DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma.

Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multiomic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening, and transcriptomic data across more than 700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of less than 10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in 3 neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma, and we propose this combination for clinical testing.

Time trends in occupational exposure to chemicals in Sweden: proportion exposed, distribution across demographic and labor market strata, and exposure levels.

OBJECTIVE: This study investigated time trends in occupational exposure to various chemicals in Sweden and the distribution across demographic and labor market sectors. METHODS: Exposure to six chemicals was investigated from 1980 to 2013 by application of a job exposure matrix to national population registers. Respirable crystalline silica (RCS), diesel engine exhaust, welding fumes, wood dust, chlorinated hydrocarbon solvents, and lead were selected to represent different groups of chemicals. Trends in exposure prevalence were investigated by linear regression and compared to the occupationally active population. Confidence intervals for the rate of change over time were obtained by bootstrapping. RESULTS: The proportion of workers born outside the Nordic countries increased over time in those exposed to RCS, diesel exhaust and wood dust. There was a shift of exposed jobs to small companies (<50 employees), especially for RCS, welding fumes, wood dust, and chlorinated hydrocarbon solvents. For RCS and welding fumes, there was a marked drop in exposure levels from 1980 to 1990 but small changes thereafter. Exposure to lead diminished, both in terms of prevalence and intensity. CONCLUSIONS: Over time, several exposures tended to shift to small companies, the construction sector, and migrant workers, all factors being indicative of less well-controlled working conditions. Occupational exposure to chlorinated organic solvents and lead diminished, while exposure levels to RCS and welding fumes have changed little since 1990. In view of the serious and well-established negative health effects, increased efforts to reduce exposure to RCS and welding fumes are needed.

Periodontal conditions and incident dementia: A nationwide Swedish cohort study.

BACKGROUND: Periodontal disease has been proposed as a putative etiological factor for dementia. The aim of this investigation was to compare the incidence of dementia in individuals with or without deep probing pocket depths (DPPD), serving as a proxy for periodontitis. METHODS: In this cohort study, conducted in Sweden, we identified 7992 individuals with DPPD and 29,182 matched individuals without DPPD (non-DPPD), using the Swedish Quality Registry for Caries and Periodontal Diseases (SKaPa). The two groups were followed for incident dementia (mean follow-up time was 7.6 years) based on data from the Swedish Dementia Registry (SveDem). The exposure-outcome relationship was explored by applying the Royston-Parmar (RP) flexible parametric survival model. RESULTS: The incidence of dementia in the two groups was similar. In the DPPD group 137 (1.7%) developed dementia and 470 (1.6%) in the non-DPPD group. The incidence rate of dementia was estimated to be 2.3 per 1000 person-years (95% confidence interval [CI] 1.9 to 2.7) in the DPPD group and 2.1 per 1000 person-years (95% CI 1.9 to 2.3) in the non-DPPD group. The RP model disclosed no association between DPPD and dementia incidence after controlling for potential confounders (the exponentiated coefficient was estimated to 1.13 [95% CI = 0.39 to 3.24]). CONCLUSION: In this sample, no association was revealed between deep probing pocket depths and the incidence of dementia.

ICU Admission in Children With Acute Lymphoblastic Leukemia in Sweden: Prevalence, Outcome, and Risk Factors.

OBJECTIVES: Despite progress in the treatment of childhood acute lymphoblastic leukemia, severe complications are common, and the need of supportive care is high. We explored the cumulative prevalence, clinical risk factors, and outcomes of children with acute lymphoblastic leukemia, on first-line leukemia treatment in the ICUs in Sweden. DESIGN: A nationwide prospective register and retrospective chart review study. SETTING: Children with acute lymphoblastic leukemia were identified, and demographic and clinical data were obtained from the Swedish Childhood Cancer Registry. Data on intensive care were collected from the Swedish Intensive Care Registry. Data on patients with registered ICU admission in the Swedish Childhood Cancer Registry were supplemented through questionnaires to the pediatric oncology centers. PATIENTS: All 637 children 0-17.9 years old with acute lymphoblastic leukemia diagnosed between June 2008 and December 2016 in Sweden were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-eight percent of the children (178/637) were admitted to an ICU at least once. The Swedish Intensive Care Registry data were available for 96% of admissions (241/252). An ICU admission was associated with poor overall survival (hazard ratio, 3.25; 95% CI, 1.97-5.36; p ≤ 0.0001). ICU admissions occurred often during early treatment; 48% (85/178) were admitted to the ICU before the end of the first month of acute lymphoblastic leukemia treatment (induction therapy). Children with T-cell acute lymphoblastic leukemia or CNS leukemia had a higher risk of being admitted to the ICU in multivariable analyses, both for early admissions before the end of induction therapy and for all admissions during the study period. CONCLUSIONS: The need for intensive care in children with acute lymphoblastic leukemia, especially for children with T cell acute lymphoblastic leukemia and CNS leukemia, is high with most admissions occurring during early treatment.

Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity.

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.

Genetic Sequence Variants in TLR4, MBL or IL-1 Receptor Antagonist is not Associated to Increased Risk for Febrile Neutropenia in Children with ALL.

Sequence variants in genes involved in the immune system have previously been linked to neutropenia as well as infections in cancer patients. Sequence variants in genes coding for TLR4, MBL, and IL-1Ra were investigated in relation to clinical utility of identifying severe episodes of febrile neutropenia (FN) in a cohort of children undergoing treatment for acute lymphoblastic leukemia. The study included 122 children, where data on FN and microbiological findings were retrospectively collected from medical records. Sequence variants in genes coding for MBL, TLR4, and IL-1Ra were identified by pyrosequencing, TaqMan SNP genotyping assay, and gel electrophoresis. A total of 380 episodes of FN were identified and in 139 episodes, there was a microbiological defined infection. Age and treatment intensity were all associated with the risk of developing FN. No sequence variant was associated to increased numbers of FN episodes. Two sequence variants in the TLR4 gene increased the risk of viral infection, whilst sequence variants in the IL-1Ra gene were associated to a decreased risk of bacterial blood-stream infection (BSI). The investigated sequence variants did not associate with increased risk for FN or to severe infections, as to why the clinical utility as a risk-stratification tool is low. Most episodes of FN were classified as fever with unknown origin, emphasizing the need for improved microbial detection methods.

Profile of macular ganglion cell-inner plexiform layer thickness in healthy 6.5 year- old Swedish children.

BACKGROUND: The purpose was to study the macular ganglion cell- inner plexiform layer (GC-IPL) thickness in healthy 6.5 year- old Swedish children using Optical Coherence Tomography (OCT) and to study topography symmetry within eyes and between eye pairs. METHODS: A total of 181 eyes of 92 healthy children (39 girls, 53 boys) aged 6.5 and serving as a term-born control group in the Extremely Preterm Infants in Sweden Study (EXPRESS), were examined with Cirrus HD-OCT. Main outcome measures were average and minimum values of GC-IPL thickness of the device's predefined macular sectors. Single sectors, combined sectors defined as superior and inferior hemispheres and temporal and nasal sectors were evaluated. Intra-individual GC-IPL thickness between eye pairs was analyzed. Visual acuity, refraction and general cognition were assessed and correlated to GC-IPL outcome. RESULTS: Eighty-five children completed the OCT examination and 155 out of 181 scans (86%) were analyzed. The mean average GC-IPL thickness was 85.9 µm (± 5.3; 5th and 95th percentiles were 76.0 and 94.6 µm). The mean minimum GC-IPL thickness was 83.6 µm (± 4.9; 5th and 95th percentiles were 75.4 and 92.3 µm). The difference in thickness between nasal and temporal sectors and between superior and inferior hemisphere sectors were less than 2 µm. The difference between average GC-IPL thickness and minimum GC-IPL thickness was 2.3 µm (± 1.9; 5th and 95th percentiles were 0.0 and 6.0 µm). The difference between the thickest and thinnest sector within eye was 6.4 µm (± 2.2; 5th and 95th percentiles were 3.0 and 10.0 µm). There was a moderate correlation in the difference between the nasal combined and the temporal combined sectors within eye pairs (p < 0.0001, Spearman's ρ 0.58). The average GC-IPL thickness was weakly positively correlated with SE (spherical equivalent; combined sphere and ½ cylinder) (p = 0.031, Spearman's ρ 0.23). CONCLUSIONS: This study provides normative GC-IPL thickness values for healthy 6.5 year- old Swedish children. The GC-IPL thickness variations within eyes and within eye pairs are generally small. It could therefore be assumed that larger variations are sensitive markers of focal GC-IPL thinning due to damage to the primary visual pathways in children.

Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study.

We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101.

Deficits in the IgG+ memory B-cell recovery after anthracycline treatment is confined to the spleen of rhesus macaques.

