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Objective To examine infertility-related fund-raising campaigns on a popular crowdfunding website and to compare campaign characteristics across states with and without legislative mandates for insurance coverage for infertility-related care. Design Retrospective cohort study. Setting Online crowdfunding platform (GoFundMe) between 2010 and 2020. Patient(s) GoFundMe campaigns in the United States containing the keywords “fertility” and “infertility.” Intervention(s) State insurance mandates for infertility treatment coverage. Main Outcome Measure(s) Primary outcomes included fund-raising goals, funds raised, campaign location, and campaigns per capita. Result(s) Of the 3,332 infertility-related campaigns analyzed, a total goal of $52.6 million was requested, with $22.5 million (42.8%) successfully raised. The average goal was $18,639 (standard deviation [SD] $32,904), and the average amount raised was $6,759 (SD $14,270). States with insurance mandates for infertility coverage had fewer crowdfunding campaigns per capita (0.75 vs. 1.15 campaigns per 100,000 population than states without insurance mandates. Conclusion(s) We found a large number of campaigns requesting financial assistance for costs associated with infertility care, indicating a substantial unmet financial burden. States with insurance mandates had fewer campaigns per capita, suggesting that mandates are effective in mitigating this financial burden. These data can inform future health policy legislation on the state and federal levels to assist with the financial burden of infertility.

This study examined the relationship between stimulant medications used for the treatment of attention deficit hyperactivity disorder and semen parameters. We performed a retrospective cohort study at a large, academic institution between 2002 and 2020. We included men with a semen analysis without prior spermatotoxic medication use, empiric medical therapy exposure or confounding medical diagnoses (varicocele, Klinefelter’s syndrome, cryptorchidism, cystic fibrosis, diabetes, cancer or cancer-related treatment, and azoospermia). Men were stratified by stimulant exposure (methylphenidate or amphetamines). A multivariable linear regression was fit to assess the association between individual semen parameters, age, stimulant exposure and non-stimulant medication use. Of 8,861 men identified, 106 men had active prescriptions for stimulants within 90 days prior to semen testing. After controlling for age and exposure to non-stimulant medications, stimulant use was associated with decreased total motile sperm count (β: −18.00 mil/ejaculate and standard error: 8.44, p = 0.033) in the setting of decreased semen volume (β: −0.35 ml, and standard error: 0.16, p = 0.035), but not sperm concentration, motility and morphology. These findings suggest a role for reproductive physicians and mental health providers to consider counselling men on the potential negative impact of stimulants prescribed for attention deficit hyperactivity disorder on semen volume during fertility planning.

INTRODUCTION AND OBJECTIVE:Prior work has shown that detrusor muscle sampling (MS) from transurethral resection of bladder tumor (TURBT) is related to oncologic outcomes. It is unknown if surgeon s...

INTRODUCTION AND OBJECTIVE:Recent work shows that reproductive endocrinologists (REI) are the primary referral base for reproductive urologists; however, many men with infertility do not undergo fe...

INTRODUCTION AND OBJECTIVE:Transperineal (TP) biopsy and adoption of magnetic resonance imaging (MRI) prior to biopsy are both increasingly utilized. Few studies have examined the cost-effectivenes...

BackgroundGenome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations.MethodsA total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS.ResultsEuropean ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p= 3× 10-7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile).ConclusionsPredictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.

To determine whether health-conscious men are more likely to be concerned about infertility and self-initiate semen analysis at a laboratory/clinic or through a direct-to-consumer at-home product without a health care provider recommendation.Cross-sectional survey conducted online via ResearchMatch.org between November 2019 and January 2020. Men age 18 and older without children (n = 634) were included for analysis. Outcomes were likelihood of self-initiating a semen analysis, prevalence of infertility concern.Of the 634 participants, 186 expressed concern about infertility but only 29% were likely to discuss these concerns with a health care provider. More men would self-initiate a semen analysis using an at-home product than through a traditional laboratory/clinic (14.2% vs 10.4%, P = .04). Odds of self-initiating a traditional semen analysis were higher for men concerned about low testosterone (odds ratio [OR] 2.30, 95% confidence interval [CI] 1.12-4.74, P = .023) and infertility (OR 3.91, 95% CI 2.14-7.15, P.001). Self-initiating an at-home semen analysis was associated with concern for low testosterone and infertility as well as middle age (age 40-59: OR 3.02, 95% CI 1.16-7.88, P = .024) and fitness tracker use (OR: 1.95, 95% CI 1.12-3.39, P = .018).Many men were unlikely to discuss infertility concerns with a health care provider. Middle aged men and those who used fitness trackers were more likely to self-initiate fertility evaluation through at-home semen analysis. Concern about low serum testosterone was pervasive and strongly associated with concern for being infertile and self-initiating a semen analysis of any kind.

SUMMARYFrontotemporal dementia (FTD) due to MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations due to the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, and glutamatergic signaling pathways and regulators including the RNA-binding protein ELAVL4. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function and build-up of tau and P-tau S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons of layers affected in patients. Mutant neurons are susceptible to glutamate toxicity which was rescued pharmacologically by treatment with the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede cell death, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

Summary Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

Traumatic brain injury confers a significant and growing public health burden and represents a major environmental risk factor for dementia. Previous efforts to model traumatic brain injury and elucidate pathologic mechanisms have been hindered by complex interactions between multiple cell types, biophysical, and degenerative properties of the human brain. Here, we use high-intensity focused ultrasound to induce mechanical injury in 3D human pluripotent stem cell-derived cortical organoids to mimic traumatic brain injury in vitro. Our results show that mechanically injured organoids recapitulate key hallmarks of traumatic brain injury, phosphorylation of tau and TDP-43, neurodegeneration, and transcriptional programs indicative of energy deficits. We present high-intensity focused ultrasound as a novel, reproducible model of traumatic brain injury in cortical organoids with potential for scalable and temporally-defined mechanistic studies.

