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In this article, I review the Stata Press publication Survey Weights: A Step-by-Step Guide to Calculationby Valliant and Dever (2018).

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome‐wide association studies (GWASs) of self‐assessed (by questionnaire) and outcome‐based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self‐assessed resilience (N= 11,492) was found to have significant common‐variant heritability (h2= 0.162, se = 0.050, p= 5.37 × 10−4), and to be significantly negatively genetically correlated with neuroticism (rg= −0.388, p= .0092). GWAS results from the EUR soldiers revealed a genome‐wide significant locus on an intergenic region on Chr 4 upstream from doublecortin‐like kinase 2(DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p= 5.65 × 10−9] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch‐like family member 36(KLHL36) was detected at gene‐wise genome‐wide significance [p= 1.89 × 10−6]. A polygenic risk score derived from the self‐assessed resilience GWAS was not significantly associated with outcome‐based resilience. In very preliminary results, genome‐wide significant association with outcome‐based resilience was found for one locus (top SNP: rs12580015 [p= 2.37 × 10−8]) on Chr 12 downstream from solute carrier family 15 member 5(SLC15A5) in subjects (N =581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress‐related psychopathology and point to new avenues for therapeutic intervention.

ObjectiveTo quantify the burden of common neurological disease in older adults in terms of lifetime risks, including their co-occurrence and preventive potential, within a competing risk framework.MethodsWithin the prospective population-based Rotterdam Study, we studied lifetime risk of dementia, stroke and parkinsonism between 1990 and 2016. Among 12 102 individuals (57.7% women) aged ≥45 years free from these diseases at baseline, we studied co-occurrence, and quantified the combined, and disease-specific remaining lifetime risk of these diseases at various ages for men and women separately. We also projected effects on lifetime risk of hypothetical preventive strategies that delay disease onset by 1, 2 and 3 years, respectively.ResultsDuring follow-up of up to 26 years (156 088 person-years of follow-up), 1489 individuals were diagnosed with dementia, 1285 with stroke and 263 with parkinsonism. Of these individuals, 438 (14.6%) were diagnosed with multiple diseases. Women were almost twice as likely as men to be diagnosed with both stroke and dementia during their lifetime. The lifetime risk for any of these diseases at age 45 was 48.2% (95% CI 47.1% to 51.5%) in women and 36.2% (35.1% to 39.3%) in men. This difference was driven by a higher risk of dementia as the first manifesting disease in women than in men (25.9% vs 13.7%; p<0.001), while this was similar for stroke (19.0%vs18.9% in men) and parkinsonism (3.3% vs 3.6% in men). Preventive strategies that delay disease onset with 1 to 3 years could theoretically reduce lifetime risk for developing any of these diseases by 20%–50%.ConclusionOne in two women and one in three men will develop dementia, stroke or parkinsonism during their life. These findings strengthen the call for prioritising the focus on preventive interventions at population level which could substantially reduce the burden of common neurological diseases in the ageing population.

Current therapies for treating antineutrophil cytoplasm autoantibody (ANCA)–associated vasculitis include cyclophosphamide and corticosteroids. Unfortunately, these agents are associated with severe adverse effects, despite inducing remission in most patients. Histone deacetylase inhibitors are effective in rodent models of inflammation and act synergistically with many pharmacological agents, including alkylating agents like cyclophosphamide. EDO-S101 is an alkylating fusion histone deacetylase inhibitor molecule combining the DNA alkylating effect of Bendamustine with a pan-histone deacetylase inhibitor, Vorinostat. Here we studied the effects of EDO-S101 in two established rodent models of ANCA-associated vasculitis: a passive mouse model of anti-myeloperoxidase IgG-induced glomerulonephritis and an active rat model of myeloperoxidase-ANCA microscopic polyangiitis. Although pretreatment with EDO-S101 reduced circulating leukocytes, it did not prevent the development of passive IgG-induced glomerulonephritis in mice. On the other hand, treatment in rats significantly reduced glomerulonephritis and lung hemorrhage. EDO-S101 also significantly depleted rat B and T cells, and induced DNA damage and apoptosis in proliferating human B cells, suggesting a selective effect on the adaptive immune response. Thus, EDO-S101 may have a role in treatment of ANCA-associated vasculitis, operating primarily through its effects on the adaptive immune response to the autoantigen myeloperoxidase.

