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Objective This study aimed to describe two cases of acute respiratory distress syndrome (ARDS) secondary to novel coronavirus disease 2019 (COVID-19) in pregnant women requiring extracorporeal membrane oxygenation (ECMO), and resulting in premature delivery. Study Design The clinical course of two women hospitalized with ARDS due to COVID-19 care in our intensive care (ICU) is summarized; both participants provided consent to be included in this case series. Results Both women recovered with no clinical sequelae. Neonatal outcomes were within the realm of expected for prematurity with the exception of coagulopathy. There was no vertical transmission to the neonates. Conclusion This case series highlights that ECMO is a feasible treatment in the pregnant woman with severe COVID-19 and that delivery can be performed safely on ECMO with no additional risk to the fetus. While ECMO carries its natural risks, it should be considered a viable option during pregnancy and the postpartum period. Key Points COVID-19 may present with a more severe course in pregnancy. ECMO may be used in pregnant woman with severe COVID-19. Delivery can be performed on ECMO without added fetal risk.

Summary Background Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation. Methods SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete. Findings Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study. Interpretation Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials. Funding British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.

Background/Objective: Low muscle mass (myopenia), poor muscle quality, myosteatosis, and muscle loss are associated with mortality in solid tumors. However, their impact in hematological malignancies remains unclear. We sought to determine how muscle phenotype relates to survival in patients with multiple myeloma. Methods: We performed a retrospective review of patients with multiple myeloma treated at Indiana University Hospital from 2012-2016. Total skeletal muscle area (SMA) (cm2) and radiodensity were measured on baseline (closest to diagnosis) and last CT scans at the third lumbar vertebrae area. SMA was normalized to height (SMA cm2/m2) to define skeletal muscle index (SKMI). Myopenia was defined as (SKMI)

Background: Cachexia, unintentional loss of muscle and fat, is frequent in patients with cancer. Cachexia, frequent with hepatocellular carcinoma, associates with decreased quality of life and survival. We sought to measure body composition changes in patients in the liver hepatocellular carcinoma (LIHC) cohort of The Cancer Genome Atlas (TCGA) preparatory to identifying tumor genomic characteristics associated with cachexia. Methods: Using CT scans from The Cancer Imaging Archive (TCIA), we measured changes in muscle area (SKMA) and height normalized skeletal muscle index (SKMI) between scans. Serum biomarkers, obtained from TCGA, and extracted data were assessed versus progression free survival (PFS) and overall survival (OS) using Spearman nonparametric correlation and log rank tests. Results: 43 patients of the LIHC cohort had two usable CT scans. 16 were female, mean age 63.4 ± 9.10 years (mean ± SD) and 27 were male, mean age 61.0 ± 15.5 years. SKMA, SKMI, and body weight were strongly correlated to male sex; conversely, platelet count was strongly correlated with female sex (r=0.400, p=0.01). We observed no correlations between change in SMA or SMKI and PFS or OS. However, variables of baseline SKMA (r=0.312, p=0.07), SKMI (r=0.312, p=0.07), patient weight (r=0.367, p=0.03), and body mass index (BMI) (r=.0404, p=0.02) correlated strongly with PFS. Serum platelet count was strongly negatively correlated with PFS (r=-0.401, p=0.02). Mutation count was strongly negatively correlated with OS (r=-0.311, p=0.04). Conclusion: This cohort is too small to draw general conclusions about body composition, muscle size, and survival. However, observing greater survival in patients with more muscle mass is consistent with studies of patients with advanced cancer showing increased risk of mortality with low muscle mass. Observing longer survival among patients with high starting BMI is consistent with prior studies in lung cancer. These results highlight the importance of body phenotype in prognosis of patients with hepatocellular carcinoma.

Background Multiple sclerosis (MS) is an immune-mediated disease that damages myelin in the central nervous system (CNS). We investigated the profile of CCN3, a known regulator of immune function and a potential mediator of myelin regeneration, in multiple sclerosis in the context of disease state and disease-modifying treatment. Methods CCN3 expression was analysed in plasma, immune cells, CSF and brain tissue of MS patient groups and control subjects by ELISA, western blot, qPCR, histology and in situ hybridization. Results Plasma CCN3 levels were comparable between collective MS cohorts and controls but were significantly higher in progressive versus relapsing-remitting MS and between patients on interferon-β versus natalizumab. Higher body mass index was associated with higher CCN3 levels in controls as reported previously, but this correlation was absent in MS patients. A significant positive correlation was found between CCN3 levels in matched plasma and CSF of MS patients which was absent in a comparator group of idiopathic intracranial hypertension patients. PBMCs and CD4+ T cells significantly upregulated CCN3 mRNA in MS patients versus controls. In the CNS, CCN3 was detected in neurons, astrocytes and blood vessels. Although overall levels of area immunoreactivity were comparable between non-affected, demyelinated and remyelinated tissue, the profile of expression varied dramatically. Conclusions This investigation provides the first comprehensive profile of CCN3 expression in MS and provides rationale to determine if CCN3 contributes to neuroimmunological functions in the CNS.

