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Research Article - (2014) Volume 5, Issue 3
Association of Protein Tyrosine Phosphatase Non-receptor, Type 22 (PTPN22) C1858T Polymorphism with Type 1 Diabetes in North India: A Replication Study
Rajni Rani*, Neetu Israni, Avinash Kumar, Smreti Vasudevan and Jaya Singh
Molecular Immunogenetics Group, National Institute of Immunology, India
*Corresponding Author: Rajni Rani, Molecular Immunogenetics Group, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi-110067, India, Tel: 9111- 26703545, Fax: 9111-26742125 Email:
Objective: Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where several genes have been associated with the disease. While the major histocompatibility complex has been shown to be the major locus, contributions of other loci in different combinations seem to have synergistic effects. PTPN22 (Protein tyrosine phosphatase non-receptor, type 22) gene encoding lymphoid tyrosine phosphatase (LYP) is a negative regulator of T cell signaling. A gain of function mutant at nucleotide position 1858 C>T has been associated with diabetes, however, it is reported to be absent in Asians. We have studied PTPN22 C1858T polymorphism in T1D patients from North India since there are no reports from this region.
Methods: PTPN22 C1858T polymorphism was studied in 250 T1D patients and 480 healthy controls using polymerase chain reaction followed by restriction digestion (PCR-RFLP). Alleles of HLA-DRB1 locus were studied using PCR followed by hybridization with sequence specific oligonucleotide probes using a bead based assay on Luminex platform.
Results: In spite of reports of absence of 1858T allele in Asians, we observed this allele to be present in North Indians, albeit with low frequency (1.98%). However, T1D patients from the same ethnic background showed significantly higher frequency of the allele and heterozygous genotype 1858CT as compared to controls. Patients with both 1858CT and 1858CC genotypes had predisposing MHC alleles.
Conclusion: The association of PTPN22 1858CT genotype with Type 1 diabetes was independent of the predisposing Human leukocyte antigen (HLA) alleles DRB1*03:01, DRB1*04:01, DRB1*04:05 in North Indian patients, suggesting their integrated roles in manifestation of T1D. Based on the reported role of PTPN22 1858CT genotype in defective innate immune responses against viral infections, and defects in early T cell signaling, it is tempting to speculate that it may be detrimental for the destruction of pancreatic beta cells in the present scenario.
Keywords: PTPN22, Major histocompatibility complex, Type 1 diabetes
Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where insulin producing pancreatic beta cells are lost before the manifestations of the disease. It has an incidence of 10.5/100,000/ year in India [1]. Several genetic and environmental factors have been implicated as the causative factors, however, a role of complex interaction of these factors leading to the autoimmune destruction of the pancreatic beta cells cannot be ruled out [2]. The cell-mediated autoimmune destruction of pancreatic beta cells is brought about by infiltrating macrophages and lymphocytes in the pancreatic islets, the phenomenon known as Insulitis. While the function of most T-cells is to mount host-defense response, regulatory T-cells are programmed to moderate the reactivity of effector T-cells, in order to protect the body from autoimmune responses. It has been proposed that an increase in the ratio of effector T-cells to regulatory T-cells may result in autoimmunity in T1D [3]. Both CD4+ helper T cells and CD8+ Cytotoxic T cells are the effector T cells required to induce beta cell autoimmunity [4]. Defects in T cell signaling may be involved in altering the ratios of effector and regulatory T cells.
Of the 20 genomic intervals implicated in the predisposition for development of T1D [5], we and others have reported association of T1D with the major histocompatibility complex (MHC) alleles on chromosome 6p21 and the 5' regulatory region of the insulin (INS) gene on 11p15.5 in North Indians and other ethnic groups [6-8]. Besides, we have also reported association and interaction of TNF-α gene with other cytokine genes [9], Vitamin D receptor gene (VDR) and their role in expression of predisposing MHC allele in manifestation of T1D [10]. Interestingly, it seems that several genes have integrated roles in manifestation of the disease since simultaneous presence of different alleles of two or more genes seem to be significantly increased in T1D patients. For instance, simultaneous presence of HLA DRB1*0301, DRB1*0401 and/or DRB1*0405 along with class-I alleles of INS-linked variable number of tandem repeats (VNTR) were very significantly associated with T1D [6]. Similarly an interaction was observed between VDR gene and predisposing HLA alleles, and this interaction of VDR with DRB1*0301 was through the vitamin D response element (VDRE) present in the promoter region of the predisposing HLA allele and was involved in regulating the expression of HLA-DRB1*0301 [10]. Besides MHC, INS, cytokine and VDR genes, there are several other genes that have been shown to be associated with T1D which include CTLA4 gene located on chromosome 2q33 [11,12] and PTPN22 gene located on chromosome 1p13 [4].