We discuss an evidence-based approach to guiding real-time design decisions during the course of survey data collection. We call it responsive and adaptive design (RAD), a scientific framework driven by cost-quality tradeoff analysis and optimization that enables the most efficient production of high-quality data. The notion of RAD is not new; nor is it a silver bullet to resolve all the difficulties of complex survey design and challenges. RAD embraces precedents and variants of responsive design and adaptive design that survey designers and researchers have practiced over decades. In this paper, we present the four pillars of RAD: survey process data and auxiliary information, design features and interventions, explicit quality and cost metrics, and a quality-cost optimization tailored to survey strata. We discuss how these building blocks of RAD are addressed by articles published in the 2017 JOS special issue and this special section. It is a tale of the three perspectives filling in each other. We carry over each of these three perspectives to articulate the remaining challenges and opportunities for the advancement of RAD. We recommend several RAD ideas for future research, including survey-assisted population modeling, rigorous optimization strategies, and total survey cost modeling.

Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to evaluate the distribution of M1 and M2 macrophage phenotypes in biopsies from the airways of patients with active granulomatosis with polyangiitis (GPA) and to analyze their associations with T and B cells in those biopsies, and with nasal carriage of Staphylococcus aureus,disease parameters and therapy. Consecutive GPA patients (n = 35) with active airway disease, who underwent respiratory tract biopsy were included. Immunohistochemical evaluation was performed to assess the distribution of macrophages and T and B cells using the markers CD68, CD3 and CD20, respectively. CD86 was used as the M1 marker and CD163 as the M2 marker while Tbet and GATA-3 were used as Th1 and Th2 markers, respectively. At the time of the biopsy patients were assessed for nasal carriage of Staphylococcus aureusand treatment. Percentages of macrophages and T cells were significantly higher than those of B cells in lesional tissue from the respiratory tract in GPA. M2 macrophages and Th2 cells were more frequent than M1 macrophages (p= 0.0007) and Th1 cells (p< 0.0001), respectively. Percentages of T cells were higher in nose biopsies than in biopsies from other sites (p= 0.021); macrophages and CD163+macrophages were more predominant in biopsy sites other than the nose (p= 0.039 and p= 0.012, respectively). Carriage of Staphylococcus aureuswas associated with higher T cell scores (p= 0.014). The frequency of macrophages, especially M2 macrophages, was higher in GPA patients treated with immunosuppressive agents (p= 0.010); daily prednisolone dose was positively correlated with all macrophage markers. However, in multivariate analysis no independent associations were found between disease parameters and therapy with macrophage markers or T cells. In GPA, M2 is the predominant macrophage phenotype in the respiratory tract. Although some associations were observed between macrophages and T cells with therapy and nasal carriage of Staphylococcus aureus, they were not independently significant in multivariate analysis.