Using the screening data collected through the University of California, Los Angeles Preschool Vision Program (UPVP) that provides free vision screening to children 2.5 to 6 years of age attending public preschools in five Supervisory Districts in Los Angeles County, this paper explores whether geographic location of where children attended preschool affects the vision screening results.62,936 children were screened using a handheld device (Nikon Retinomax) between academic years 2012 and 2015. The criteria for failing the screening was set to sphere of ≤ -3.25 diopters (D), sphere ≥ +1.75 D, or cylinder of ≥1.50 D in either eye, or inter-ocular difference of2.00 D in spherical error (1.50D in case of antimetropia) or ≥1.00 D in cylinder error.Higher fail rates were found among girls, Latino race, and those who primarily spoke Spanish at home. In addition, there was a geographical variance in screening outcomes among Supervisory Districts with District 1 having the highest fail rate and District 4 having the lowest fail rate.This paper provides preliminary evidence of geographic factors contributing to the development of refractive errors among preschoolers which may be used in future studies to address the unmet needs of children with vision impairments in Los Angeles County.

Gastroesophageal reflux disease (GERD) is mainly a clinical diagnosis based on typical symptoms of heartburn and acid regurgitation. Current guidelines indicate that patients with typical symptoms should first try a proton pump inhibitor (PPI). If reflux symptoms persist after 8 weeks on a PPI, endoscopy of the esophagus is recommended, with biopsies taken to rule out eosinophilic esophagitis. This review discusses the evidence for different medical, endoscopic, and surgical therapies and presents a management algorithm.

Background: Repair of abdominal aortic aneurysms (AAA) decreases the incidence of rupture and death. In cancer patients, sarcopenia has been associated with increased surgical complications and mortality. The impact of sarcopenia on survival after AAA repair has yet to be described. Methods: Patient demographic, laboratory, body composition measurements and survival data were obtained from patients undergoing AAA repair at the Indiana University medical campus over a 5-year period. Univariate and multivariate analyses were performed to identify factors associated with overall survival. Results: Overall, 58.2% presented with sarcopenia. Sarcopenic patients were older (71.8±8.3 versus 66.8±8.1 years; p

Background: Cachexia, manifested as progressive adipose and muscle wasting, affects up to 80% of patients with pancreatic ductal adenocarcinoma (PDAC) and significantly increases morbidity and mortality. Increased inflammation is an underlying mechanism in almost all cases of cachexia. Trans-signaling of Interleukin-6 (IL-6) via the soluble form of its receptor (sIL6R) has been shown to promote inflammation. Certain polymorphisms of the IL6R gene such as rs2228145 (Asp358Ala substitution) are associated with increased levels of sIL6R. We hypothesize that patients with PDAC possessing IL6R alleles correlated with higher levels of circulating sIL6R will have increased systematic inflammation manifested as increased cachexia prevalence or severity. Methods: DNA was extracted from prospectively collected blood samples acquired from patients with PDAC and from non-cancer controls. Genotype at the rs2228145 polymorphism was determined by TaqMan qPCR genotyping. The resulting genotypes (A/A, A/C, C/C) were compared against cachexia-related metrics, including presence of cachexia (>5% body weight loss in the prior 6-months), body mass index (BMI), BMI-adjusted weight loss grade (BMI-WLG), and muscle and adipose volumes calculated from height-adjusted surface areas obtained from CT scans at the level of the third lumbar vertebra. Results: 83.3% of patients with PDAC heterozygous (A/C) and 84.6% of the patients homozygous for the rs2228145 polymorphism (C/C) exhibited cachexia, versus 57.9% of patients homozygous for the reference allele (A/A), (P = 0.0364, Chi-square test). No significant difference was found among genotypes for BMI, 6-month weight loss, BMI-WL grade, or muscle and adipose tissue indices. Conclusion: Patients with PDAC who are possess at least one copy of the rs2228145 polymorphism have a higher incidence of cachexia than those who are homozygous for the reference allele. This association suggests a causal role for sIL6R in cancer cachexia.