The PTPN22 (Protein tyrosine phosphatase non-receptor, type 22) gene codes for lymphoid tyrosine phosphatase (LYP) which is an 807 amino acid residue protein with a molecular weight of 110 kDa and is involved in negative regulation of T cell signaling [13-15]. A single nucleotide polymorphism (SNP) in the PTPN22 gene at nucleotide position 1858 C>T results in the amino acid change from arginine (R) to tryptophan (W) (CGG to TGG) at codon 620 which has been shown to be a gain-of-function mutant [16]. The negative regulation of T cells by LYP is brought about by its dissociation from C-terminal Src kinase (CSK) and recruitment of LYP to the plasma membrane where it down-regulates TCR signaling. LYP*W620, however, cannot bind CSK and negatively regulates LCK-mediated phosphorylation of the TCRξ chain, reduces tyrosine phosphorylation of LAT and reduces activation of ERK2 as compared to LYP*R620. In essence, LYP*W620 has been reported be more efficient at dephosphorylation than LYP*R620 [15,16]. Several autoimmune disorders like systemic lupus erythematosus [17], rheumatoid arthritis [18,19] and type 1 diabetes [20-22] have been shown to be associated with the mutant T allele i.e., LYP*W620.
The allele frequency of the minor 1858T allele varies from 0% in some Asian populations [23] to 8-17% in different ethnic groups of European origin [17,18,24]. Africans [24] also have a very low frequency of the minor 1858T allele [10]. Such ethnic differences make it important to study the role of the minor allele in manifestations of autoimmune disorders in different populations. While earlier studies reported absence of 1858T allele in Asia [23], we had reported a very low frequency (2.03%) of this allele in normal healthy individuals [25]. In spite of this low frequency in the normal population, we observed a disease specific increase in the frequency of 1858T allele in leprosy patients. So, we investigated if the same was true for T1D as well, since several reports have shown association of 1858T allele with Type 1 diabetes in different ethnic groups [4,20-22], however, there are no studies reported so far from the Indian sub-continent with respect to PTPN22 polymorphism in T1D, probably due to presumption that the allele is absent in Asian populations. Here, we report the association of PTPN22 1858T allele and its association with predisposing MHC class- II alleles in T1D in patients from North India.
Two hundred and Fifty T1D patients and 480 normal healthy controls based in Delhi, originally from North Indian states of Uttar Pradesh, Haryana and Punjab, were studied after obtaining informed consent from patients and controls and Institutional Human Ethics Committee's clearance from National Institute of Immunology and All India Institute of Medical Sciences, New Delhi, India. The patient group consisted of 106 females and 144 males with a mean age of 25.96 ± 9.79 and age at onset of diabetes<30 years (Mean age at onset ± SD=15.995 ± 7.43), attending 'Juvenile Diabetes Clinic' at the All India Institute of Medical Sciences, Delhi, India. All the patients attending 'Juvenile Diabetes Clinic' were carefully assessed and categorized as type 1, type 2 and fibrocalculous pancreatopathy according to the classification of the American Diabetes Association expert committee [26] as reported earlier [9,10]. Controls included 480 healthy subjects (135 women and 345 men), with a mean age ± SD of 30.16 ± 9.02.
For controls, we preferred higher age group to rule out their possibility of developing T1D at a later date after the collection of their blood samples as normal healthy controls. Controls were asked for their clinical history and only those without any history of infectious or autoimmune diseases were included in the study.
DNA was extracted using a standard protocol from 10 ml of blood from T1D patients and healthy controls from the same ethnic background after obtaining informed consent and Institutional Ethics Committee's approval.
PTPN22 Genotyping using PCR-RFLP Polymerase Chain Reaction followed by restriction fragment length polymorphism
The genotyping for PTPN22 single nucleotide polymorphism at position C1858T in the codon 620 was carried out using PCRRFLP methods where standard PCR protocol was followed by restriction digestion of the PCR amplified product with restriction enzyme Rsa1. Primers used for amplification were forward primer (5'-ACTGATAATGTTGCTTCAA-3') and reverse primer (5'-TCACCAGCTTCCTCAACCA-3'), as described by Zheng et al., 2005 (Genbank accession # AL 137856). Briefly, 100 ng of genomic DNA (5 μl) was mixed with 2.5 μl of 10X buffer, 0.25 μl of dNTPs (100 mM), 2.5 μl MgCl2 (25 mM), 2.0 μl (5 pm/μl) each of the primers, and 0.125 μl ( 5 U/μl ) of Taq polymerase in 25 μl reaction volume. After initial denaturation at 94°C for 2 minutes, 35 cycles of denaturation at 94°C, annealing at 60°C and extension at 72°C, each for 30 seconds, were carried out followed by final extension cycle at 72°C for 7 minutes in Gene Amp 2700 thermocycler (Applied Biosystems, CA, USA). After confirmation of the amplified products on 1% Agarose gel, 10 μl each of the amplified products were digested with 5 U of RsaI enzyme (New England Biolabs) overnight at 37°C. The digested PCR products were run on 2.5% agarose gel in 0.5X TBE buffer along with 50 bp ladder. The restriction endonuclease Rsa 1 cleaves the DNA strand which contains the C nucleotide at 1858th position and gives two bands of 176 bp and 42 bp sizes, the mutant 1858T, however, is not digested by Rsa 1 and gives a single band of 218 bp size (Figure 1).