OBJECTIVES: Loss of vaccine-induced antibodies (Abs) after chemotherapy against paediatric acute lymphoblastic leukaemia (ALL) is common and often necessitates re-immunisation after cessation of treatment. Even so, some ALL survivors fail to mount or to maintain protective Abs. Germinal centres (GCs) are clusters of proliferating B cells in follicles of secondary lymphoid tissues (SLTs) formed during adaptive immune responses and the origins of long-lived memory B and plasma cells that are the source of Abs. Furthermore, productive GC reactions depend on T follicular helper (TFH) cells. To understand why chemotherapy induces deficits in Ab responses, we examined how SLTs were affected by chemotherapy. METHODS: Rhesus macaques were infused with either three cycles of the anthracycline doxorubicin or saline, followed by immunisation with a de novo and booster antigen. Spleen and lymph nodes were removed, and memory B, bulk T and TFH cells were examined. RESULTS: Despite adequate GC morphology, a diminished memory and IgG+ B-cell population along with diminished total and booster vaccine-specific IgG-producing memory B cells were noted in the spleens of macaques with past doxorubicin exposure compared to the saline-treated controls (P < 0.05). Intact bulk T and TFH cells were found in the SLTs of treated macaques, which displayed higher CD40L upregulation capacity by their splenic CXCR5+ helper T cells (P < 0.01). In contrast to the spleen, the immune cell populations studied were comparable between the lymph nodes of both saline- and doxorubicin-treated macaques. CONCLUSION: Our findings suggest that the splenic memory B-cell subset, compared to its lymph node counterpart, is more severely altered by anthracycline treatment.

Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy.

The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

Dengue Infection Complicated by Hemophagocytic Lymphohistiocytosis: Experiences From 180 Patients With Severe Dengue.

BACKGROUND: Globally, ~500 000 people with severe dengue (SD) require hospitalization yearly; ~12 500 (2.5%) die. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially fatal hyperinflammatory condition for which HLH-directed therapy (as etoposide and dexamethasone) can be life-saving. Prompted by the high mortality in SD and the increasing awareness that patients with SD may develop sHLH, our objectives were to (1) determine the frequency of dengue-HLH in SD, (2) describe clinical features of dengue-HLH, (3) assess mortality rate in SD and dengue-HLH, and (4) identify mortality-associated risk factors in SD. METHODS: A 5-year retrospective single-center study in all adult patients with SD admitted to a tertiary intensive care unit in Malaysia. RESULTS: Thirty-nine of 180 (22%) patients with SD died. Twenty-one of 180 (12%) had HLH defined as an HLH probability ≥70% according to histo score (HScore); 9 (43%) died. Similarly, 12 of 31 (39%) fulfilling ≥4 and 7 of 9 (78%) fulfilling ≥5 HLH-2004 diagnostic criteria died. Peak values of aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, and creatinine correlated to fatality (odds ratios [ORs], 2.9, 3.4, 5.8, and 31.9; all P < .0001), as did peak ferritin (OR, 2.5; P = .0028), nadir platelets (OR, 1.9; P = .00068), hepatomegaly (OR, 2.9; P = .012), and increasing age (OR, 1.2; P = .0043). Multivariable logistic regression revealed peak AST (OR, 2.8; P = .0019), peak creatinine (OR, 7.3; P = .0065), and SOFA (Sequential Organ Failure Assessment) score (OR, 1.4; P = .0051) as independent risk factors of death. CONCLUSIONS: Be observant of dengue-HLH due to its high mortality. A prospective study is suggested on prompt HLH-directed therapy in SD patients with hyperinflammation and evolving multiorgan failure at risk of developing dengue-HLH.

The spectrum of acute central nervous system symptoms during the treatment of childhood acute lymphoblastic leukaemia.