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

Purpose To summarize the results of 5 years of vision screening with the University of California, Los Angeles (UCLA) Preschool Vision Program (UPVP). Design Retrospective evaluation of a screening program. Methods The UPVP performed visual acuity and undilated noncycloplegic refractive screening using an autorefractor on 93,097 children between 2012 and 2017. Of these, 79,451 children, who were between 3 and 5 years old, were screened for the first time, and 14,259 were referred for full cycloplegic examination if they met specific refractive criteria for myopia, hyperopia, astigmatism, or anisometropia. UPVP performed 6779 cycloplegic examinations on this population. Data from the right eye only were included in this analysis. Results Of the examined population, hyperopia was found in 61% (4018), myopia in 20% (1336), and astigmatism in 93% (6122) of children. Latino children had higher rates of astigmatism and worse visual acuity compared to all other races/ethnicities. An astigmatism cutoff of ≥1.50 diopters (D) in either eye correctly predicted the need for glasses 93% of the time; increasing this cutoff to ≥1.50 D in both eyes increased the positive predictive value to 96%. Refractive amblyopia was found in 780 children (1.0% of the screened population and 11.5% of the examined population), and of these, 211 (27%) were bilaterally amblyopic. Conclusions These data represent the largest published sample of vision screening results on preschool-aged children, provide additional insight on the proportion of common refractive errors and their association with race/ethnicity, and can inform screening criteria to more accurately identify children who need intervention to prevent permanent vision loss.

Tetratricopeptide repeat domain-7A (TTC7A) deficiency causing combined immunodeficiency with inflammatory bowel disease (IBD) is rare. This case report alerts physicians to the possibility of TTC7A deficiency causing combined immunodeficiency with IBD and also highlights some of the current treatment options. We describe a 19-year-old patient with a compound heterozygote TTC7A mutation causing combined immunodeficiency, IBD, and multiple intestinal atresia. Compound heterozygote TTC7A mutations are known to cause combined immunodeficiency and IBD. Although rare, clinicians should be alerted to this variant and should understand the general approach to treatment.

Introduction: Cachexia is a metabolic syndrome leading to weight loss and muscle wasting. Pancreatic ductal adenocarcinoma (PDAC) frequently associates with cachexia, which contributes to its high mortality rate. Sex differences have been observed in cancer cachexia (Zhong and Zimmers, Curr Osteopor Rep 2020); however, the underlying molecular mechanisms are mostly unknown. We studied this here in both humans and mouse models. Because Activin is an important mediator of PDAC cachexia (Zhong et al., J Cachexia Sarcopenia Muscle 2019); thus, we also evaluated how sex affects anti-Activin treatment response. Design: Mice: Male and female mice with autochthonic PDAC (KPC mice) were evaluated for cachexia phenotype and anti-Activin treatment response. Muscles were subjected to molecular and transcriptome/proteome analyses. Patients: Longitudinal change in body composition was measured retrospectively from CT scans of >130 patients with PDAC treated with first-line gemcitabine/nab-paclitaxel and compared by sex. TCGA was queried for Activin gene expression versus mortality. Rectus abdominus muscles from PDAC patients were profiled for Activin pathway gene expression. Results: Despite identical tumor latency and size, male KPC mice experienced earlier and more severe muscle wasting and responded positively to treatment with the Activin trap, ACVR2B/Fc, exhibiting muscle preservation, while female mice did not. Mediators and markers of muscle catabolism were increased in male KPC mice. RNAseq revealed increased muscle-specific E3 ligases, decreased myosin heavy chains, and inhibited canonical pathways in males with early cachexia, with fewer alterations in females. ACVR2B/Fc prevented many of these changes in late cachexia in males, but not in females, despite increased plasma Activin concentration in both sexes. Pathway analysis revealed sex-specific upstream regulators and mediators of muscle function. Muscle proteomics revealed impaired mitochondrial function in males only. Inhibitors of Activin-related ligands were upregulated in the muscle of female KPC mice only. Like mice, men with PDAC demonstrated greater loss of skeletal muscle area and index, and greater rate of muscle loss versus women. TCGA query revealed high tumor INHBA expression correlated with mortality, but only in men. Muscle from female patients with PDAC showed increased expression of Activin inhibitors, FSTL1, FSTL3, and WFIKKN2. Conclusions: Male mice and cancer patients have higher prevalence of cachexia and greater muscle wasting compared with females. Furthermore, the Activin pathway mediates cachexia in a sex-specific fashion, potentially through muscle-specific expression of Activin inhibitors. These results demonstrate sex as the first premise for cachexia precision therapy. Citation Format: Xiaoling Zhong, Ashok Narasimhan, Andrew R. Young, Libbie M. Silverman, Jianguo Liu, Sheng Liu, Emma H. Doud, Jun Wan, Yunlong Liu, Amber L. Mosley, Leonidas G. Koniaris, Teresa A. Zimmers. Sex differences in pancreatic cancer cachexia manifestations and mechanisms in mice and humans: Role of activin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2657.