Figure 1: A representative picture of PCR-RFLP of PTPN22 C1858T on 2.5% Agarose gel: lanes 1-4 and 6-8 show homozygous 1858CC genotype with 176 bp and 42 bp bands. Lane 5 shows heterozygous 1858CT genotype with 218 bp, 176 bp and 42 bp bands, last lane is 50 bp ladder.
HLA-DRB1 polymorphism
Alleles of HLA-DRB1 locus were determined for 243 T1D patients and 327 controls for whom PTPN22 C1858T data was available. For 100 patient samples and 94 controls samples, the second exons of the DRB1 genes were PCR amplified using standard conditions and hybridized with 32P-labeled sequence specific oligonucleotide probes (SSOP) as described earlier [6,9]. For additional 143 patients and 233 control samples, Luminex based typing was done using Labtype SSO kit from One Lambda, (Canoga Park, CA, USA) according to the manufacturer's instructions as described earlier [9]. Briefly, 40 ng of DNA was amplified in master mix, primers and 2 μl of Taq DNA polymerase in Gene Amp 2700 thermocycler (Applied Biosystems, CA, USA). After confirmation of amplification, on 1% agarose gel, 5 μl of amplified product was denatured and hybridized with appropriate amount of multiplex beads conjugated with oligonucleotide probes, in hybridization buffer at 60°C for 15 minutes followed by washings and incubation with 50 μl 1X SAPE solution (Steptavidin Phycoerythin) at 60°C for 5 minutes. Fluorescence of the labeled beads was acquired on Luminex 2.2 flow cytometer (Luminex corporation, Austin, TX). Acquired data was analysed using Labtype software provided by One Lambda for analysis of MHC alleles. Reproducibility of the Luminex based HLA typing method had been checked by us earlier [9].
Chi-square test was used to examine the statistically significant differences between patients and controls using Stata 9.2 software. Odds Ratios and 95% confidence Intervals were also calculated using the same software. p values were corrected using Bonferroni's correction for multiple comparisons. Fisher's exact test was used whenever the numbers in any group were less than 5 i.e. in cases or controls for any allele. In such cases, Odds ratios were calculated using Woolf 's method [27] with Haldane's [28] modification as described earlier [29].
We have genotyped 250 T1D patients and 480 healthy controls from the same ethnic background for C1858T alleles of PTPN22 as shown in Figure 1. Table 1 shows that that the mutant 1858T allele is significantly increased in patients with T1D as compared to controls (p<0.0004, Odds Ratio=2.82, 95% confidence Interval=1.49-5.4). While homozygous genotype CC was significantly reduced (p<0.0003, Odds Ratio=0.34, 95% confidence Interval=0.18-0.65), heterozygous CT was significantly increased in T1D patients compared to controls (p<0.0003, Odds Ratio=2.93, 95% confidence Interval=1.53-5.71). And these differences remained significant even after Boneferroni's correction. All genotype frequencies in patients as well as controls were in Hardy Weinberg equilibrium.
Allele/Genotype
T1D Patients N=250
ControlsN=480
T1D vs. Controls
95% C.I.
Allele1858C 473 94.6 941 98.02 0.0004 0.35 0.18-0.67
Allele1858T 27 5.4 19 1.98 0.0004 2.82 1.49-5.4
Genotype CC 223 89.2 461 96.04 0.0003 0.34 0.18-0.65
Genotype CT 27 10.8 19 3.96 0.0003 2.93 1.53-5.71
Table 1: Allele and genotype frequencies of PTPN22 C1858T in T1D as compared to normal healthy controls.
To study if there was any gender bias, we stratified the samples for association of 1858CT genotype with gender of the patients. While genotype CT and T allele were significantly increased in both males and females when compared to male and female controls respectively, the association was stronger in females (for CT p<0.002, OR=6.4 and for T p<0.003, OR=6.12) since the frequencies of CT genotype and T allele were much less in female controls (1.5% and 0.75% respectively) compared to male controls (4.9% and 2.51% respectively), although the same were comparable in male and female patients (Table 2).
