Performance of eight commercial immunoassays for the detection of cytomegalovirus-specific IgM antibodies in pregnancy - no test fits all needs.

Detection of cytomegalovirus (CMV)-specific immunoglobulin M (IgM) antibodies as first-line serologic diagnosis plays an important role in identifying CMV primary infection during pregnancy. The performance characteristics of eight commercially available CMV IgM assays were compared. Sensitivity and IgM antibody kinetics were assessed using 100 acute phase and follow-up sera from 39 pregnant women with a well-defined onset of CMV primary infection. Specificity was analyzed using 50 well-characterized serum samples from pregnant women not infected or latently infected with CMV and from patients with other acute infections. Until 12 weeks after the onset of primary infection, four assays showed sensitivities of 100%, whereas the others had individual gaps to detect all primary infections in this time period. All assays showed a time-dependent decrease of IgM levels. More than 12 weeks after the onset of infection, the IgM-positive rates varied considerably between tests. The specificity was between 92% and 98% in all but one assay. The observed differences in the performance characteristics must be taken into account in CMV screening and diagnosis of primary infection during pregnancy.

Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by an obliterative vasculopathy of the distal pulmonary circulation. Despite significant progress in our understanding of the pathophysiology, currently approved medical therapies for PAH act primarily as pulmonary vasodilators and fail to address the underlying processes that lead to the development and progression of the disease. Endothelial dysregulation in response to stress, injury or physiologic stimuli followed by perivascular infiltration of immune cells plays a prominent role in the pulmonary vascular remodeling of PAH. Over the last few decades, our understanding of endothelial cell dysregulation has evolved and brought to light a number of transcription factors that play important roles in vascular homeostasis and angiogenesis. In this review, we examine two such factors, SOX17 and one of its downstream targets, RUNX1 and the emerging data that implicate their roles in the pathogenesis of PAH. We review their discovery and discuss their function in angiogenesis and lung vascular development including their roles in endothelial to hematopoietic transition (EHT) and their ability to drive progenitor stem cells toward an endothelial or myeloid fate. We also summarize the data from studies that link mutations in Sox17 with an increased risk of developing PAH and studies that implicate Sox17 and Runx1 in the pathogenesis of PAH. Finally, we review the results of recent studies from our lab demonstrating the efficacy of preventing and reversing pulmonary hypertension in animal models of PAH by deleting RUNX1 expression in endothelial or myeloid cells or by the use of RUNX1 inhibitors. By investigating PAH through the lens of SOX17 and RUNX1 we hope to shed light on the role of these transcription factors in vascular homeostasis and endothelial dysregulation, their contribution to pulmonary vascular remodeling in PAH, and their potential as novel therapeutic targets for treating this devastating disease.

Migraine headache: When to consider these newer agents.

These agents are as effective as traditional acute and preventive treatments, cause fewer adverse effects, and can simplify regimens.

Low Graft Invariant Natural Killer T-Cell Dose Is a Risk Factor for Cytomegalovirus Reactivation After Allogeneic Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) reactivation is common after allogeneic hematopoietic cell transplantation (HCT) and may result in fatal CMV disease. Invariant natural killer T (iNKT) cells are potent modulators of the immune system preventing graft-versus-host disease while promoting graft-versus-leukemia effects. It is thought that iNKT cells selectively influence mediators of both innate and adaptive immunity. Here, we investigated the impact of graft iNKT cells on CMV reactivation in patients undergoing allogeneic HCT. We found a significantly decreased cumulative incidence of CMV reactivation in patients with higher numbers of iNKT cells in the allograft. Therefore iNKT-cell-enriched grafts or adoptive transfer of iNKT cells are compelling cytotherapeutic strategies to improve outcomes after allogeneic HCT.

Prolonged norovirus infections correlate to quasispecies evolution resulting in structural changes of surface-exposed epitopes.

