal episodes. Laboratory workup revealed a low ACTH with low baseline cortisol and normal levels of rest of the anterior pituitary hormones. The imaging study did not reveal any pituitary abnormality. The patient was diagnosed with opiate-induced isolated ACTH deficiency. Her symptoms improved after treatment with hydrocortisone. This case would further improve clinician's awareness towards opiate-induced endocrinopathies, including isolated ACTH deficiency, which can present with nonspecific signs and symptoms, creating a diagnostic challenge.

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.