T1D Male N=144
T1D Female N=106
Controls Male N=345
Controls Female N=135
Male T1Dvs. Male Controls
Female T1Dvs. Female Controls
Allele1858C 272 (94.4) 201
(99.25) 0.015 0.43 0.2-0.9 0.003* 0.16** 0.06-0.43
Allele1858T 16
(5.6) 11
(2.5) 2
(0.75) 0.015 2.33 1.08-4.97 0.003* 6.12** 2.3-16.26
Genotype CC 128 (88.9) 95
(98.5) 0.013 0.41 0.19-0.9 0.002* 0.15** 0.05-0.42
Genotype CT 16
(11.1) 11
(1.5) 0.013 2.4 1.1-5.2 0.002* 6.4** 2.4-17.2
*Fisher's exact test was used to calculate p values.
**Haldane's modification was used to calculate the Odds Ratio.
Table 2: Gender-wise distribution of allele and genotype frequencies of PTPN22 C1858T in T1D as compared to matched normal healthy controls (07.01.14).
We further checked whether CT genotype and T allele had any significant association with age at the onset of T1D (Table 3). For this we divided the patients in two groups based on their ages at the onset of the disease i.e., more than (>) 14 years and less than or equal to (≤) 14 years. Interestingly, while both age groups had significant association with the predisposing genotype CT and allele T, patients who had early age at onset i.e. ≤ 14 years showed more significant association (for CT p<0.0007, OR=3.13, for T p<0.0008, OR=3.15).
T1D >14 years N=133
T1D ≤ 14 years N=117
Age at onset>14 yearsvs.controls
Age at onset ≤ 14 yearsvs.controls
Allele1858C 253
(98.02) 0.008 0.39 0.18-0.88 0.0008 0.32 0.15-0.69
(5.98) 19
(1.98) 0.008 2.54 1.1-5.5 0.0008 3.15 1.43-6.73
Genotype CC 120
(96.04) 0.0076 0.38 0.17-0.86 0.0007 0.3 0.14-0.68
(3.96) 0.0076 2.62 1.1-5.8 0.0007 3.3 1.5-7.2
Table 3: Genotype frequencies of PTPN22 C1858T in T1D based on age at onset as compared to normal healthy controls (07.01.14).
We had earlier reported HLA-DRB1*03:01, *04:01 and 04:05 to be predisposing for T1D in North Indians [6], To study the role of predisposing HLA alleles in combination with the PTPN22 alleles, 243 T1D patients and 327 normal healthy controls who were studied for PTPN22 C1858T were also typed for HLA-DRB1 locus alleles. Our results were in accordance with the earlier results i.e. all three alleles, HLA-DRB1*03:01, *04:01 and 04:05 were significantly increased in T1D patients (Table 4) and DRB1*07:01 was significantly reduced in the patients as compared to healthy controls. Simultaneous presence of PTPN22 1858CT and 1858CC along with predisposing HLA alleles was investigated and interestingly both PTPN22 1858CT and 1858CC along with HLA-DRB1*03:01 were significantly increased in the T1D patients as compared to controls (Table 5), suggesting that while predisposing HLA alleles have a dominant effect, association of PTPN22CT genotype is independent of MHC associations.
DRB1*03:01 188 77.4 52 15.9 6.58 × 10-49 18.07 11.61-28.21
DRB1*04:01 28 11.5 8 2.45 0.00001 5.19 2.24-13.4
DRB1*04:03 8 3.29 29 8.87 0.0075 0.35 0.13-0.8
DRB1*04:05 22 9.05 1 0.31 5.71 × 10-8* 22.11** 6.82-71.59
DRB1*07:01 30 12.35 103 31.5 8.96 × 10-8 0.31 0.19-0.49
* Fisher's exact test was used to calculate p values.
** Haldane's modification was used to calculate the Odds Ratio.
Table 4: Frequencies of predisposing HLA-DRB1 alleles In T1D patients and controls typed for PTPN22 C1858T.