The role of conventional 2D echocardiography in the setting of acute myocarditis is limited as often it reveals no significant changes in global systolic function. Published studies have demonstrated the usefulness of myocardial deformation imaging in acute myocarditis with global longitudinal strain (GLS) being more sensitive in the recognition of myocardial dysfunction even in preserved systolic function and its strong correlation to the amount of myocardial oedema found on cardiac MRI. It also has the advantage of being more readily available, requiring a shorter interpretation time and is significantly cheaper as compared to cardiac MRI. GLS has also been shown to play a role in risk stratification with a lower GLS being associated with a higher rate of major adverse cardiac events (MACE) among all myocarditis cases independent of LV ejection fraction. We describe a case where there was strong correlation between GLS and myocardial oedema on CMR T1 weighted imaging. A 26 year old with no relevant past medical history presented to hospital complaining of pleuritic sounding chest pain. ECG showed ST segment changes suggestive of pericarditis. White blood cell count and troponin levels were elevated. Echocardiography performed on the same day showed apical akinesia and reduced longitudinal LV function. Global longitudinal strain was an average of -8% and was notably reduced in the apical, inferior, posterior and lateral regions. The overall left ventricular function was normal (55% by bi-plane Simpson"s method). Cardiac MRI showed normal LV size and function with myocardial oedema in the mid inferolateral, apical inferior and apical anterior segments. These findings were consistent with acute myocarditis affecting the involved segments. Our case demonstrates that the global longitudinal strain reduction correlated very similarly to the pattern of myocardial oedema in the affected segments and is consistent with similar findings from published studies. GLS by 2D speckled imaging may therefore play an important role in the assessment of acute myocarditis especially in patients with preserved ejection fraction and may help in risk stratification. Abstract P1318 Figure. combined GLS CMR

Humans have been preoccupied with penile augmentation from time immemorial. In modern times, a wide variety of approaches have sought to increase penile length, girth, or, in some cases, both. While there is no consensus regarding appropriate indications, penile augmentation has been used in the setting of microphallus, fibrosis, trauma, and penile dysmorphia. Techniques for girth enhancement include injectable therapies, grafting, and implants. Penile lengthening procedures include traction therapy, suspensory ligament division, flap and liposuction procedures. This chapter aims to provide a brief review of historical and current approaches to penile augmentation, as well as a critical review of evidence regarding efficacy and complications.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse etiologies. Therefore, the identification of common disease mechanisms and therapeutics targeting these mechanisms could dramatically improve clinical outcomes. To this end, we developed induced motor neuron (iMN) models from C9ORF72 and sporadic ALS (sALS) patients to identify targets that are effective against these types of cases, which together comprise ~90% of patients. We find that iMNs from C9ORF72 and several sporadic ALS patients share two common defects - impaired autophagosome formation and the aberrant accumulation of glutamate receptors. Moreover, we show that an anticoagulation-deficient form of activated protein C, 3K3A-APC, rescues these defects in both C9ORF72 and sporadic ALS iMNs. As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs. Importantly, 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models. Thus, motor neurons from C9ORF72 and at least a subset of sporadic ALS patients share common, early defects in autophagosome formation and glutamate receptor homeostasis and a single therapeutic approach may be efficacious against these disease processes.

A 53-year-old woman is admitted with a serum creatinine of 16 mg/dl. Seven months earlier, she was diagnosed with heart failure and started on several medications, including Hydralazine. Laboratory studies revealed the presence of dual Anti-Neutrophil Cytoplasmic Antibodies (anti-MPO and anti-PR3), anti-nuclear and anti-histone antibodies. The clinical diagnosis was Drug-Induced ANCA Vasculitis (DIAV). Kidney histology, however, did not reveal crescents, but showed characteristic features of Alport’s syndrome.

Background Scavenger receptors play a significant role in clearing aged proteins from the plasma, including the large glycoprotein coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII). A large genome-wide association study meta-analysis has identified genetic variants in the gene SCARA5, which encodes the class A scavenger receptor SCARA5, as being associated with plasma levels of VWF and FVIII. Objectives The ability of SCARA5 to regulate the clearance of VWF-FVIII was characterized. Methods VWF-FVIII interactions with SCARA5 were evaluated by solid phase binding assays and in vitro cell based assays. The influence of SCARA5 deficiency on VWF:Ag and half-life was assessed in a murine model. The expression pattern of SCARA5 and its colocalization with VWF was evaluated in human tissues. Results VWF and the VWF-FVIII complex bound to human recombinant SCARA5 in a dose- and calcium-dependent manner. SCARA5 expressing HEK 293T cells bound and internalized VWF and the VWF-FVIII complex into early endosomes. In vivo, SCARA5 deficiency had a modest influence on the half-life of human VWF. mRNA analysis and immunohistochemistry determined that human SCARA5 is expressed in kidney podocytes and the red pulp, white pulp, and marginal zone of the spleen. VWF was found to colocalize with SCARA5 expressed by littoral cells lining the red pulp of the human spleen. Conclusions SCARA5 is an adhesive and endocytic receptor for VWF. In human tissues, SCARA5 is expressed by kidney podocytes and splenic littoral endothelial cells. SCARA5 may have a modest influence on VWF clearance in humans.