In this study, we analyzed norovirus (NoV) evolution in sequential samples of six chronically infected patients. The capsid gene was amplified from stool samples, and deep sequencing was performed. The role of amino acid flexibility in structural changes and ligand binding was studied with molecular dynamics (MD) simulations. Concentrations of capsid-specific antibodies increased in sequential sera. Capsid sequences accumulated mutations during chronic infection, particularly in the surface-exposed antigenic epitopes A, D, and E. The number of quasispecies increased in infections lasting for >1 month. Interestingly, high genetic complexity and distances were followed by ongoing NoV replication, whereas lower genetic complexity and distances preceded cure. MD simulation revealed that surface-exposed amino acid substitutions of the P2 domain caused fluctuation of blockade epitopes. In conclusion, the capsid protein accumulates numerous mutations during chronic infection; however, only those on the protein surface change the protein structure substantially and may lead to immune escape.

Testing configurations of attractive toxic sugar bait (ATSB) stations in Mali, West Africa, for improving the control of malaria parasite transmission by vector mosquitoes and minimizing their effect on non-target insects.

BACKGROUND: Application methods of |Attractive Toxic Sugar Baits (ATSB) need to be improved for wide-scale use, and effects on non-target organisms (NTOs) must be assessed. The goals of this study were to determine, at the village level, the effect of different configurations of bait stations to (1) achieve < 25% Anopheles mosquito vector daily feeding rate for both males and females and (2) minimize the effect on non-target organisms. METHODS: Dye was added to Attractive Sugar Bait Stations (without toxin) to mark mosquitoes feeding on the baits, and CDC UV light traps were used to monitor for marked mosquitoes. An array of different traps were used to catch dye marked NTOs, indicating feeding on the ASB. Stations were hung on homes (1, 2, or 3 per home to optimize density) at different heights (1.0 m or 1.8 m above the ground). Eight villages were chosen as for the experiments. RESULTS: The use of one ASB station per house did not mark enough mosquitoes. Use of two and three stations per house gave feeding rates above the 25% goal. There was no statistical difference in the percentage of marked mosquitoes between two and three stations, however, the catches using two and three bait stations were both significantly higher than using one. There was no difference in An. gambiae s.l. feeding when stations were hung at 1.0 and 1.8 m. At 1.8 m stations sustained less accidental damage. ASB stations 1.8 m above ground were fed on by three of seven monitored insect orders. The monitored orders were: Hymenoptera, Lepidoptera, Coleoptera, Diptera, Hemiptera, Neuroptera and Orthoptera. Using one or two stations significantly reduced percentage of bait-fed NTOs compared to three stations which had the highest feeding rates. Percentages were as follows: 6.84 ± 2.03% Brachycera followed by wasps (Hymenoptera: Vespidae) 5.32 ± 2.27%, and Rhopalocera 2.22 ± 1.79%. Hanging the optimal number of stations per house for catching mosquitoes (two) at 1.8 m above ground, limited the groups of non-targets to Brachycera, Chironomidae, Noctuoidea, Rhopalocera, parasitic wasps and wasps (Hymenoptera). Feeding at 1.8 m only occurred when stations were damaged. CONCLUSIONS: The goal of marking quarter of the total Anopheles population per day was obtained using 2 bait stations at 1.8 m height above the ground. This configuration also had minimal effects on non-target insects.

Quetiapine augmentation of prolonged exposure therapy in veterans with PTSD and a history of mild traumatic brain injury: design and methodology of a pilot study.

BACKGROUND: Selective serotonergic reuptake inhibitors (SSRIs) are first-line pharmacologic treatments for patients with posttraumatic stress disorder (PTSD), but must be given over extended period of time before the onset of action. The use of SSRIs in PTSD patients with mild traumatic brain injury (mTBI) is problematic since SSRIs could exacerbate post-concussion syndrome (PCS) symptoms. VA/DOD guidelines identify trauma-focused psychotherapy as the best evidence-based treatment for PTSD, but overall effectiveness is limited by reduced levels of patient engagement and retention. A previous study from this research group suggested that quetiapine monotherapy, but not risperidone or valproate, could increase engagement in trauma-focused psychotherapy. METHODS: We report the study protocol of a pilot study funded under the South-Central Mental Illness Research, Education, and Clinical Center pilot study program from the U.S. Department of Veterans Affairs. This randomized, open-label study was designed to evaluate the feasibility of completing a randomized trial of quetiapine vs. treatment as usual to promote patient engagement in PTSD patients with a history of mTBI. DISCUSSION: We expect that the success of this ongoing study should provide us with the preliminary data necessary to design a full-scale randomized trial. Positive efficacy results in a full- scale trial should inform new VA guidelines for clinical practice by showing that quetiapine-related improvements in patient engagement and retention may be the most effective approach to assure that VA resources achieve the best possible outcome for veterans. TRIAL REGISTRATION: NCT04280965 .