The clinical extent of psoriasis pathology is regulated in part by defects in immune networks, including a defect in the suppressive actions of regulatory T cells. Recently, CD14(+) HLA-DR(-/low) monocytic myeloid-derived suppressor cells (Mo-MDSCs) have been shown to suppress T-cell activation as one of their suppressive mechanisms. However, little is known about the role of Mo-MDSCs and their functional relationship to T-cell suppression in relation to human chronic immune-mediated inflammatory diseases, including psoriasis. Despite psoriasis being a hyperinflammatory condition, Mo-MDSCs were elevated in psoriatic patient peripheral blood mononuclear cells compared to nonpsoriatic healthy controls (2.6% vs. 0.9%, P0.002). Freshly isolated psoriatic Mo-MDSCs directly suppressed CD8 T-cell proliferation less efficiently than healthy control Mo-MDSCs. In addition, psoriatic Mo-MDSCs expressed reduced surface expression of programmed cell death protein 1 compared to healthy controls. Additional in vitro assays also demonstrated that psoriatic and control Mo-MDSCs both induce regulatory T-cell conversion from naïve T effector cells, but, importantly, the regulatory T cells induced by psoriatic Mo-MDSCs displayed decreased suppressive functionality. These results suggest that aberrations in psoriatic Mo-MDSCs prevent proper suppression of effector T-cell expansion and hamper the immune system's ability to correctly self-regulate.

It is 03:00 and you are staring at the X-ray of an umbilical venous catheter (UVC) you inserted earlier in the shift. The nursing team want to know if they can start to use the line. Is it safe? Does it need adjustment? Can you start total parenteral nutrition (TPN)? What about inotropes? This article aims to equip you with the ability to answer these questions using an understanding of the relevant anatomy and which UVC positions on X-ray are most likely to cause harm. UVCs are commonly used to administer: drugs, fluid and blood products, TPN, hypertonic fluid (concentrations of glucose solution above 12.5% in hypoglycaemic infants needing fluid restriction, for instance) or for exchange transfusion in the early neonatal period. There are various formulae that are employed to determine how far UVCs should be inserted.1 2 The distance from the base of the umbilical stump to the xiphisternum, adding the length of the umbilical stump, works as an acceptable approximation for emergency insertion. UVCs can sometimes be inserted some days after birth when deemed essential, but as the umbilical stump dries the procedure becomes increasingly difficult. As for any form of indwelling central vascular access, UVCs are subject to complications such as infection and thrombus formation. Butler-O’Hara et al ’s prospective study in infants with birth weights below 1251 g found that the overall rate of UVC-related infection was 17% and thrombus formation was 11%.3 Again, in common with other forms of vascular access, the risk of line-related infection may be limited by strict adherence to insertion protocols and minimising the length of time that the UVC is left in place.3 4 Specific problems relating to different catheter tip positions are listed in table 1. Of particular note, if UVCs with tips in the liver …

Brain metastasis (BM) are the most common type of brain tumor with an estimated incidence of 200,000–400,000/yr. in the US alone. BM are also the most common indication for stereotactic radiosurgery (SRS). However, while SRS is highly effective in achieving local control, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatment for primary systemic cancers improves. Among the challenges at the time of apparent imaging recurrence is differentiating “true” recurrence of BM from RN. Since conventional imaging is not always reliable for this, many patients must undergo surgical biopsy or resection due to this uncertainty. Here, we demonstrate the utility of the novel biomarker Vanin-2 (VNN2) combined with expression of MHC Class II molecule HLA-DR on CD14+ cells in order to differentiate recurrent BM from RN. Our preliminary data indicate that presence of Mo-MDSC is significantly increased in BM compared to RN (49% vs 4%, p=0.005). In contrast, VNN2 expression on CD14+ in BM is decreased compared to RN (4.3% vs 36%, p=0.02). In order to further decrease overlap between outliers in each group of patients, we define the ratio of HLA-DR expression to VNN2 expression on CD14+ cells from as the DR-VNN Index or DVI. While a DVI >1 is considered BM (average= 15.5), a DVI

IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. In addition, de novo psoriasis onset has been reported after IL-6 blockade in patients with rheumatoid arthritis. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6-deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation; however, this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36α/β/γ, Il24, Epgn, and S100a8/a9 to levels higher than those found in IL-17C+ mice. A comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin revealed significant correlation among transcripts of skin of patients with psoriasis and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why patients with arthritis being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.