Introduction Autologous or allogeneic natural killer (NK) cells possess efficient cytotoxicity against tumor cells without severe side effects such as CRS or graft-versus-host disease (GvHD). In addition to chimeric antigen receptor (CAR) strategy, antibody-cell conjugates (ACCTM) platform provides more efficient way to arm NK cells with binding specificity and enhanced potency against target cells. In this work, we develop a NK cell therapy product ACE1702, a novel NK cell line oNK conjugated with Trastuzumab, and assess its potency against HER2+ solid tumors. Methods oNK cells, a fluorescence-activated cell sorting (FACS) isolated CD16+ population sorted from NK-92 cells, was covalently conjugated with monoclonal antibody Trastuzumab after sublethal irradiation by our patented antibody-cell conjugates (ACCTM) platform to become our cryopreserved final product ACE1702 compliant with current good manufacturing practice (cGMP). Characterization of ACE1702 was analyzed by flow cytometry. Function of ACE1702 was validated by real-time xCELLigence analyzer in vitro. Efficacy of intraperitoneally (ip.) delivered ACE1702 was evaluated in tumor-bearing female immune compromised NSG mice. Tumorigenic potential of non-irradiated oNK and ACE1702 was evaluated in subcutaneous implantation female BALB/c nude mice model. Results We demonstrated that newly established CD16+ oNK cells harbor elevated basal cytotoxicity against target cells in the absence of antibodies without tumorigenic potential. The Trastuzumab-armed oNK cells, ACE1702, exerted human epidermal growth factor 2 (HER2) binding specificity and enhanced cytotoxicity against various types of cancer cells with grade 1 (MCF-7), grade 2 (OVCAR-3) and grade 3 (SK-OV-3) HER2 expression compared to control oNK cells in vitro. ACE1702 also displayed similar potency against Herceptin-resistant human breast cancer cell line BT-474 clone 5 and parental BT-474 cells in vitro. Furthermore, in vivo results in human ovarian cancer cell line SK-OV-3-bearing xenograft mouse model supported the in vitro observations. Compared to other immunotherapeutic strategies such as antibody-drug conjugate, allogeneic NK and chimeric antigen receptor (CAR) modification, ACCTM platform underscores its power in compatibility with diverse antibodies, ease for mass production compliant with good manufacturing practice and affordability to patients. Conclusion Here we introduced a novel Trastuzumab-modified oNK cell product with enhanced specificity against myriad types of HER2+ cancers even in the presence of Herceptin resistance, and demonstrated the non-tumorigenic potential of non-irradiated oNK cells and ACE1702. Citation Format: Hao-Kang H. Li, Tai-Sheng E. Wu, Ching-Wen S. Hsiao, Sen-Han S. Yang, Chia-Yun S. Lee, Yan-Liang J. Lin, Zih-Fei Z. Cheng, Yu-Bei Cheng, Yan-Da D. Lai, Hsiu-Ping C. Yang, Sai-Wen S. Tang, Wei-Lun S. Lo, Janet Pan, Shih-Chia S. Hsiao. ACE1702: A potent and off-the-shelf oNK cell therapy product [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2169.

Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.

Essentials Initial immune cell interactions leading to factor (F) VIII immunity are not well characterized. We assessed cellular interactions and expression profiles in hemophilia A mice. MARCO+, followed by SIGLEC1+ and SIGNR1+ macrophages co-localize most with human FVIII. The splenic transcriptome highlights potential therapeutic targets to prevent inhibitors.SUMMARY: Background Developing factor VIII (FVIII) inhibitory antibodies is the most serious complication in hemophilia A treatment, representing a significant health and economic burden. A better understanding of the early events in an immune response leading to this outcome may provide insight into inhibitor development. Objective To identify early mediators of FVIII immunity and to detail immune expression profiles in the spleen and liver. Methods C57Bl/6 F8 E16 knockout mice were infused with 5-20 μg (2000-8000 IU kg-1 ) of recombinant FVIII. Spleens were frozen at various time-points post-infusion and stained for FVIII and cellular markers. Splenic and liver RNA expression analysis was performed 3 h post-infusion of 0.6 μg (240 IU kg-1 ) FVIII by nCounter technology using a 561-gene immunology panel. Results FVIII localization in the spleen did not change over 2.5 h. We observed significantly higher co-localization of FVIII with MARCO+ cells compared with SIGLEC1+ and SIGNR1+ in the splenic marginal zone. FVIII exhibited little co-localization with CD11c+ dendritic cells and the macrophage mannose receptor, CD206. Following FVIII infusion, the splenic mRNA profiling identified genes such as Tnfaip6 and Il23r, which are implicated in chemotaxis and a proinflammatory Th17 response, respectively. In contrast, an upregulation of Gfi1 in the liver suggests an anti-inflammatory environment. Conclusions FVIII co-localizes predominantly with marginal zone macrophages (MARCO+ ) in the murine spleen following intravenous infusion. Targeting pathways that are implicated in the early FVIII innate immune response in the spleen may lead to therapeutic interventions to prevent inhibitor formation.

