Analysis of Step Therapy Reform on Floridians with Autoimmune Conditions

Background: Step therapy is a cost-saving measure employed by insurance companies to reduce rising drug costs; however, studies have indicated this policy has neutral or – in some cases – negative effects on patients. Specifically for indivdiuals with autoimmune diseases, the delay of proper treatment, increased risk of negative, irreversible side effects, and an underdeveloped preferred drug lists harm autoimmune patients because of the disconnect between the heterogeneity of autoimmune disease and the one-size-fits-all approach of step therapy. Objective: To determine the most effective policy for dealing with the harms of step therapy as they currently affect Floridians. Methods: Five policy options, gathered from various research experts in the field, named Insurance Company Directed Reform, Patient Direct Reform, Complete Reform, Insurance Company Directed Reform only for autoimmunity, and Patient Directed Reform only for autoimmunity were review and judged on a scale from 1 to 10, the higher the number indicating a more beneficial rating, with respect to feasibility, benefits to insurance companies, benefits to patients, and benefits to physicians. The rankings of each evaluative criteria were averaged to determine the most beneficial policy. Results: Insurance Company Directed Reform only for autoimmunity ranked lowest with an average score of 4.25. Patient Directed Reform ranked fourth with an average score of 4.375. Insurance Company Directed Reform ranked third with an average score of 4.5 followed by Patient Directed Reform with an average score of 5.5. Finally, Complete Reform had the highest average score of 5.625. Conclusion: After the evaluation, Complete Reform which includes clinical review reform, transparency and rereporting requirements, exemptions criteria, and a streamlined appeals process ranked the highest. It will increase all patients’ access to appropriate, doctor-prescribed medication in a timely manner dramatically increasing health while preserving physician autonomy and protecting insurance companies’ revenues

Effects of Deficit and Cutoff Irrigation During Different Phenological Stages of Fruit Growth on Production in Mature Almond Trees cv. 'Mamaei'

Abstract Regulated deficit irrigation (RDI) is commonly used during different phenological stages of fruit growth and development in almond trees to reduce the amount of irrigation water applied without or with only very small reductions in yield. Therefore, to study the effects of deficit and cutoff irrigation during different phenological stages of fruit growth and development in almond cv. "Mamaei" production, an experiment was carried out in a split plot on randomized block design with three replications. The main plots were three different phenological stages of fruit growth and development i.e. Stage I (fruit growth period), Stage II (kernel growth period) and stage III (preharvest period). The subplots had different irrigation regimes, namely T1= 100% ETc (Full irrigation), T2= 80% ETc (deficit irrigation), T3= 40% ETc (deficit irrigation) and T4= 0% ETc (cutoff or drought period). Traits such as fruit size (length, width and diameter), fresh and dry weight of fruit, fresh and dry weight of kernel, percentage of fruit drop, kernel percentage and yield were measured. The results showed that deficit and cutoff irrigation during stage-I decreased fruit size, both fresh and dry weight of fruit. Deficit and cutoff irrigation during stage-II decreased fruit fresh weight, fresh and dry weights of kernel, but no significant differences were observed for the measured traits when irrigation treatments were applied at stage III. These results indicated that preharvest stage (stage III) in 'Mamaei' cultivar has low sensitivity to deficit irrigation. Therefore, it is concluded that deficit irrigation with 40% of full irrigation (%40 ETc) during stage III for two months prior to harvest can be used without considerable reduction of yield for this cultivar under the climatic conditions in Saman region

Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology

Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches

Genomics in premature infants: A non-invasive strategy to obtain high-quality DNA

We used a cost-effective, non-invasive method to obtain high-quality DNA from buccal epithelial-cells (BEC) of premature infants for genomic analysis. DNAs from BEC were obtained from premature infants with gestational age ≤ 36 weeks. Short terminal repeats (STRs) were performed simultaneously on DNA obtained from the buccal swabs and blood from the same patient. The STR profiles demonstrated that the samples originated from the same individual and exclude any contamination by external DNAs. Whole exome sequencing was performed on DNAs obtained from BEC on premature infants with and without necrotizing enterocolitis, and successfully provided a total number of reads and variants corroborating with those obtained from healthy blood donors. We provide a proof of concept that BEC is a reliable and preferable source of DNA for high-throughput sequencing in premature infants

Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis?

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52). Neonates with TGFβ-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08-0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01 - 8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09-19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFβ-1 (rs2241712) were associated with NEC- related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC

Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

This is the peer reviewed version of the following article: Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut 64.12 (2015): 1921-1935 and which has been published in final form at http://dx.doi.org/10.1136/gutjnl-2014-308935OBJECTIVES: The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour-associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance. DESIGN: Microarray analyses, tumour microarray immunohistochemical assays, in vitro co-culture experiments, recombinant protein treatment approaches and in vivo intervention studies were performed to understand the role that the immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) plays in PDAC biology. RESULTS: We found that hCAP-18/LL-37 was strongly expressed in the stroma of advanced primary and secondary PDAC tumours and is secreted by immune cells of the stroma (eg, tumour-associated macrophages) in response to tumour growth factor-β1 and particularly CSC-secreted Nodal/ActivinA. Treatment of pancreatic CSCs with recombinant LL-37 increased pluripotency-associated gene expression, self-renewal, invasion and tumourigenicity via formyl peptide receptor 2 (FPR2)- and P2X purinoceptor 7 receptor (P2X7R)-dependent mechanisms, which could be reversed by inhibiting these receptors. Importantly, in a genetically engineered mouse model of K-Ras-driven pancreatic tumourigenesis, we also showed that tumour formation was inhibited by either reconstituting these mice with bone marrow from cathelicidin-related antimicrobial peptide (ie, murine homologue of hCAP-18/LL-37) knockout mice or by pharmacologically inhibiting FPR2 and P2X7R. CONCLUSIONS: Thus, hCAP-18/LL-37 represents a previously unrecognised PDAC microenvironment factor that plays a critical role in pancreatic CSC-mediated tumourigenesis.CH: ERC Advanced Investigator Grant (Pa-CSC 233460), European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 256974 (EPC-TM-NET) and n° 602783 (CAM-PaC), the Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PS09/02129 & PI12/02643) and the Programa Nacional de Internacionalización de la I+D, Subprogramma: FCCI 2009 (PLE2009-0105; both Ministerio de Economía y Competitividad (es), Spain), BSJr: Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain and Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY, NY. MC: La Caixa Predoctoral Fellowshi

Primary subcutaneous cyst hydatic disease in proximal thigh: an unusual localisation: a case report

BACKGROUND: Musculoskeletal hydatidosis is very rare and represents 1% – 5.4% of all cases of echinococcosis. On clinical basis, infection mimics a soft-tissue tumor, and the preoperative radiological diagnosis is very important to avoid biopsy. CASE PRESENTATION: We report an unusual case of primary subcutaneous hydatidosis in proximity to vastus lateralis muscle. It was diagnosed according to the computed tomography appearance, clinical and pathological findings. A 43 year old female patient was admitted with a history of pain at proximal thigh for the last 30 days. On physical examination, a mass which was 4 × 5 cm in diameter, painful and erythamatous, was palpated over greater trochanter. Sedimentation rate was 40 mm in the first hour. CT (Computed Tomography) scan demonstrated, a soft tissue mass with central cystic component in the subcutaneous tissue near vastus lateralis muscle. Histopathological examination of the specimen revealed a pericystic structure, which consisted of connective tissue and scattered hyaline cells showing a necrotic basophilic structure that resembled a cuticular membrane. Treatment with high dose albendazole was conducted for 4 weeks. CONCLUSIONS: This case illustrates that echinococcal disease should be considered in the differential diagnosis of every cystic mass in every anatomic location, especially when they occur in areas where the disease is endemic

Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats

Background: Aging influences immune response and susceptibility to EAE in a strain specific manner. The study was designed to examine influence of aging on EAE induction in Albino Oxford (AO) rats. Results: Differently from 3-month-old (young) rats, which were resistant to EAE induction, the majority of aged (24-26-month-old) rats developed mild chronic form of EAE. On 16th day post-immunization, when in aged rats the neurological deficit reached plateau, more mononuclear cells, including CD4+ T lymphocytes was retrieved from spinal cord of aged than young rats. The frequencies of IL-17+ and GM-CSF+ cells within spinal cord infiltrating CD4+ lymphocytes were greater in aged rats. To their increased frequency contributed the expansion of GM-CSF + IL-17 + IFN-gamma+ cells, which are highly pathogenic in mice. The expression of the cytokines (IL-1 beta and IL-23/p19) driving GM-CSF + IL-17 + IFN-gamma + cell differentiation in mice was also augmented in aged rat spinal cord mononuclear cells. Additionally, in aged rat spinal cord the expansion of GM-CSF + IL-17-IFN-gamma- CD4+ T lymphocytes was found. Consistently, the expression of mRNAs for IL-3, the cytokine exhibiting the same expression pattern as GM-CSF, and IL-7, the cytokine driving differentiation of GM-CSF + IL-17-IFN-gamma- CD4 + lymphocytes in mice, was upregulated in aged rat spinal cord mononuclear cells, and the tissue, respectively. This was in accordance with the enhanced generation of the brain antigen-specific GM-CSF+ CD4+ lymphocytes in aged rat draining lymph nodes, as suggested by (i) the higher frequency of GM-CSF+ cells (reflecting the expansion of IL-17-IFN-gamma- cells) within their CD4+ lymphocytes and (ii) the upregulated GM-CSF and IL-3 mRNA expression in fresh CD4+ lymphocytes and MBP-stimulated draining lymph node cells and IL-7 mRNA in lymph node tissue from aged rats. In agreement with the upregulated GM-CSF expression in aged rats, strikingly more CD11b + CD45(int) (activated microglia) and CD45(hi) (mainly proinflammatory dendritic cells and macrophages) cells was retrieved from aged than young rat spinal cord. Besides, expression of mRNA for SOCS1, a negative regulator of proinflammatory cytokine expression in innate immunity cells, was downregulated in aged rat spinal cord mononuclear cells. Conclusions: The study revealed that aging may overcome genetic resistance to EAE, and indicated the cellular and molecular mechanisms contributing to this phenomenon in AO rats