Little is known about cimicosis, the resultant dermal reaction from feeding activity by the common bedbug, Cimex lectularius L. We fed C. lectularius on human study subjects four times over four weeks and measured serum cytokine and antibody levels, and subjects recorded any cimicosis. The average time for subjects to develop cimicosis decreased with each feeding from 8.4, to 2.1, 1.5 and 1.3 days, respectively. There were no significant changes in total IgG, IgG1, IgG2, IgG4 or IgE levels between the first and fourth bedbug feedings, but there was a significant decrease in total IgG3 levels (P

Previous studies have employed generic 3D-multiscale models to predict haemodynamic effects of the hybrid procedure in hypoplastic left heart syndrome. Patient-specific models, derived from image data, may allow a more clinically relevant model. However, such models require long computation times and employ internal pulmonary artery band [dint] dimension, which limits clinical application. Simpler, zero-dimensional models utilize external PAB diameters [dext] and provide rapid analysis, which may better guide intervention. This study compared 0-D and 3-D modelling from a single patient dataset and investigated the relationship dint versus dext and hemodynamic outputs of the two models. Optimum oxygen delivery defined at dint = 2 mm corresponded to dext = 3.1 mm and 3.4 mm when models were matched for cardiac output or systemic pressure, respectively. 0-D and 3-D models when matched for PAB dimension produced close equivalence of hemodynamics and ventricular energetics. From this study we conclude that 0-D model can provide a valid alternative to 3D-multiscale in the hybrid–HLHS circulation.

CCR5 expression on CD4+CD25highFoxp3+ regulatory T cells (Tregs) has been reported to be crucial for limiting Th1 inflammation associated with autoimmunity and bacterial infections. We inquired whether abnormalities in chemokine receptors expressed on Tregs might be involved in the psoriatic pathogenesis. Indeed, the proportion of CCR5+ Treg was 58.8% in healthy individuals (n = 9), whereas only half as many CCR5+ Treg cells were found in psoriatic individuals (29.1%, n = 8, p

OBJECTIVES: Hybrid palliation for hypoplastic left heart syndrome (HLHS) is associated with mortality and late ventricular dysfunction. Increased ventricular workload and coronary perfusion limitation may be the important factors. Using mathematical modelling, this study investigated the effects of differing hybrid configurations on the demands on this single ventricle circulation. METHODS: A multicompartmental Windkessel model of hybrid HLH-aortic atresia circulation was adopted, with a time-varying elastance representing ventricular functionality. The effects of diameter increases in bilateral pulmonary artery bandings (PABs) (+0.5, 2.5– 4 mm) and ductal stent (+1, 4–10 mm) on cardiovascular haemodynamics, systemic oxygenation and ventricular energetics were assessed. RESULTS: Simulations showed that an increase in PAB diameter of 2.5–4 mm resulted in an increased Q (0.61–2.66), and diastolic stent backflow (−0.2 to −0.78 l/min) with reduced systemic perfusion (0.82–0.77 l/min) and diastolic pressures (48.3–41.2 mmHg). Arterial and venous saturations increased, SaO2 (%) was 62–88 and SvO 2 41–65. To maintain mean systemic pressures, substantial increases in cardiac output (1.3–2.8 l/min) and ventricular stroke work (576–1360 mmHg ml) were required. A decrease in the ductal stent diameter over the range 10–7 mm had a negligible haemodynamic effect: reduced systemic systolic pressure (77–72 mmHg) and increase in ventricular stroke work (781–790 mmHg ml). When the ductal diameter was restricted to

Mineralo-protein nanoparticles (NPs) formed spontaneously in the body have been associated with ectopic calcifications seen in atherosclerosis, chronic degenerative diseases, and kidney stone formation. Synthetic NPs are also known to become coated with proteins when they come in contact with body fluids. Identifying the proteins found in NPs should help unravel how NPs are formed in the body and how NPs in general, be they synthetic or naturally formed, interact within the body. Here, we developed a proteomic approach based on liquid chromatography (LC) and tandem mass spectrometry (MS/MS) to determine the protein composition of carbonate-apatite NPs derived from human body fluids (serum, urine, cerebrospinal fluid, ascites, pleural effusion, and synovial fluid). LC-MS/MS provided not only an efficient and comprehensive determination of the protein constituents, but also a semiquantitative ranking of the identified proteins. Notably, the identified NP proteins mirrored the protein composition of the contacting body fluids, with albumin, fetuin-A, complement C3, α-1-antitrypsin, prothrombin, and apolipoproteins A1 and B-100 being consistently associated with the particles. Since several coagulation factors, calcification inhibitors, complement proteins, immune regulators, protease inhibitors, and lipid/molecule carriers can all become NP constituents, our results suggest that mineralo-protein complexes may interface with distinct biochemical pathways in the body depending on their protein composition. We propose that LC-MS/MS be used to characterize proteins found in both synthetic and natural NPs.

We examined the population dynamics and seasonal change in body size of a population of Daphnia galeata mendotae experiencing strong vertebrate predation. The intensity of food limitation was quantified seasonally by in situ food addition. We also collected live animals early and late in the summer for laboratory studies designed to estimate genetic variation and seasonal change in life-history traits for the population. The population was characterized by nearly equal short-term birth and death rates that were strongly correlated with population density, suggesting density dependence. The population generally exhibited very high birth and death rates and no significant response to experimental food addition. The one exception was June 1988, when the population achieved high densities and exhibited strong food limitation. Throughout both summers, minimal and average body sizes of adults decreased. Laboratory studies document substantial genetic variation for body size and other life-history traits among animals collected early in summer. By late summer, however, there was little genetic variation for these same traits. Furthermore, clones collected early in summer were genetically larger in body size at birth and maturity than clones collected in late summer. We interpret these results as indicating natural selection for body size.