In the treatment of hemophilia A, the 20%-30% risk of developing of anti-factor VIII (FVIII) antibodies, or inhibitors, is the dominant concern among healthcare providers. Immune tolerance induction remains the only effective method of eradicating inhibitors in approximately 75% of patients, but is accompanied by significant emotional and economical burden. While certain risk factors, such as the type of FVIII mutation, offer some insight, there remains no strategy to confidently predict the development of an inhibitor. Moreover, even if such a predictive tool existed, there is currently no proven protocol for tolerance induction of a previously untreated patient. In recent years, the growing body of knowledge concerning the fundamental immunology of inhibitors has shed light on potential therapeutic interventions. In this review, we highlight these new findings and their influences on translational medicine.

Acute appendicitis (AA) is among the most common causes of acute lower abdominal pain leading patients to the emergency department. Significant debate remains on whether AA should be operated or not. A propensity score-matched analysis was performed in seven Italian Hospitals, with the aim to assess safety and feasibility both nonoperative management with antibiotics (AT) and surgical therapy with appendectomy (ST) for patients with AA. Data regarding all patients discharged from the participating centers with a diagnosis of appendicitis from January 1st, 2014 to December 31st, 2014 were collected retrospectively. Follow-up data were collected from January 1st, 2015 to December 31st, 2016. The complication-free treatment success of AT (53.7%) was significantly inferior to that of ST (86.4%) (P

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing disease that affects upper and lower motor neurons eventually leading to paralysis and death by respiratory dysfunction. The most common genetic variant among ALS patients is a hexanucleotide repeat expansion within the first intron of the gene C9ORF72. This expansion elicits a complex cascade of events as a result of both gain- and loss-of-function mechanisms that contribute to neurodegeneration. Increasing evidence suggests that this repeat expansion in C9ORF72 also influences the immune homeostasis. In this review, we consolidate the current understanding of C9ORF72-mediated pathogenesis in both the central nervous system and peripheral immune system and propose mechanisms by which the immune system contributes to ALS.

Objectives Ovarian cancer stem-like cells (CSCs), which can form non-adherent sphere cells in a stem-cell selection culture system, exhibit stemness and drug resistance to chemotherapeutics, which are properties not observed in differentiated cells. Recent studies have demonstrated that Kruppel-like factor 5 (KLF5) is involved in cell proliferation and mediates cell survival and tumourigenesis. Here, we investigated the role of KLF5 and its downstream target survivin, in strengthening drug resistance of ovarian CSCs. Materials and methods Ovarian cancer cell line SKOV3 was cultured under serum-free conditions and differentiating conditions to promote formation of sphere cells and differentiated cells, respectively. siRNA-KLF5 was used to knock down KLF5, and survivin expression vector was used to overexpress survivin. Cells were further analysed by qPCR, immunofluorescence staining and western blotting. Chromatin immunoprecipitation (ChIP) assay and electrophoretic mobility shift assay (EMSA) were performed to investigate the relationship between KLF5 and survivin expression. Drug resistance was examined by MTT and apoptosis assays. Results KLF5 was highly expressed in the ovarian cancer cell line SKOV3 sphere cells, accompanied by elevated survivin expression. Silencing KLF5 by small interfering RNA in sphere cells down-regulated survivin expression, which also sensitized the sphere cells to apoptosis induced by chemotherapeutic drugs (cisplatin or paclitaxel). Furthermore, ChIP assay, survivin overexpression and EMSA results indicated that KLF5 controlled survivin expression by directly binding the surivin promoter in the cells. Conclusions The KLF5-mediated signalling pathway is a potential target for elimination of ovarian CSCs.

Aim: Vascular endothelial growth factor (VEGF) and VEGF receptor are over-expressed in lymphomagenesis. The aim of this study was to evaluate the usefulness of 123 I-VEGF165 scintigraphy for imaging of B-cell lymphoma of the Mucosa-Associated Lymphoid TissueMALT lymphoma). Methods: Three Patients (age range: 52-71 years) with histopathological verified MALT lymphoma were included in the study. Two patients had disseminated MALT-lymphoma and one patient had parotid MALT-lymphoma with involvement of cervical lymph nodes. Recombinant VEGF165 was radiolabeled with 123 I by electrophilic radioiodination using the chloramine T method. Each patient received 172 MBq (

In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25% to 30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, which could be either recombinant or plasma derived. Differential immunogenicity of these concentrates has been documented in several recent epidemiologic studies, thus generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus regarding how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this article, we complement the existing epidemiologic investigations with an overview of the range of possible biochemical and immunologic mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.

Nine obese postmenopausal women aged 59±6.3 years having a body mass index of 35.2±2.0 kg/m2 performed a 12-week training protocol three times a week. Each training session, lasting about 80 min, consisted of general warmup and stretching exercises, free-body exercises, exercises with small implements (clubs, dumbbells, medicine ball), aerobic activity consisting of walking/running on the treadmill or open ground and cooling-down exercises. The training impulse method was utilized to indirectly quantify the amount of exercise intensity on the basis of heart rate values assessed during training sessions. The value adopted for training impulses prescribed for patients was about 130 arbitrary units and corresponded to 50 ∼ 60% of their maximum oxygen consumption. Immediately before and at the end of the training patient took an incremental cycle-ergometer test (20W every 3 min), up to exhaustion, in such a way as to assess maximum values of: oxygen consumption, workload and the ratio between these two variables (i.e. the oxidative cost), heart rate, systolic and diastolic arterial blood pressures. At the trial end, in correspondence of the maximum workload reached during the cycle-ergometer exercise, both body mass and body mass index had significantly decreased, as had diastolic arterial blood pressure and oxidative cost of exercise, while fat free mass had increased, when refered to the trial entry. It can be concluded that the precise amount of training, as established by utilizing training impulses, may facilitate the choice of the strategy to ameliorate physical and mental health in postmenopausal obese women.