PTPN22 CC/CT with predisposing and protective HLA alleles
T1DN=243
CT- HLA-DRB1*03:01 24 9.9 3 0.91 6.34×10-7* 10.34** 4.64-23.05
CC- HLA-DRB1*03:01 164 67.9 49 14.98 1.36 × 10-37 11.77 7.71-18.05
CT- HLA-DRB1*04:01 2 0.82 0 0 0.18* 6.78** 0.78-58.22
CC- HLA-DRB1*04:01 26 10.7 8 2.453 0.00003* 4.78** 2.05-12.41
CT- HLA-DRB1*04:03 0 0 0 0 - - -
CC- HLA-DRB1*04:03 8 3.3 29 8.86 0.0075 0.35 0.14-0.8
CC- HLA-DRB1*04:05 20 8.23 1 0.31 3.17 × 10-7* 19.96** 6.14-64.87
CT- HLA-DRB1*07:01 3 1.23 5 1.53 0.53* 0.85** 0.33-2.22
CC- HLA-DRB1*07:01 27 11.11 98 29.97 7.39 × 10-8 0.29 0.17-0.47
*Fisher's exact test was used to calculate p values
Table 5: Association of predisposing PTPN22 C1858T allele with predisposing HLA alleles.
Several genes have been implicated for predisposition to develop T1D. While the MHC region has been shown to account for 50% of the inherited risk [8], an integrated role of other genes like INS-VNTR, CTLA-4, Vitamin D receptor (VDR), cytokine genes and PTPN22 amongst a number of other genes cannot be ruled out [6,9,10,12,30,31] since it is a very complex autoimmune disorder where most of the implicated genes have some functional relevance. For example, INS-VNTR class-I alleles have been shown to have poor expression of insulin in thymii of fetuses as compared to those with Class-III alleles [32,33] which may be responsible for poor thymic education for insulin resulting in autoimmunity against insulin producing pancreatic beta cells [32,33]. Similarly, the products of CTLA-4 and PTPN22 genes have roles in negative T cell signaling. CTLA-4 is constitutively expressed on regulatory T cells [34,35] and defect in CTLA-4 expression may be detrimental for the manifestations of autoimmunity since autoimmune responses may not be regulated in these cases [35].
The other negative regulator of T cell signaling, PTPN22 with SNP C1858T, has been implicated in many autoimmune disorders [18,19,36] and was first reported by Bottini et al. in Type 1 diabetes patients from two independent populations [4,37], followed by several reports where the associations were reported with either T1D per se, or with female gender or with beta cell dysfunction or autoantibodies and even with early age at onset in children fed with cow milk formula, in different populations [20-22,38-41]. Our observations replicated earlier reports, and show a significantly higher number of T1D patients from North India to have 1858CT genotype and T allele as compared to controls [37,39,42,43]. Fedetz et al. [42], observed a significantly higher number of T1D patients from Ukraine to have TT genotype and T allele as compared to healthy controls. They also observed the association was stronger in female patients and in those at younger age at onset, similar to our findings where 1858CT genotype showed stronger association in female patients and early age at onset.
While we do find a significant increase of T allele and CT genotype in T1D patients, total absence of homozygous 1858TT genotype was surprising. Under normal Mendelian inheritance pattern, one would expect some homozygous TTs as well since 10.8% of the patients had heterozygous CT genotype. However, since the frequency of the T allele is very low in healthy controls, the chances of getting homozygous TT would probably be very low. While no association of 1858T allele was observed with T1D in Japanese population, another SNP in the region, rs1310182, was significantly associated in them. In fact, this nucleotide position C1858T was reported to be non-polymorphic in Japanese [44]. Frequency of 1858T alleles varies in different populations. While we observed a very low frequency of 1858T allele in North Indians [25], earlier studies reported a total absence of T allele in Asian populations [23]. Our study suggests that Asian populations cannot be generalized as one ethnic group since the earlier reports of absence of the T allele have been from Asian populations from Japan, Korea and China, which being Mongoloid in origin, are ethnically different from Indians who are basically Caucasoid with racial admixture of Mongoloid and Negroid elements [45].
Our data further suggests that association of PTPN22 1858CT genotype was independent of the predisposing MHC alleles, suggesting that the primary association is with DRB1*03:01 which was observed in 77.4% of T1D patients, compared to 10.8% of the patients having PTPN22 1858CT genotype. Recently several papers have been published on functional relevance of the PTPN22 1858T or LYP*W620 allele, where PTPN22 encoded LYP has been shown to have roles in both innate and adaptive immune responses. Expression of LYP*W620 has been associated with reduced TLR signaling resulting in defective type 1 IFN-mediated host response to infection which may have role in initiation of T1D that is associated with viral infection [46]. Also, LYP negatively regulates T cell functions by dissociating from C-terminal Src tyrosine kinase (CSK) which is essential for recruitment of LYP to the lipid rafts where it regulates TCR mediated signaling. And the disease associated LYP*W620 (1858T allele) was shown to partition into lipid rafts more efficiently than LYP*R620 due to its inefficiency to bind CSK and was thus shown to be more potent inhibitor of TCR induced responses [15].