Putative living entities called nanobacteria (NB) are unusual for their small sizes (50–500 nm), pleomorphic nature, and accumulation of hydroxyapatite (HAP), and have been implicated in numerous diseases involving extraskeletal calcification. By adding precipitating ions to cell culture medium containing serum, mineral nanoparticles are generated that are morphologically and chemically identical to the so-called NB. These nanoparticles are shown here to be formed of amorphous mineral complexes containing calcium as well as other ions like carbonate, which then rapidly acquire phosphate, forming HAP. The main constituent proteins of serum-derived NB are albumin, fetuin-A, and apolipoprotein A1, but their involvement appears circumstantial since so-called NB from different body fluids harbor other proteins. Accordingly, by passage through various culture media, the protein composition of these particles can be modulated. Immunoblotting experiments reveal that antibodies deemed specific for NB react in fact with either albumin, fetuin-A, or both, indicating that previous studies using these reagents may have detected these serum proteins from the same as well as different species, with human tissue nanoparticles presumably absorbing bovine serum antigens from the culture medium. Both fetal bovine serum and human serum, used earlier by other investigators as sources of NB, paradoxically inhibit the formation of these entities, and this inhibition is trypsin-sensitive, indicating a role for proteins in this inhibitory process. Fetuin-A, and to a lesser degree albumin, inhibit nanoparticle formation, an inhibition that is overcome with time, ending with formation of the so-called NB. Together, these data demonstrate that NB are most likely formed by calcium or apatite crystallization inhibitors that are somehow overwhelmed by excess calcium or calcium phosphate found in culture medium or in body fluids, thereby becoming seeds for calcification. The structures described earlier as NB may thus represent remnants and by-products of physiological mechanisms used for calcium homeostasis, a concept which explains the vast body of NB literature as well as explains the true origin of NB as lifeless protein-mineralo entities with questionable role in pathogenesis.

Myasthenia gravis (MG) is a neuromuscular transmission disease caused primarily by acetylcholine receptor (AChR) autoantibodies,1,2 and several lines of evidence indicate that the fixation of complement at the neuromuscular junction (NMJ) is an important factor in determining disease severity.3 C3 activation fragments and the membrane attack complex are detected at the NMJ of patients with MG, depletion of serum C3 and C4 is appreciated in some patients, and terminal complement components are found in patient sera.4 – 6 In humans, antigenic modulation and direct blockade of the AChR also likely contribute to MG pathology, but their relative significance is not known.7,8 Complement is paramount in driving disease pathology in both models of the experimentally acquired myasthenia gravis (EAMG), whether produced by administration of AChR antibodies or through immunization with purified AChR. With rare exception,9 passive transfer EAMG is induced only by complement-fixing antibodies, and complement depletion by cobra venom factor eliminates NMJ injury and weakness.10 Antibodies directed toward C511 and soluble complement receptor (sCR1)12 are protective in EAMG produced by AChR antibody administration. C5-deficient mice13 or anti-C6 Fab antibody–treated EAMG rats14 are more resistant and develop less severe disease, whereas an absence of cell surface regulators of complement leads to significantly greater disease with EAMG induced by AChR antibodies.15–17 The inhibition of complement as a therapeutic approach is beginning to be applied to human disorders. Pexelizumab, a monoclonal antibody directed against C5, has demonstrated short-term safety and efficacy in humans in myocardial infarction,18 coronary artery bypass graft surgery,19 and lung transplantation.20 A phase 3 trial of eculizumab, a single-chain fragment of anti-C5, in treatment of paroxysmal nocturnal hemoglobinuria21 demonstrated significant clinical benefits with minimal adverse effects. MG would be expected to respond well to complement inhibition especially in acute exacerbations when complement-mediated NMJ injury is expected to be maximal. rEV576 is a novel complement inhibitor, which appears ideally suited for consideration as a therapeutic agent. It is a 17kDa protein22 identified from the saliva of the tick Ornithodoros moubata and belongs to the lipocalin family of proteins, which inhibit inflammatory mediators.23 Because the agent is derived from ticks that apply themselves to mammalian species for weeks without inducing a reaction, there is an expectation that rEV576 will have limited adverse effects in humans. The compound is not known to cause allergic reactions or to have effects beyond those related to complement inactivation.24 rEV576 specifically targets the C5 activation step and has been shown to inhibit both the classic and the alternative pathways, and act specifically at the C5 step of complement activation.25 The simplest explanation for the activity of rEV576 is direct binding to C5 that prevents interaction with the C5 convertase rather than by blocking the C5a cleavage site.26 In this study, the active and passive models of EAMG were used to investigate the therapeutic activity of rEV576. Rats treated with rEV576 demonstrated dramatic improvements in weakness, recovery from weight loss, and reduced C9 deposition at the NMJ. The findings suggest that this novel complement inhibitor could prove to be an effective treatment in human MG.