Large-scale field trial of attractive toxic sugar baits (ATSB) for the control of malaria vector mosquitoes in Mali, West Africa.

BACKGROUND: The aim of this field trial was to evaluate the efficacy of attractive toxic sugar baits (ATSB) in Mali, where sustained malaria transmission occurs despite the use of long-lasting insecticidal nets (LLINs). ATSB bait stations were deployed in seven of 14 similar study villages, where LLINs were already in widespread use. The combined use of ATSB and LLINs was tested to see if it would substantially reduce parasite transmission by Anopheles gambiae sensu lato beyond use of LLINs alone. METHODS: A 2-day field experiment was conducted to determine the number of mosquitoes feeding on natural sugar versus those feeding on bait stations containing attractive sugar bait without toxin (ASB)-but with food dye. This was done each month in seven random villages from April to December 2016. In the following year, in seven treatment villages from May to December 2017, two ATSB bait stations containing the insecticide dinotefuran were placed on the outer walls of each building. Vector population density was evaluated monthly by CDC UV light traps, malaise traps, pyrethrum spray (PSCs) and human landing catches (HLCs). Female samples of the catch were tested for age by examination of the ovarioles in dissected ovaries and identification of Plasmodium falciparum sporozoite infection by ELISA. Entomological inoculation rates (EIR) were calculated, and reductions between treated and untreated villages were determined. RESULTS: In the 2-day experiment with ASB each month, there was a lower number of male and female mosquitoes feeding on the natural sugar sources than on the ASB. ATSB deployment reduced CDC-UV trap female catches in September, when catches were highest, were by 57.4% compared to catches in control sites. Similarly, malaise trap catches showed a 44.3% reduction of females in August and PSC catches of females were reduced by 48.7% in September. Reductions of females in HLCs were lower by 19.8% indoors and 26.3% outdoors in September. The high reduction seen in the rainy season was similar for males and reductions in population density for both males and females were > 70% during the dry season. Reductions of females with ≥ 3 gonotrophic cycles were recorded every month amounting to 97.1% in October and 100.0% in December. Reductions in monthly EIRs ranged from 77.76 to 100.00% indoors and 84.95% to 100.00% outdoors. The number of sporozoite infected females from traps was reduced by 97.83% at treated villages compared to controls. CONCLUSIONS: Attractive toxic sugar baits used against Anopheles mosquitoes in Mali drastically reduced the density of mosquitoes, the number of older females, the number of sporozoite infected females and the EIR demonstrating how ATSB significantly reduces malaria parasite transmission.

Feasibility of successfully breeding rhesus macaques (Macaca mulatta) to obtain healthy infants year-round.

Rhesus monkeys are typically seasonal breeders but can be induced to extend the timing of their mating and births under captive conditions. The following analyses evaluated the potential impact of extending their pregnancies and deliveries year-round. Birth records from a large breeding colony housed in an indoor facility with a constant 14-hr light/10-hr dark cycle were analyzed across 25 years to examine seasonal trends in monkeys that mated in one of two ways: spontaneous in social groups or with a scheduled, timed-mating protocol. The dates of delivery and birth weights for 2,084 infants were used in these analyses. Younger nulliparous females mating in social groups evinced a clear seasonal peak when birthing their first infant. However, older females, both primiparous and multiparous, could be bred continuously, which enable the birth of infants in every month of the year. Based on the live birth rate, infant birth weights, high survival rates, and the normal sex ratio of infants birthed year-round, there were no adverse effects of breeding rhesus monkeys in this way. The continuous availability of infant births can be very advantageous for many types of research programs.

Low-dose cidofovir and conversion to mTOR-based immunosuppression in polyomavirus-associated nephropathy.