To determine how robotic prostatectomy affects practice patterns of urologists, we examined the case volume characteristics among certifying urologists for the surgical treatment of prostate cancer. We hypothesized that the utilization of open and robotic prostatectomy as well as lymph node dissection changed dynamically over the last 10 years.A total of 6-month case log data of certifying urologists from 2003 to 2013 were obtained for the American Board of Urology. Cases were identified using Current Procedural Terminology codes for open radical prostatectomy (ORP) and laparoscopic or robotic-assisted laparoscopic prostatectomy (RALP) with a corresponding diagnosis of prostate cancer as defined by ICD-9 code 185.0.A total of 6,563 urologists submitted case logs, of which 68% (4,470/6,563) reported performing at least one radical prostatectomy (RP), totaling 46,030 RPs logged. There was a 376% increase in the performance of RALP over the study period with robotic volume increasing from 22% of all RP in 2003 to 85% in 2013. Among surgeons performing ORP, the median number performed was 2; of surgeons who performed RALP, the median number performed was 8 (P0.001). Overall, 39% of surgeons logging ORP performed 2 or fewer RP, whereas 19% of surgeons who performed RALP performed 2 or less RP (P0.001). The highest volume robotic surgeons (top 10% surgical volume) performed 41% of all RALP with the highest performing robotic surgeon recording 658 prostatectomies over 6 months. Oncologists represented 4.1% of all surgeons performing RP and performed 15.1% of all RP (P0.001); general urologists performed the majority of RP (57.8%). When performed open, there was no influence of surgeon specialty on the performance of lymph node dissection (LND); if performed robotically, oncologists were significantly more likely to perform LND compared with general surgeons (47% vs. 25.9%, respectively, P0.001).Robotic prostatectomies are performed 5 times more commonly than open prostatectomy and represent 85% of all RP performed by board-certified urologists in 2013. Compared to RALP, ORP are significantly more likely to be performed by lower volume surgeons. Oncologists perform a higher relative percentage of RPs and are significantly more likely to perform LND if performed robotically when compared with general urologists.

Objective: Vascular endothelial growth factor (VEGF) is an important angiogenic factor, and its receptors have been shown to be overexpressed in various human carcinomas. In this study, we investigated the role of scanning with iodine-123 (123I)-labelled VEGF165 in patients with highly malignant osteosarcoma. Methods: Two patients (a 15-year-old female and a 14-year-old male) with osteosarcoma were injected with 140 MBq [165 per patient] of 123I-VEGF165. Dynamic acquisition was initiated immediately after administration and carried out until 30 min after injection. Whole-body images were done in anterior and posterior views at various time points. All patients underwent single-photon emission tomography imaging. Results:123I-VEGF165 scans were positive in these patients. Sequential images clearly showed increased 123I-VEGF165 activity in osteosarcoma lesions. The tumour lesions were still visualized in whole-body images and single-photon emission tomography examinations 2 h after injection. Intravenous injection of 123I-VEGF165 did not cause any side effects. Conclusion: Our results suggest that 123I-VEGF165 receptor scintigraphy may be useful for the visualization of highly malignant osteosarcoma and/or metastasis and the angiogenic activity of the tumour.

The cytomegalovirus (CMV) promoter is considered to be one of the strongest promoters for driving the in vivo expression of genes encoded by DNA vaccines. However, the efficacy of DNA vaccines has so far been disappointing (particularly in humans), and this might be explained in part by histone deacetylase (HDAC)-mediated chromatin condensation. Hence, we sought to investigate whether increasing the expression of DNA vaccine antigens with the HDAC inhibitor OSU-HDAC42 would enhance the efficacy of DNA vaccines in vivo. A luciferase assay was used to determine the effects of OSU-HDAC42 on CMV promoter-driven DNA plasmids in vitro and in vivo. Three HDAC inhibitors were able to activate expression from the CMV promoter in NIH3T3 cells and MBT-2 bladder cancer cells. The expression of luciferase was significantly enhanced by co-administration of pCMV-luciferase and OSU-HDAC42 in mice. To explore whether OSU-HDAC42 could enhance the specific antitumor activity of a neu DNA vaccine driven by the CMV promoter, we evaluated therapeutic effects and immune responses in a mouse tumor natively overexpressing HER2/neu. Mice receiving OSU-HDAC42 in combination with the CMV-promoter neu DNA vaccine exhibited stronger antitumor effects than mice given the DNA vaccine only. In addition, a correlation between the antitumor effects and the specific cellular immune responses was observed in the mice receiving the DNA vaccine and OSU-HDAC42.