Background: The increasing rate of health care expenditures in the United States has placed a significant burden on the nation’s economy. Predicting future health care utilization of patients can provide useful information to better understand and manage overall health care deliveries and clinical resource allocation. Objective: This study developed an electronic medical record (EMR)-based online risk model predictive of resource utilization for patients in Maine in the next 6 months across all payers, all diseases, and all demographic groups. Methods: In the HealthInfoNet, Maine’s health information exchange (HIE), a retrospective cohort of 1,273,114 patients was constructed with the preceding 12-month EMR. Each patient’s next 6-month (between January 1, 2013 and June 30, 2013) health care resource utilization was retrospectively scored ranging from 0 to 100 and a decision tree–based predictive model was developed. Our model was later integrated in the Maine HIE population exploration system to allow a prospective validation analysis of 1,358,153 patients by forecasting their next 6-month risk of resource utilization between July 1, 2013 and December 31, 2013. Results: Prospectively predicted risks, on either an individual level or a population (per 1000 patients) level, were consistent with the next 6-month resource utilization distributions and the clinical patterns at the population level. Results demonstrated the strong correlation between its care resource utilization and our risk scores, supporting the effectiveness of our model. With the online population risk monitoring enterprise dashboards, the effectiveness of the predictive algorithm has been validated by clinicians and caregivers in the State of Maine. Conclusions: The model and associated online applications were designed for tracking the evolving nature of total population risk, in a longitudinal manner, for health care resource utilization. It will enable more effective care management strategies driving improved patient outcomes. [J Med Internet Res 2015;17(9):e219]

The diseases of cystic fibrosis, chronic obstructive pulmonary disease (COPD), and chronic bronchitis are characterized by mucus-congested and inflamed airways. Anti-inflammatory agents that can simultaneously restore or enhance mucociliary clearance through cystic fibrosis transmembrane conductance regulator (CFTR) activation may represent new therapeutics in their treatment. Herein, we report the activation of CFTR-mediated chloride secretion by phosphodiesterase (PDE) 4 inhibitors in T84 monolayer using (125)I anion as tracer. In the absence of forskolin, the iodide secretion was insensitive to PDE4 inhibitor L-826,141 [4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-ethyl]-3-methylpyridine-1-oxide], roflumilast, or to PDE3 inhibitor trequinsin. However, these inhibitors potently augmented iodide secretion after forskolin stimulation, with efficacy coupled to the activation states of adenylyl cyclase. The iodide secretion from PDE3 or PDE4 inhibition was characterized at first by a prolonged efflux duration, followed by progressively elevated peak efflux rates at higher inhibitor concentrations. Paralleled with an increased phosphor-cAMP response element-binding protein formation, the CFTR activation dissociated from a global cAMP elevation and was blocked by H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide]. 2-(4-Fluorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)ethyl]nicotinamide, a stereoselective PDE4D inhibitor, augmented iodide efflux more efficiently than its less potent (R)-isomer. The peak efflux from maximal PDE4 and PDE3 inhibition matched that from full adenylyl cyclase activation. These data suggest that PDE3 and PDE4 (mainly PDE4D) form the major cAMP diffusion barrier in T84 cells to ensure a compartmentalized CFTR signaling. Together with their potent anti-inflammatory properties, the potentially enhanced airway mucociliary clearance from CFTR activation may have contributed to the efficacy of PDE4 inhibitors in COPD and asthmatic patients. PDE4 inhibitors may represent new opportunities to combat cystic fibrosis and other respiratory diseases in future.

From May 1996 to July 1996, three male patients with advanced esophageal cancer with complete obstruction were treated with concurrent chemoradiotherapy. The first two courses of chemotherapy using 5-Fluorouracil (500mg/m 2 ) and Leucovorin (200mg/m 2 ) on day one through day five were given concurrently with radiotherapy. After completion of radiotherapy, four more courses of chemotherapy using the same regimen were given every four weeks. The total dose of irradiation using six MV linear accelerator given to the primary tumor was 5,000 cGy in 28 fractions. All three patients had relief of their obstruction with complete regression of the tumor after the completion of their treatment. All patients improved clinically and were able to remain symptom-free until the time of their death. The first patient survived for 12 months and died of respiratory failure because of his chronic obstructive pulmonary disease. The second patient also survived 12 months but died of liver metastasis. The third patient lived for 10 months and died of aspiration pneumonia.