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) remains a relevant complication following kidney transplantation with allograft loss rates of up to 50%. Reduction in overall immunosuppression is a cornerstone of therapy, whereas no specific antiviral regimen has shown conclusive benefit to date. The present case series demonstrates the efficacy of a dual therapeutic approach with low-dose cidofovir and conversion to mTOR-based immunosuppression in PVAN. METHODS: Patients with biopsy-proven PVAN having received low-dose cidofovir (0.25 mg/kg) according to the Tübingen Cidofovir Protocol and been converted to mTOR-based immunosuppression were analyzed retrospectively. RESULTS: Twenty-three patients with a median follow-up of 2.24 [IQR 1.55-5.01] years were included in the analysis. Median time to PVAN diagnosis was 268 [IQR 153-869] days after transplantation. Polyomavirus clearance from plasma was achieved in 78% of patients after a median of 118 [IQR 76-293] days. Of the 23 patients, nine patients (39%) lost their allograft function during follow-up, but only three of these (13%) due to PVAN. Fourteen patients (61%) stabilized or improved allograft function. The cidofovir protocol allowed for specific antiviral therapy without adverse nephrotoxicity, even in patients with low allograft function. CONCLUSIONS: Low-dose cidofovir and conversion to mTOR-based immunosuppression allow for effective virus clearance and preservation of allograft function in a high proportion of patients with PVAN and progressive allograft dysfunction and may prolong allograft survival in these patients.

First-Line Doublet Chemotherapy for Metastatic Triple-Negative Breast Cancer: Circulating Tumor Cell Analysis of the tnAcity Trial.

PURPOSE: Circulating tumor cells (CTCs) are prognostic biomarkers in metastatic breast cancer, but their role in predicting treatment outcomes in metastatic triple-negative breast cancer (mTNBC) is less clear. The tnAcity trial demonstrated a significant progression-free survival (PFS) benefit with nab-paclitaxel (nab-P)/carboplatin (C) over nab-P/gemcitabine (G) or G/C in patients with mTNBC. We assessed the correlation between CTC dynamics and clinical benefit in all patients and by treatment arm. METHODS: CTC enumeration, performed using CELLSEARCH technology (Menarini Silicon Biosystems, Huntingdon Valley, PA, USA), was a prespecified exploratory endpoint in the tnAcity trial. Patients with TNBC were categorized based on pre- and post-treatment CTC levels: Group 1 (+ + +; elevated CTCs at baseline and postbaseline), Group 2 (+ ± ±; CTCs elevated at baseline and cleared postbaseline [cycle 3 and/or cycle 5]), or Group 3 (-; no CTCs detected at baseline). The baseline cutoff was ≥1 CTC/7.5 mL for the main analysis; cutoffs of ≥2 and ≥5 CTCs were used for supporting analyses. RESULTS: The main analysis included 126 patients (Group 1, n = 24; Group 2, n = 54; and Group 3, n = 48). The median PFS was longer in Group 2 vs Group 1 (8.5 vs 4.7 months; HR, 0.30 [95% CI, 0.17-0.54]). These results were supported by the ≥2- and ≥5-CTC cutoff analyses. The median overall survival rates were 17.8, 16.0, and 9.8 months in Groups 2, 3, and 1, respectively. The overall response rates were 79.6%, 43.8%, and 29.2%, respectively. A numerically higher percentage of patients had CTC clearance during nab-P/C treatment vs nab-P/G or G/C. CONCLUSION: Efficacy outcomes trended positively with chemotherapy-induced elimination of CTCs, suggesting that CTC clearance may predict the chemosensitivity of mTNBC tumors. TRIAL REGISTRATION: EudraCT Number: 2013-000113-20; ClinicalTrials.gov number: NCT01881230.

Enhancing Completion of Cognitive Processing Therapy for Posttraumatic Stress Disorder with Quetiapine in Veterans with Mild Traumatic Brain Injury: a Case Series.