Inflammatory signals such as pathogen- and danger-associated molecular patterns have been hypothesized as risk factors for the initiation of the anti-factor VIII (FVIII) immune response seen in 25% to 30% of patients with severe hemophilia A (HA). In these young patients, vaccines may be coincidentally administered in close proximity with initial exposure to FVIII, thereby providing a source of such stimuli. Here, we investigated the effects of 3 vaccines commonly used in pediatric patients on FVIII immunogenicity in a humanized HA murine model with variable tolerance to recombinant human FVIII (rhFVIII). Mice vaccinated intramuscularly against the influenza vaccine prior to multiple infusions of rhFVIII exhibited a decreased incidence of rhFVIII-specific neutralizing and nonneutralizing antibodies. Similar findings were observed with the addition of an adjuvant. Upon exposure to media from influenza- or FVIII-stimulated lymph node or splenic lymphocytes, naive CD4(+) lymphocytes preferentially migrated toward media from influenza-stimulated cells, indicating that antigen competition, by means of lymphocyte recruitment to the immunization site, is a potential mechanism for the observed decrease in FVIII immunogenicity. We also observed no differences in incidence or titer of rhFVIII-specific antibodies and inhibitors in mice exposed to the live-attenuated measles-mumps-rubella vaccine regardless of route of administration. Together, our results suggest that concomitant FVIII exposure and vaccination against influenza does not increase the risk of inhibitor formation and may in fact decrease anti-FVIII immune responses.

The development of neutralizing anti-factor VIII (FVIII) antibodies (inhibitors) remains a major challenge for FVIII replacement therapy in hemophilia A patients. The adaptive immune response plays a crucial role in the development and maintenance of inhibitors. In this review, we focus on our current understanding of FVIII interactions with cells of the adaptive immune system and the phenotype of the resultant response. Additionally, we examine both current and novel FVIII tolerance induction methods that function at the level of the adaptive immune response.

The term “obesity paradox” corresponds to the research observation that overweight or obese patients may counterintuitively have a survival benefit once a disease is established. This appears also true in type 2 diabetes mellitus, where it has been shown that being overweight or obese is associated with better survival. The reasons behind this paradox remain unclear but likely derive from an intricate relationship between insulin resistance, fat storage, and inflammatory responses in type 2 diabetes. In this review, we look at what the potential mechanisms may be underlying this paradox.

Background There is evidence to suggest osteoporosis may result in premature tooth loss. The pathology behind this relationship is poorly understood. A correlation with osteoporosis and greater susceptibility to periodontal disease has been suggested. Objectives To investigate the association between osteoporosis and periodontal disease, accounting for the effect of confounding variables of age, smoking status and oral hygiene. Setting Three hundred and fifty-nine postmenopausal women aged 45-70 years were recruited from the Greater Manchester area between March 2008 and June 2010. Subjects and methods Data were collected on osteoporosis status, smoking status, pocket probing depths, suppuration, plaque, bleeding and calculus indices. Dental panoramic tomographs were taken and periodontal bone support assessed on all teeth. Data were analysed using SPSS software (version 20). Results Complete data were available for 348 patients. Twenty-six percent (91) of individuals were osteoporotic. Logistic regression was used. The relationship between osteoporosis status and moderate to severe periodontal disease of both molar teeth and the whole mouth was not significant (p = 0.088 and p = 0.296 respectively). Conclusions Osteoporosis is not a causal factor in the development of moderate to severe chronic periodontitis.

Fibulin-2 (FBLN2) has been identified as a candidate tumor-suppressor gene in nasopharyngeal carcinoma (NPC). Originally identified through a chromosome 3 NotI genomic microarray screen, it shows frequent deletion or methylation in NPC. FBLN2 is located on chromosome 3p25.1 and is associated with tumor development through its important interactions with the extracellular matrix (ECM) proteins. FBLN2 encodes two isoforms. The short isoform (FBLN2S) is expressed abundantly in normal tissues, but is dramatically downregulated in NPC, while the long isoform (FBLN2L) is either not detectable or is expressed only at low levels in both normal and tumor tissues. Reintroduction of this FBLN2S inhibited cell proliferation, migration, invasion and angiogenesis in vitro. Furthermore, in vivo studies in nude mice show its expression is associated with tumor and angiogenesis suppression. FBLN2-associated angiogenesis occurs via concomitant downregulation of vascular endothelial growth factor and matrix metalloproteinase 2. This study provides compelling evidence that FBLN2S has an important tumor-suppressive and anti-angiogenic role in NPC.

Pulmonary epithelium is known to undergo a preneoplastic process prior to the development of lung carcinoma. Squamous dysplasia and atypical adenomatous hyperplasia have been identified and classified as preinvasive lesions of squamous cell carcinoma and peripheral pulmonary adenocarcinoma, respectively. However, these commonly recognized preinvasive lesions do not completely explain the development of all histological types of lung carcinoma. By examining 114 resection lung specimens, we concluded that there are four histological patterns of bronchial epithelial dysplasia based on morphological features (basal cell dysplasia, columnar cell dysplasia, bronchial epithelial dysplasia with transitional differentiation, and squamous dysplasia). The histological patterns were further characterized by immunohistochemistry. Basal cell dysplasia was focally positive for cytokeratin (CK) 17 and 10/13; columnar cell dysplasia was generally positive for CK7, 8, and 18; bronchial epithelial dysplasia with transitional differentiation had a heterogeneous immunoprofile, while squamous dysplasia was positive for CK10/13 and focally positive for CK17. Various degrees of abnormal expression of p53 and Ki-67 were found in the different types of bronchial epithelial dysplasia. The cases were divided into three groups based on degree and extent of bronchial epithelial dysplasia. By Crosstabs McNemar test, the Mann-Whitney U-test (for two independent groups), the Kruskal-Wallis one-way nonparametric ANOVA (for >2 independent groups) and Spearman correlation analysis, the degree and extent of bronchial epithelial dysplasia was shown to be positively correlated with the incidence of bronchogenic carcinoma and multifocal primary lung carcinoma (P