BACKGROUND: Children with central nervous system (CNS) toxicity during therapy for acute lymphoblastic leukaemia (ALL) are at risk for treatment modifications, long-term sequelae and even higher mortality. A better understanding of CNS symptoms and their complications improves the potential to prevent and treat them. METHODS: Patient files from 649 children treated with Nordic Society of Pediatric Hematology and Oncology ALL92 and ALL2000 protocols in Finland were reviewed retrospectively for any acute CNS symptom. Detailed data on symptoms, examinations and treatment of the underlying CNS complications were collected from the medical records. Disease-related and outcome data were retrieved from the Nordic leukaemia registry. RESULTS: Altogether, 13% (86) of patients with ALL had acute CNS symptoms. Most symptoms (64%) occurred during the first 2 months of therapy. Posterior reversible encephalopathy syndrome was the most frequent complication (4.5%). Cerebrovascular events were diagnosed in 10 cases (1.6%), while methotrexate-related stroke-like syndrome (SLS) was observed in only one patient (0.2%). CNS symptoms due to systemic or unclear conditions, especially sepsis, were important for differential diagnosis. CNS leukaemia was associated with CNS symptoms (hazard ratio [HR] = 4.03; P = .003), and epilepsy was a common sequel of CNS complications (19%). CONCLUSIONS: Acute CNS symptoms are common during ALL therapy, occurring mainly during the first 2 months of treatment. Patients with CNS leukaemia at diagnosis are at a higher risk for CNS toxicity. Despite intensive CNS-directed methotrexate treatment, SLS was diagnosed extremely rarely in our series.

Clostridium difficile Infection in Children: Epidemiology and Trend in a Swedish Tertiary Care Hospital.

BACKGROUND: Several studies have shown an increasing trend in pediatric Clostridium difficile infection (CDI). However, the Public Health Agency in Sweden reports a decreasing incidence of CDI in the Swedish population since 2007. The main aim of this study is to analyze the epidemiology of CDI in children. METHODS: Retrospective chart-review of patients 1 to <19 years old, positive for Clostridium difficile toxin B, tested at Karolinska University Hospital Units, over the time period from July 1, 2010 to June 30, 2018. Episodes were classified as recurrences (≥2 weeks, ≤8 weeks from previous episode) or new episodes (>8 weeks from previous episode). New episodes were classified as hospital- (HA-CDI) or community-associated (CA-CDI). Annual infection rates/100,000 children in the catchment area were calculated. RESULTS: Three hundred twenty-eight positive tests in 206 patients were included of which 259 (79.0%) tests were new episodes and 69 (21.0%) recurrences. In 63/206 (30.6%) children, >1 episode of CDI was recorded. The mean infection rate was 8.5/100,000 children. There was an overall increasing trend in CDI-rate July 2010-June 2018, however not statistically significant (P = 0.061) nor for the incidence in HA-CDI (P = 0.720) or CA-CDI (P = 0.179). Underlying medical conditions were present in 226/259 (87.3%) new episodes of which the most common was malignancy. Of the new episodes, 188/259 (72.6%) were HA-CDI and 46/259 (17.8%) were CA-CDI. CONCLUSIONS: There was an increasing trend in CDI in children in Sweden from 2010 to 2018, although not statistically significant. CDI was associated with comorbid conditions and repeated episodes were common.

Hypertriglyceridemia during asparaginase treatment in children with acute lymphoblastic leukemia correlates with antithrombin activity in adolescents.

BACKGROUND: Asparaginase (ASP) is a cornerstone in the treatment of acute lymphoblastic leukemia (ALL). It is also known for its ability to cause side effects, such as allergy and pancreatitis, as well as lipid and coagulation disturbances. The most important laboratory abnormalities are hypertriglyceridemia (HTG) and low antithrombin (AT). HTG is usually considered to be transient and benign in children with ALL, whereas low AT activity predisposes to thrombosis. Studies on the incidence and significance of HTG in children with ALL are scarce, and their findings have not always been congruent. We investigated the incidence and significance of ASP-related HTG, defined as triglyceride values more than five times the upper normal limit, in children with ALL. PROCEDURE: We analyzed the laboratory and clinical data of children diagnosed with ALL at the Karolinska Hospital, Stockholm, Sweden, from July 2008 to December 2014. Triglyceride and AT values were measured before each injection of pegylated ASP. RESULTS: The study group comprised of 92 patients, aged 1-17.9 years at diagnosis (median 4.8 years), almost half (42/92, 46%) of whom had HTG. A significant negative correlation between triglyceride and AT values was observed in those aged over 10 years (P = 0.0002). No significant correlation was found between HTG and thrombosis, osteonecrosis, or pancreatitis. CONCLUSIONS: Although common, ASP-associated HTG was not associated with other ASP-related toxicities. HTG correlated with decreased AT activity in older children, which may explain previous association between HTG and thrombosis. Larger studies are of interest with regard to establishing guidelines for HGT management.

Sick leave among parents of children with cancer - a national cohort study.