To evaluate the outcomes of the antiarousal medications valproate, risperidone, and quetiapine on completion of treatment of cognitive processing therapy (CPT) for PTSD. A case series of fifty treatment-seeking adult (≥18 years) veterans with mild traumatic brain injury and combat-related PTSD who had unsuccessful trials of 2 or more first-line agents and previously declined treatment with trauma-focused therapy, seen at the psychiatric outpatient services of the local Polytrauma Rehabilitation Center from January 1, 2014, through December 31, 2017. Patients were prescribed valproate (n = 8), risperidone (n = 17), or quetiapine (n = 25) and were referred for individual weekly treatment with CPT. Outcome measurements of interest were measures of engagement and completion rate of CPT, PTSD Checklist total score (range, 0-80; higher scores indicate greater PTSD severity) and arousal subscale score (range, 0-24; higher scores indicate greater arousal severity), and clinical observations of sleep variables. Of the 50 patients included in the study, 48 (96%) were men; mean (SD) age was 36 (8) years. Eighteen (86%) patients initially receiving quetiapine and none taking valproate or risperidone became adequately engaged in and completed CPT. Among patients who completed CPT, the mean decrease in the PTSD Checklist score was 25 [95% CI, 30 to 20] and 9 (50%) patients no longer met criteria for PTSD. These preliminary findings support quetiapine as an adjunctive medication to facilitate CPT. A pragmatic trial is needed to evaluate the efficacy, safety, and feasibility of quetiapine to improve engagement in and completion rate of CPT.

Potential role of CT-textural features for differentiation between viral interstitial pneumonias, pneumocystis jirovecii pneumonia and diffuse alveolar hemorrhage in early stages of disease: a proof of principle.

BACKGROUND: Pulmonary involvement is common in several infectious and non-infectious diagnostic settings. Imaging findings consistently overlap and are therefore difficult to differentiate by chest-CT. The aim of this study was to evaluate the role of CT-textural features(CTTA) for discrimination between atypical viral (respiratory-syncitial-virus(RSV) and herpes-simplex-1-virus (HSV1)), fungal (pneumocystis-jirovecii-pneumonia(PJP)) interstitial pneumonias and alveolar hemorrhage. METHODS: By retrospective single-centre analysis we identified 46 consecutive patients (29 m) with RSV(n = 5), HSV1(n = 6), PJP(n = 21) and lung hemorrhage(n = 14) who underwent unenhanced chest CTs in early stages of the disease between 01/2016 and 02/2017. All cases were confirmed by microbiologic direct analysis of bronchial lavage. On chest-CT-scans, the presence of imaging features like ground-glass opacity(GGO), crazy-paving, air-space consolidation, reticulation, bronchial wall thickening and centrilobular nodules were described. A representative large area was chosen in both lungs and used for CTTA-parameters (included heterogeneity, intensity, average, deviation, skewness). RESULTS: Discriminatory CTTA-features were found between alveolar hemorrhage and PJP consisting of differences in mean heterogeneity(p < 0.015) and uniformity of skewness(p < 0.006). There was no difference between CT-textural features of diffuse alveolar hemorrhage and viral pneumonia or PJP and viral pneumonia. Visual HRCT-assessment yielded great overlap of imaging findings with predominance of GGO for PJP and airspace consolidation for pneumonia/alveolar hemorrhage. Significant correlations between HRCT-based imaging findings and CT-textural features were found for all three disease groups. CONCLUSION: CT-textural features showed significant differences in mean heterogeneity and uniformity of skewness. HRCT-based imaging findings correlated with certain CT-textural features showing that the latter have the potential to characterize structural properties of lung parenchyma and related abnormalities.

Transgenerational propensities for infant birth weight reflect fetal growth history of the mother in rhesus monkeys.

Birth weight (BW) at delivery is an important developmental milestone indicative of prenatal conditions and portends of the postnatal growth trajectory that will occur during infancy and childhood. Previous research has documented that there are also many physiological and health consequences of being born either small-for-gestational age (SGA) or large-for-gestational age (LGA). Analyses of breeding animals have demonstrated further that a gravid female exerts a strong influence on the size of her infant by term, and this permissiveness or constraint over fetal growth can be transmitted from mothers to their daughters. The following research tested additional hypotheses about matrilineal effects on BW by examining records from a large breeding colony of rhesus monkeys across multiple generations. The analyses utilized BW of 1710 infant monkeys obtained over 4 decades. In addition to determining the association between the birth weight (BW) of a female and her own infants birthed later as a mother, the multi-generational transmission of birth size from a grandmother through her daughters to the next generation was examined. Other maternal influences were evident, including a progressive increase in infant BW with parity, which synergized with matrilineal effects across a female's reproductive life. In addition, our modeling indicated that if an infant's BW was discordant-a SGA female birthing a larger daughter-the discrepant fetal growth pattern could be accentuated in the next generation. Overall, the findings confirm that the size of an infant at term is significantly influenced by a type of gestational imprinting on daughters during the prenatal period, which then continues to shape birth outcomes in subsequent generations.