Introduction: The etiology of inhibitory factor VIII (FVIII) antibodies in 25-30% of hemophilia A (HA) patients remains poorly understood. It is possible that concurrent exposure to inflammatory stimuli, or ‘danger signals’, with FVIII increases the risk of inhibitor formation. HA patients generally begin FVIII replacement therapy around 12 months of age, and the median age of inhibitors onset is between 15-21 months. During this time frame, patients may be exposed to vaccines, such as the mumps-measles-rubella (MMR) and seasonal influenza vaccines. Our investigation is the first to address the concern that these vaccines may serve as danger signals that augment FVIII immunogenicity. Methods: Our studies used 8-12 week-old FVIII E17KO C57Bl6/S129 HA mice, which carry a complete knockout of all murine MHC class II molecules, and instead express a chimeric human-mouse HLA-DRB1*1501 allele associated with increased inhibitor risk. Our preliminary studies show that 40-80% of these animals develop FVIII inhibitors following treatment. HA mice were immunized with 10x the standard human dose of live-attenuated MMR vaccine (Priorix) subcutaneously or intravenously 24 hrs prior to 4 weekly intravenous infusions of 2 IU recombinant human FVIII (rhFVIII, Advate). Mice were subsequently re-challenged with MMR 24 hrs prior to 4 biweekly infusions of 6 IU rhFVIII. Blood samples were collected retro-orbitally or via cardiac puncture. Plasma from weeks 5 and 9 was assessed for anti-FVIII IgG by ELISA; inhibitor concentrations were assessed by a Bethesda assay on week 9. The inactivated influenza vaccine (Agriflu) was administered at standard human doses either intramuscularly or intravenously 24 hrs before, after, or concurrently with the first of 7 biweekly infusions of 6 IU rhFVIII. Week 5 plasma samples were subjected to anti-FVIII and anti-influenza IgG ELISA and Bethesda assays. Statistical comparisons were made using the Fisher’s exact Mann-Whitney U tests, as appropriate. Results: Subcutaneous MMR vaccination exhibited no significant differences in the incidence or titres of anti-FVIII IgG compared to HBSS-injected controls at weeks 5 and 9 (n=13). Similarly, no differences in the incidence or concentration of inhibitors were detected at week 9. We next evaluated the effects of intravenous MMR immunization on FVIII immunogenicity. Surprisingly, we again observed no differences in the incidence or magnitude of the anti-FVIII immune response at weeks 5 and 9 (n=28-30). Importantly, we found a significant decrease in the incidence of FVIII-specific IgG in mice that were immunized intramuscularly with the influenza vaccine 24 hrs after and at the same time as the first infusion of rhFVIII (t=-24 hrs: 30%, t=0 hrs: 20%, t=+24 hrs: 26% vs control: 67%; p=0.11, 0.06, 0.04; n=10-15). Similarly, there was a significant decrease in the incidence of inhibitors at all immunization time points (t=-24 hrs: 30%, t=0 hrs: 43%, t=+24 hrs: 11% vs control: 80%; p=0.03, 0.02, 0.0022). No differences in IgG titres or inhibitor concentrations were detected. When immunized intravenously with the influenza vaccine, we observed an increase in the presence of FVIII-specific IgG, but no differences in titres. However, these differences were not statistically significant and need confirmation (t=-24 hrs: 80%, t=0 hrs: 90%, t=+24 hrs 40% vs control: 50%; p=0.58, 0.14, 1.00; n=5-10). Conclusion: These are the first experimental studies to address vaccination as a potential danger signal in the development of an anti-FVIII immune response. Our results suggest that both subcutaneous and intravenous immunization of HA mice with the MMR vaccine do not influence the incidence or magnitude of the anti-FVIII immune response. In contrast, our data suggest that intramuscular immunization with the inactivated influenza vaccine modulates the anti-FVIII immune response and may enhance tolerance induction to FVIII, possibly through antigen competition. However, this proposal awaits further confirmation. Finally, a trend in increased antibody and inhibitor incidence in intravenously immunized mice suggests that the influenza vaccine can serve as a danger signal, but is dependent on the route of administration. Our findings contradict current vaccination concerns in the treatment of young HA patients, and instead suggest an inhibitor-protective effect from influenza immunization. Disclosures Moorehead: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Steinitz:Baxter: Employment. Reipert:Baxter: Employment. Hough:Bayer: Research Funding. Lillicrap:Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding.