BACKGROUND: Due to psychological distress and an increased care burden, parents of children diagnosed with cancer may face a higher risk of sickness absence from work. The objective of this study was to examine the association of childhood cancer with parents' sick leave. MATERIAL AND METHODS: The sample comprised 3626 parents of 1899 children diagnosed with cancer in Sweden during 2004-2009, and a matched control group of parents (n = 34 874). Sick leave was measured as number of days with sickness benefit, retrieved from national registries. Logistic and negative binomial regression models were used to compare outcomes with parents from the control cohort. RESULTS: The risk of sick leave was statistically significantly higher up to six years following a child's cancer diagnosis. The increase in number of days with sickness benefit was most pronounced the year after diagnosis. Although mothers' sick leave prevalence was higher, the increase in risk relative to control parents was similar for mothers and fathers. Bereavement was associated with a heightened risk of sick leave, especially on the year of the child's death. CONCLUSIONS: Findings confirm that mothers and fathers of children diagnosed with cancer are at higher risk of sickness absence from work, with particularly pronounced risk among bereaved parents. Acquisition of further knowledge is warranted regarding possibilities and constraints of parents trying to combine their work life with caring for both their child and themselves.

Epstein-Barr Virus, but Not Cytomegalovirus, Latency Accelerates the Decay of Childhood Measles and Rubella Vaccine Responses-A 10-Year Follow-up of a Swedish Birth Cohort.

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are ubiquitous and persistent herpesviruses commonly acquired during childhood. Both viruses have a significant impact on the immune system, especially through mediating the establishment of cellular immunity, which keeps these viruses under control for life. Far less is known about how these viruses influence B-cell responses. OBJECTIVES: To evaluate the impact of latent EBV and CMV infection on rubella- and measles-specific antibody responses as well as on the B-cell compartment in a prospective birth cohort followed during the first 10 years of life. METHODS: IgG titers against rubella and measles vaccines were measured in plasma obtained from the same donors at 2, 5, and 10 years of age. Peripheral B-cell subsets were evaluated ex vivo at 2 and 5 years of age. Factors related to optimal B-cell responses including IL-21 and CXCL13 levels in plasma were measured at all-time points. RESULTS: EBV carriage in the absence of CMV associated with an accelerated decline of rubella and measles-specific IgG levels (p = 0.003 and p = 0.019, respectively, linear mixed model analysis), while CMV carriage in the absence of EBV associated with delayed IgG decay over time for rubella (p = 0.034). At 5 years of age, EBV but not CMV latency associated with a lower percentage of plasmablasts, but higher IL-21 levels in the circulation. CONCLUSION: Our findings suggest that EBV carriage in the absence of CMV influences the B-cell compartment and the dynamics of antibody responses over time during steady state in the otherwise healthy host.

Depression among Parents Two to Six Years Following the Loss of a Child by Suicide: A Novel Prediction Model.

BACKGROUND: Parents who lose a child by suicide have elevated risks of depression. No clinical prediction tools exist to identify which suicide-bereaved parents will be particularly vulnerable; we aimed to create a prediction model for long-term depression for this purpose. METHOD: During 2009 and 2010 we collected data using a nationwide study-specific questionnaire among parents in Sweden who had lost a child aged 15-30 by suicide in years 2004-2007. Current depression was assessed with the Patient Health Questionnaire (PHQ-9) and a single question on antidepressant use. We considered 26 potential predictors assumed clinically assessable at the time of loss, including socio-economics, relationship status, history of psychological stress and morbidity, and suicide-related circumstances. We developed a novel prediction model using logistic regression with all subsets selection and stratified cross-validation. The model was assessed for classification performance and calibration, overall and stratified by time since loss. RESULTS: In total 666/915 (73%) participated. The model showed acceptable classification performance (adjusted area under the curve [AUC] = 0.720, 95% confidence interval [CI] 0.673-0.766), but performed classification best for those at shortest time since loss. Agreement between model-predicted and observed risks was fair, but with a tendency for underestimation and overestimation for individuals with shortest and longest time since loss, respectively. The identified predictors include female sex (odds ratio [OR] = 1.84); sick-leave (OR = 2.81) or unemployment (OR = 1.64); psychological premorbidity debuting during the last 10 years, before loss (OR = 3.64), or more than 10 years ago (OR = 4.96); suicide in biological relatives (OR = 1.54); with non-legal guardianship during the child's upbringing (OR = 0.48); and non-biological parenthood (OR = 0.22) found as protective. CONCLUSIONS: Our prediction model shows promising internal validity, but should be externally validated before application. Psychological premorbidity seems to be a prominent predictor of long-term depression among suicide-bereaved parents, and thus important for healthcare providers to assess.