Persistent expansion of circulating CD4+effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4+TEMcell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4+TEMcell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4+TEMcells subsets may reveal distinct contributions of specific CD4+TEMsubsets to the disease pathogenesis in GPA. Peripheral blood of 63 GPA patients in remission and 42 age- and sex-matched healthy controls was stained immediately after blood withdrawal with fluorochrome-conjugated antibodies for cell surface markers (CD3, CD4, CD45RO) and chemokine receptors (CCR4, CCR6, CCR7, CRTh2, CXCR3) followed by flow cytometry analysis. CD4+TEMmemory cells (CD3+CD4+CD45RO+CCR7-) were gated, and the expression patterns of chemokine receptors CXCR3+CCR4-CCR6-CRTh2-, CXCR3-CCR4+CCR6-CRTh2+, CXCR3-CCR4+CCR6+CRTh2-, and CXCR3+CCR4-CCR6+CRTh2-were used to distinguish TEM1, TEM2, TEM17, and TEM17.1 cells, respectively. The percentage of CD4+TEMcells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4+TEMcell population demonstrated a significant increase in the proportion of TEM17 cells with a concomitant significant decrease in the TEM1 cells in GPA patients compared to HC. The percentage of TEM17 cells correlated negatively with TEM1 cells in GPA patients. Moreover, the circulating proportion of TEM17 cells showed a positive correlation with the number of organs involved and an association with the tendency to relapse in GPA patients. Interestingly, the aberrant distribution of TEM1 and TEM17 cells is modulated in CMV- seropositive GPA patients. Our data demonstrates the identification of different CD4+TEMcell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between TEM1 and TEM17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.

Suicide is a global public health problem with particular resonance for the US military. Genetic risk factors for suicidality are of interest as indicators of susceptibility and potential targets for intervention. We utilized population‐based nonclinical cohorts of US military personnel (discovery: N= 473 cases and N= 9778 control subjects; replication: N = 135 cases and N= 6879 control subjects) and a clinical case‐control sample of recent suicide attempters (N = 51 cases and N= 112 control subjects) to conduct GWAS of suicide attempts (SA). Genomewide association was evaluated within each ancestral group (European‐, African‐, Latino‐American) and study using logistic regression models. Meta‐analysis of the European ancestry discovery samples revealed a genomewide significant locus in association with SA near MRAP2(melanocortin 2 receptor accessory protein 2) and CEP162(centrosomal protein 162); 12 genomewide significant SNPs in the region; peak SNP rs12524136‐T, OR = 2.88, p= 5.24E‐10. These findings were not replicated in the European ancestry subsamples of the replication or suicide attempters samples. However, the association of the peak SNP remained significant in a meta‐analysis of all studies and ancestral subgroups (OR = 2.18, 95%CI 1.70, 2.80). Polygenic risk score (PRS) analyses showed some association of SA with bipolar disorder. The association with SNPs encompassing MRAP2, a gene expressed in brain and adrenal cortex and involved in neural control of energy homeostasis, points to this locus as a plausible susceptibility gene for suicidality that should be further studied. Larger sample sizes will be needed to confirm and extend these findings.

Sepsis is a severe systemic inflammatory response to infection. Endothelial activation and dysfunction play a critical role in the pathophysiology of sepsis and represent an important therapeutic target to reduce sepsis mortality. Interferon regulatory factor 1 (IRF-1) was recently identified as a downstream target of TNF-α-mediated signal transduction in endothelial cells. The aim of this study was to explore the importance of IRF-1 as a regulator of lipopolysaccharide (LPS)-induced endothelial proinflammatory activation. We found that renal IRF-1 was upregulated by LPS in vivo as well as in LPS-stimulated endothelial cells in vitro. Furthermore, we identified intracellular retinoic acid inducible gene-I (RIG-I) as a regulator of LPS-mediated IRF-1 induction. IRF-1 depletion specifically resulted in diminished induction of VCAM-1 in response to LPS, but not of E-selectin or ICAM-1, which was independent of NFκB signaling. When both IRF-1 and the RIG-I adapter protein mitochondrial antiviral signaling (MAVS) were absent, VCAM-1 induction was not additionally inhibited, suggesting that MAVS and IRF-1 reside in the same signaling pathway. Surprisingly, E-selectin and IL-6 induction were no longer inhibited by MAVS knockdown when IRF-1 was also absent, revealing a redundant endothelial activation pathway. In summary, we report an IRF-1-mediated proinflammatory signaling pathway that specifically regulates LPS-mediated VCAM-1 expression, independent of NFκB.