Type 1 diabetes is a multifactorial disease with several components like a jigsaw puzzle with several genomic loci implicated in the manifestation of the disease. We have been trying to put some of the pieces of the puzzle together where some components are interrelated while others are independently affecting the manifestations in the presence of other predisposing factors. We have reported earlier that simultaneous presence of DRB1*0301 along with homozygous INS-VNTR class-I alleles was significantly increased (p < 10-8) in T1D patients, giving a relative risk of 70.81 [6]. We also provided evidence of statistically significant interaction between the predisposing HLA allele and high producer alleles of VDR which may be detrimental for the manifestation of T1D in the absence of 1,25-(47)2D3 in early childhood and/or in-utero. Our studies on HLA-DRB1*03:01 homozygous cell lines showed enhanced expression of HLA-DR on the B-LCLs stimulated with 100 nM calcitriol as compared to the unstimulated ones confirming that indeed the interaction of VDR with HLA-DRB1*03:01 is occurring through the VDRE present in the promoter region of the gene [10]. Based on these studies we speculated that in the absence of required amount of Vitamin D in early life in the predisposed individuals with HLA-DRB1*0301, the expression of the allele may be impaired in the thymus [47,48] resulting in escape from thymic deletion of autoreactive T cells leading to T1D manifestations. Poor thymic education for insulin and HLA-DRB1*03:01 proteins along with environmental factors like viral infections, vitamin D deficiency and some milk proteins may be involved in initiation of the autoimmune responses against the pancreatic beta cells. While predisposing HLA class-II molecules may be involved in auto-antigen presentation to T helper cells, higher producing genotypes of pro-inflammatory cytokines like IFN-gamma and TNF-alpha may be involved in enhancing the cell mediated immune responses through proliferation of CD4+ and CD8+ T cells, and higher producing genotypes of IL-10 and TGF-beta may have a role in recruitment of these autoreactive T cells in the pancreas through ICAM-1 and Integerin dependent pathways [9]. Additionally, PTPN22 1858CT genotype may have a role in defective innate immune responses against viral infections that may trigger islet cell autoimmunity [46] combined with defects in early T cell signaling due to which autoreactive T cells may not be deleted and may lead to insufficient activity of regulatory T cells, thus leading to autoimmune [4,16] destruction of pancreatic beta cells which may occur through CD4+ and CD8+ T cells and nitric oxide production.
Author Contribution
RR conceived the project and critically evaluated the data, NI, AK SV and JS were involved in generating the Type1 diabetes and control data for PTPN22 and HLA. RR analysed the data and wrote the manuscript.
Authors are thankful to study participants for providing blood samples without which the study would not have been possible. We would like to thank our collaborator, Dr. Ravinder Goswami, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences for T1D patient samples. Mr. Kapoor Chand's technical support is acknowledged. This work was supported by grant from Department of Science & Technology, New Delhi, India, grant No. SP/ SO/B54/98 and core grant from National Institute of Immunology, New Delhi, India.
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Rani R, Singh A, Israni N, Singh A, Sharma P, et al. (2009) The role of polymorphic protein tyrosine phosphatase non-receptor type 22 in leprosy. J Invest Dermatol 129: 2726-2728.
American Diabetes Association (2009) Standards of medical care in diabetes--2009. Diabetes Care 32: S13-61.
WOOLF B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19: 251-253.
HALDANE JB (1956) The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 20: 309-311.
Rani R, Fernandez-Viña MA, Stastny P (1998) Associations between HLA class II alleles in a North Indian population. Tissue Antigens 52: 37-43.
Guja C, Marshall S, Welsh K, Merriman M, Smith A, et al. (2002) The study of CTLA-4 and vitamin D receptor polymorphisms in the Romanian type 1 diabetes population. J Cell Mol Med 6: 75-81.
Guo SW, Magnuson VL, Schiller JJ, Wang X, Wu Y, et al. (2006) Meta-analysis of vitamin D receptor polymorphisms and type 1 diabetes: a HuGE review of genetic association studies. Am J Epidemiol 164: 711-724.
Pugliese A, Zeller M, Fernandez AJr, Zalcberg LJ, Bartlett RJ, et al. (1997) The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15: 293-297.
Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, et al. (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15: 289-292.
Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24: 65-97.
Romo-Tena J, Gómez-Martín D, Alcocer-Varela J (2013) CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun Rev 12: 1171-1176.
Laberge GS, Birlea SA, Fain PR, Spritz RA (2008) The PTPN22-1858C>T (R620W) functional polymorphism is associated with generalized vitiligo in the Romanian population. Pigment Cell Melanoma Res 21: 206-208.
Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, et al. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36: 337-338.
Kahles H, Ramos-Lopez E, Lange B, Zwermann O, Reincke M, et al. (2005) Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto's thyroiditis or Addison's disease in the German population. Eur J Endocrinol 153: 895-899.