The Pyraloidea (Lepidoptera) fauna of the woody savannah belt in Mali, West Africa.

Seventy-nine taxa of Pyraloidea were collected in 2014 with light traps in the woody savannah zone south of Bamako, Mali. Three taxa out of 79 were identified to genus level only. 78 of the 79 species are new records for Mali, 17 are new for West Africa. Most species (54) belong to the subfamily Spilomelinae (family Crambidae). The majority of observed species have wide distribution areas. The only regional endemic is Hypsopygia bamakoensis (Leraut, 2006). Concerning the biogeographical categories most of the species (34) are Afrotropical, seven species cosmopolitan, and the remaining species occur in the Palaearctics with a preference to the Palaeotropics. The most common species, Patania balteata (Fabricius, 1798) comprised 40.0% of all specimens collected. It is known to be a pest of the mango tree, which is common in the light-trapping area.

Variations in Initiation Dates of Chemotherapy and Radiation Therapy for Definitive Management of Inoperable Non-Small Cell Lung Cancer Are Associated With Decreases in Overall Survival.

BACKGROUND: We evaluated trends in administration of concurrent chemoradiation therapy (CRT) and how variations in start dates of chemotherapy and radiotherapy affected overall survival (OS) in patients with non-small cell lung cancer (NSCLC) undergoing a course of definitive CRT. MATERIALS AND METHODS: Cases of NSCLC treated with definitive CRT were obtained from the National Cancer Database. A survival analysis was performed with Kaplan-Meier curves and Cox proportional hazards models. Propensity score matching was conducted. RESULTS: On a national level, only 48.6% of patients began concurrent CRT on the same day. In a propensity-matched population, starting CRT within 6 days was associated with improved OS (17.9 months) compared with starting 7 to 13 days apart (16.5 months; P = .04). Starting dual therapy within 6 days of each other was associated with a 7% reduction in the risk of death (hazard ratio, 0.93; P = .05). Furthermore, in a propensity-matched cohort, starting CRT within 3 days was associated with longer survival (18.7 months) compared with 4 to 6 days apart (17.5 months; P = .02). Starting treatment 4 to 6 days apart was associated with an 8% increased risk of death (hazard ratio, 1.08; P = .04). CONCLUSION: A large proportion (48.6%) of patients with unresectable NSCLC do not initiate CRT on the same day as is considered standard by national guidelines. In this population, nonsimultaneous initiation of CRT was associated with differences in OS. Further efforts to understand the mitigating factors and barriers that interfere with timely delivery of concurrent CRT are needed.

One consensual depression diagnosis tool to serve many countries: a challenge! A RAND/UCLA methodology.

OBJECTIVE: From a systematic literature review (SLR), it became clear that a consensually validated tool was needed by European General Practitioner (GP) researchers in order to allow multi-centred collaborative research, in daily practice, throughout Europe. Which diagnostic tool for depression, validated against psychiatric examination according to the DSM, would GPs select as the best for use in clinical research, taking into account the combination of effectiveness, reliability and ergonomics? A RAND/UCLA, which combines the qualities of the Delphi process and of the nominal group, was used. GP researchers from different European countries were selected. The SLR extracted tools were validated against the DSM. The Youden index was used as an effectiveness criterion and Cronbach's alpha as a reliability criterion. Ergonomics data were extracted from the literature. Ergonomics were tested face-to-face. RESULTS: The SLR extracted 7 tools. Two instruments were considered sufficiently effective and reliable for use: the Hospital Anxiety and Depression Scale and the Hopkins Symptoms Checklist-25 (HSCL-25). After testing face-to-face, HSCL-25 was selected. A multicultural consensus on one diagnostic tool for depression was obtained for the HSCL-25. This tool will provide the opportunity to select homogeneous populations for European collaborative research in daily practice.