To the Editor: As data accumulate on the recently identified genetic variant in the 3′-untranslated region of the prothrombin (factor II) gene (G20210A), it is apparent that this mutation confers a moderate risk for venous thrombosis.[1-3][1] Data from several abstracts presented at the 1997 ISTH

Therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. Compared to de novo AML, there is a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, and complex cytogenetics in t-AML. The response to chemotherapy is also reduced compared to de novo AML, and long-term remissions are rare. From a pathogenesis perspective, the key difference between de novo AML and t-AML is the prior exposure of t-AML patients to cytotoxic therapy during treatment of their primary cancer. We previously reported the initial findings of our study to sequence the genome of 22 cases of t-AML (Ramsingh et al, Abstract #784, 2012). These data were compared to the genomic sequence of 49 cases of de novo AML (TCGA, NEJM, 2013). Surprisingly, the data showed that the total number of somatic single nucleotide variants (SNVs) and the percentage of transversions (which are associated with chemotherapy-induced DNA damage) were similar in t-AML and de novo AML. Thus, there is no evidence that chemotherapy induces genome-wide DNA damage in t-AML. We extended this data set by sequencing 149 genes of interest in an additional 89 patients with t-AML/t-MDS. Mutations of TP53 were the most frequent (31.5%), and TP53 was the only gene mutated at a higher frequency in t-AML or t-MDS compared with de novo AML or MDS respectively. The mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unclear. Since t-AML/t-MDS has a similar mutation burden compared to de novo AML, it is not likely that chemotherapy directly induces TP53 mutations. We recently reported that individual HSCs accumulate somatic mutations as a function of age. By age 50, there are on average 5 coding gene mutations per HSC clone (Welch et al, Cell, 2012). As it is estimated that there are 10,000 HSCs in humans, it is possible that HSC clones harboring aging-related TP53 mutations are present in a subset of healthy individuals. Based on these observations, we propose a model in which rare TP53 mutant-bearing HSC clones have a selective growth advantage in patients undergoing chemotherapy. This results in their clonal expansion, with additional mutations in the HSC clone undoubtedly required for full leukemic transformation. This model predicts that TP53 mutations are present in many patients years prior to the development of t-AML/t-MDS. To test this prediction, we developed a next generation sequencing technique able to detect rare subclones harboring TP53 mutations to as low as 1 in 1,000 cells. We identified 7 cases of t-AML/t-MDS with specific TP53 mutations for whom we had blood or bone marrow banked 3-10 years prior to the development of t-AML/t-MDS. The specific TP53 mutations were detected in two cases. In patient UPN 530447, bi-allelic mutations of TP53 were identified in mobilized peripheral blood leukocytes 6 years prior to the development of t-AML at frequencies of 0.5 and 0.7%. In patient UPN 341666, a heterozygous TP53 mutation was identified in mobilized peripheral blood leukocytes 3 years prior to t-MDS diagnosis at a frequency of 0.1%. In at least some cases, we have clear evidence that the TP53 mutations occurred prior to the acquisition of other driver mutations or the development of cytogenetic abnormalities. To directly test the hypothesis that TP53 mutations confer a clonal advantage after chemotherapy, we generated mixed bone marrow chimeras containing wild type and Tp53+/- cells. No clonal advantage of Tp53+/- cells was identified in untreated chimeras. However, upon treatment with N-ethyl-N-nitrosourea, Tp53+/- HSCs had a significant growth advantage. Collectively, these data suggest that HSCs that acquire heterozygous TP53 mutations as a function of normal aging may be selected for in the presence of cytotoxic therapy. This provides a potential mechanism for the high incidence of TP53 mutations in t-AML/t-MDS. The early acquisition of TP53 mutations in the founding clone likely contributes to the frequent cytogenetic abnormalities and poor response to chemotherapy that are typical of t-AML/t-MDS. Disclosures: Welch: Eisai: Research Funding.

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal.

Background Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-β production. Methods To determine the role of IRF3 in autoimmune inflammation, we immunised wild-type (WT) and irf3−/− mice to induce EAE. Splenocytes from WT and irf3−/− mice were also activated in vitro in Th17-polarising conditions. Results Clinical signs of disease were significantly lower in mice lacking IRF3, with reduced Th1 and Th17 cells in the central nervous system. Peripheral T-cell responses were also diminished, including impaired proliferation and Th17 development in irf3−/− mice. Myelin-reactive CD4+ cells lacking IRF3 completely failed to transfer EAE in Th17-polarised models as did WT cells transferred into irf3−/− recipients. Furthermore, IRF3 deficiency in non-CD4+ cells conferred impairment of Th17 development in antigen-activated cultures. Conclusion These data show that IRF3 plays a crucial role in development of Th17 responses and EAE and warrants investigation in human multiple sclerosis.