Ladner MB, Bottini N, Valdes AM, Noble JA (2005) Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum Immunol 66: 60-64.
Chelala C, Duchatelet S, Joffret ML, Bergholdt R, Dubois-Laforgue D, et al. (2007) PTPN22 R620W functional variant in type 1 diabetes and autoimmunity related traits. Diabetes 56: 522-526.
Lempainen J, Vaarala O, Mäkelä M, Veijola R, Simell O, et al. (2009) Interplay between PTPN22 C1858T polymorphism and cow's milk formula exposure in type 1 diabetes. J Autoimmun 33: 155-164.
Fedetz M, Matesanz F, Caro-Maldonado A, Smirnov II, Chvorostinka VN, et al. (2006) The 1858T PTPN22 gene variant contributes to a genetic risk of type 1 diabetes in a Ukrainian population. Tissue Antigens 67: 430-433.
Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, et al. (2004) Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53: 3020-3023.
Taniyama M, Maruyama T, Tozaki T, Nakano Y, Ban Y (2010) Association of PTPN22 haplotypes with type 1 diabetes in the Japanese population. Hum Immunol 71:795-798.
Rani R, Fernandez-Viña MA, Zhang S, Stastny P (1995) HLA-DPB1 alleles in a population from north India and description of a new variant (DPB1*5601). Tissue Antigens 45: 264-269.
Wang Y, Shaked I, Stanford SM, Zhou W, Curtsinger JM, et al. (2013) The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity 39: 111-122.
Lim YS, Oh HB, Choi SE, Kwon OJ, Heo YS, et al. (2008) Susceptibility to type 1 autoimmune hepatitis is associated with shared amino acid sequences at positions 70-74 of the HLA-DRB1 molecule. J Hepatol 48: 133-139.
Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, et al. (2009) Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 5: e1000369.
Citation: Rani R, Israni N, Kumar A, Vasudevan S, Singh J (2014) Association of Protein Tyrosine Phosphatase Non-receptor, Type 22 (PTPN22) C1858T Polymorphism with Type 1 Diabetes in North India: A Replication Study. J Diabetes Metab 5:342.
Copyright: © 2014 Rani R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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Hard Rock Music Time Machine – 7/6/17
July 6, 2017 by AW Leave a Comment
Each Thursday, Hard Rock Music Time Machine takes a journey back in time to feature a variety of songs that date back as far as the '70s.
In addition to appearing on the embedded YouTube playlist below, all songs featured on Hard Rock Music Time Machine can be listened to individually by clicking on the hyper-linked song titles above each review.
AEROSMITH – "Girls Of Summer" (2002)
There's something about summer that just makes people feel happier. It's a vibe that cannot be easily put into words, but Aerosmith captured it perfectly with "Girls Of Summer" (the only single to be released off of O, Yeah! Ultimate Aerosmith Hits).
When it comes to using double entendre and sexual innuendo, Aerosmith is as good as it gets (thanks to Steven Tyler). This video for this song offers an interesting twist, placing women in the roles that are more commonly seen in men in the pursuit of "love."
"Girls Of Summer" was written in Hawaii by Tyler, Joe Perry, and songwriter/producer/musician Marti Fredricksen (known for being the lead singer in the fictitious band Stillwater in the movie Almost Famous) at the end of the Just Push Play tour. The song would go on to become a mainstream rock hit, and also be the name of the band's 2002 tour.
THE ATARIS – "Boys Of Summer" (2005)
Don Henley (Eagles) original version of "Boys Of Summer" is a mellow, melodic, nostalgic walk down memory lane. On the other hand, The Ataris cover is an adrenaline-fueled, pop punk interpretation that stays fairly true to the original, yet feels totally unique. The only change to the lyrics was replacing "Deadhead sticker" with "Black Flag sticker." A few years later, Five Finger Death Punch would take the same approach with their cover of "Bad Company." Although "Boys Of Summer" was a big hit, the band has never been able to leverage that success into other hits throughout their career. Still, if you have to be known for just one song, this is a memorable one for sure.
BLACK STONE CHERRY – "Lonely Train" (2006)
I was in a blues/hard rock band about a decade ago that worked hard and tried to do all the right things. Black Stone Cherry – a band that inspired my playing and writing style – is a band that we were often compared to. They were classified as a metal act, but definitely had southern rock and blues influences. Their self-titled debut album had some great songwriting, and some memorable singles (including "Lonely Train"), which featured some pretty good musicianship.