A previous study has shown that UV activates the PI3K/AKT cell survival pathway while inducing cell death in human skin in vivo and cultured human keratinocytes in vitro, and yet the upstream pathway leading to the activation of AKT has not been thoroughly investigated. In this study we found that UV-induced phosphorylation of p38 and AKT in a time-dependent manner. The phosphorylation of p38 started at 5 min post UV irradiation, peaked at about 30 min, and remained elevated up to 2 h. The phosphorylation of AKT started at 15 min post UV treatment, peaked at about 1 h, and remained elevated up to 2 h. We also found that H2O2 induced phosphorylation of p38 and AKT in a time- dependent manner. Pretreatment with NAC abolished UV-induced AKT phosphorylation, suggesting the involvement of reactive oxygen species in AKT activation. Interestingly, SB203085, a known p38 inhibitor, had partially inhibited UV-induced AKT phosphorylation. Further studies showed that cytokines such as TNF-alpha and IL-1beta induced AKT phosphorylation in a time-dependent manner. Pretreatment with SB203085 inhibited IL-1beta-induced p38 and AKT phosphorylation. Collectively, our data suggest that UV activation of PI 3-kinase/AKT pathway is initiated by ROS and prolonged by feedback activation of p38 induced by released cytokines in response to UV irradiation in cultured human keratinocytes.

Suitable silicon-oxynitride films for constructing the attenuated phase shifting masks to be operated in the 157 nm excimer laser regime are obtained by varying the gas flow rations in a RF sputtering process. Characteristics of the films such as optical constants, material compositions, etching selectivity, surface profiles, and adhesion strength are experimentally analyzed. These results indicate that he silicon-oxynitride films thus fabricated can meet the requirements for building such APSM's working in the wavelength of 157 nm.

Summary: This study investigates the birthweight, gestational age, and body proportions of home births in a malarious area of Papua New Guinea. A population based cohort of pregnant women was followed longitudinally through pregnancy. Within the first few days of birth anthropometric measures were taken and a gestational age assessment made. Of the 121 live singleton infants, forty per cent were low birthweight and the preterm rate was 4 per cent. Infants appeared to be proportionally growth retarded. Low birthweight was associated with short maternal stature, and preterm delivery with maternal illness. Mean birthweight derived from hospital statistics of babies born to women from the same area was higher than the mean derived from this population based study.

IntroductionThe increase of immigrants in Canada has set an example for Western countries on how cultural diversity affects health, mental health, and needs. The mental health of elderly immigrants, however, is often forgotten in service delivery system.ObjectivesThis paper examines the socio-cultural determinants of mental health of elderly immigrants in Canada through synthesizing research findings from various studies. The presentation aims to highlight a few key intervention focuses for addressing mental health of this vulnerable immigrant subgroup.MethodsSecondary data analysis was used, using three national surveys and a local community survey, including the Ethnic Diversity Survey, the General Social Survey, the Health and Well Being of Older Chinese in Canada, and the Health and Well Being of Older South Asian in Calgary. Mental health was presented by life satisfaction, self-reported stress, self-reported happiness, self-reported level of trust, sense of belonging, feeling out of place, worrying about hate crime, depressive symptoms, and general mental health measured by SF-36.ResultsSocio-cultural determinants related to a higher level of social support, a higher level of trust, and better financial resources were found to be correlates of more positive mental health. Racial discrimination, culture related beliefs, and barriers often led to negative mental health outcomes.ConclusionsPromoting a better mental health should expand beyond the use of individual interventions and treatments. Socio-cultural determinants have to be addressed through creating a more positive social and structural environment for the elderly immigrants.

e20691 Background:Febrile neutropenia (F/N) is a relatively common and serious side effect for oncology patients undergoing chemotherapy. Due to varying dosages and frequency of cytotoxic agents administered to oncology patients, the incidence and grade of neutropenia varies. The purpose of this study was to establish the frequency of febrile neutropenia in different chemotherapy regimens. Methods: Data was collected on 343 patients who underwent chemotherapy over a 9 month period. Regimens that caused at least one episode of febrile neutropenia in patients within that period were assessed in the study. A list of the patients on identified chemotherapy regimens during the time period was generated by the pharmacy department. Data on patients who had febrile neutropenia was obtained from their clinical notes. Clinical data was then obtained on all those patients. This information was then used to compare the frequency of febrile neutropenia in the included chemotherapy regimens. Results: 343 patients were included in this study. Of those, 41 patients developed febrile neutropenia within the 9 month period (11%); there were 49 cases of febrile neutropenia (14%) in total as some patients had more than one episode. Conclusions: Febrile neutropenia (FN) is a known potential side-effect from treatment with chemotherapy. This study highlights the rates of FN in patients treated within one centre. In patients being treated with specific chemotherapy regimens this study may guide the increased use of G-CSF and better outline the risk profile of such therapy to patients. [Table: see text] No significant financial relationships to disclose.

Ultrathin TiO2 amorphous films are deposited on ultraviolet grade fused silica substrates and CaF2 by using rf reactive unbalanced magnetron sputtering from a Ti metal target in atmosphere of Ar and O2. For an O2/Ar flow rate ratio of more than 1.5, the deposited TiO2 thin films are stoichiometric. TiO2 thin films that meet the optical requirements of a high transmittance attenuated phase-shifting mask (HTAPSM) at 157 and 193 nm wavelengths can also be properly inspected since the transmittance at 257 nm wavelength is less than 28%. The simulated thickness range of such a TiO2 thin film is found to be between 16 and 20 nm. A TiO2 amorphous thin film with thickness of 23.5 nm, transmittance of 24.9% and reflectance of 15.0% at wavelength of 193 nm, transmittance of 16.3% at 157 nm wavelength and transmittance of 23.0% at 257 nm wavelength is shown to be able to serve as an absorber layer for HTAPSM blanks at 157 and 193 nm wavelength.