PORCUPINE TREE – "Arriving Somewhere But Not Here" (2005)
In the realm of progressive rock and progressive metal, students of the genre will automatically name Porcupine Tree as one of the top bands in this genre. It is music written and performed with intelligence for intelligent people. From their eighth studio album, Deadwing, this concept album is based on a screenplay written by Steve Wilson (the band's founder and lead songwriter). It is an epic album in terms of subject matter, musicianship, emotion and feel. The album even features contributions from Mikael Akerfeldt of the death metal giant Opeth on vocal harmonies and guitars. The songwriting and production on this album is topnotch and should be in every progressive rock/metal fan's inventory.
DOKKEN – "Alone Again" (1984)
The classic Dokken lineup consisted of vocalist Don Dokken, guitarist George Lynch, bassist Jeff Pilson and drummer "Wild" Mick Brown. Formed in 1979, they enjoyed great commercial success during the '80s, before breaking up in 1989. The band would reunite with different lineups in later years, but it was only last year that the classic lineup came back together (if only for one brief tour, playing one date in America and six in Japan).
Dokken's first album, Breaking the Chains, was considered a flop by their label, though it did boast a title song that is considered by some to be one of the best rockers of its era. The video for that song brought the band some fame, and their follow-up album Tooth and Nail was wildly successful. This iconic ballad comes from that 1984 album.
DOKKEN – "In My Dreams" (1985)
The band quickly followed up their first hit album with another huge commercial success, 1985's Under Lock and Key. Layered vocal harmonies are punctuated by driving guitars and pounding rhythms in this big hit from the band's third album.
Hard Rock Music Time Machine See more
Filed Under: Hard Rock Music Time Machine Tagged With: Aerosmith, Black Stone Cherry, Boys Of Summer, Dokken, Girls Of Summer, Hard Rock Music Time Machine, Hard Rock Summer Songs, Joe Perry, Marti Fredricksen, O Yeah! Ultimate Aerosmith Hits, Porcupine Tree, Steven Tyler, The Ataris

redpajama_set_name: RedPajamaCommonCrawl


Caprara, Christian. Role of Hypoxia-Inducible Factor 1A and Erythropoietin in Retinal Physiology and Development. 2014, University of Zurich, Faculty of Science.
This list was generated on Fri Apr 26 10:57:33 2019 CEST.


Oh, I got my free copy months ago! I just don't like posting reviews too far ahead of release. People forget if the review is too early. I've loved all her books and she's a really great human being, too.
I wrote one of Gretchen's very first reviews and we've been friends ever since, though we've yet to meet. I hope we will yet!
I now have enough of your books to make quite a nice showing of them. What I lack is something I used to have — indoor lighting. I finally gave it away because I only used it maybe once or twice a year and it took up half the dining room which is also half a photo studio. Now I have to wait for the light to show up on its own … and it hasn't been a bright year. I had fun with the review, actually and it's already up on Twitter, Facebook (and your Bellissimo group) AND Goodreads and Twitter. As soon as it's released, it'll go up on Amazon. I have a few co-bloggers who do each other favors. So many of us ARE writers and many have written series of books for kids and adults — GOOD books that in another time and place would have had home with real publishing houses but now have gone from "big" (right, sure) contracts to very small or no contracts. Lots of "Indie" work, some of it very high class. But some of it, there's just no one interested in it. Historical fiction is moribund … as is learning books for children. And SO much else.
Anyway, I loved your book. There was a LOT to this book and I couldn't give it ll way, so I did a lot of hinting which I hoped wasn't too much information. I don't think so (hope not!).
I'll pass you around as much as I can!!!!!
I know she's one of your favourites, Marilyn. I must see if she's in our local library.
I don't know. I know she has sold very well on Kindle and in paperback. Don't know about libraries, but I'm betting if you ask, they might order the books. They are very inexpensive on Kindle, though.
They usually can get them in on request….
Usually, you just ask. And since this is a real publishing house, there should be no trouble getting it.


Ensure your workplace has an up to date fire policy. Examples can be found here. Make sure all your staff know what the policy says and understand the role they all individually have to play in keeping your workplace safe.
Regularly complete and update a fire risk assessment of the premises. Guidance can be found here. We recommend you schedule this is once a year and don't forget to include remote buildings/spaces.
Ensure the workplace is clear of waste and debris, things like shredding and discarded fabric can rapidly go up in flames! This is also good opportunity to go paperless and tackle the mountain of archived paper files you have.
Keep and maintain sufficient firefighting equipment for the office and the type of work you are carrying out… and get it serviced in line with recommendations.
If appropriate and relevant, hold regular drills in line with your fire policy, remembering to include all those who have physical challenges so they are familiar with what will happen in the event of lifts etc being shut down.
Block fire exits or allow anyone else to do this – not even for ten minutes! It is your legal responsibility to keep them clear as well as being a sensible way to reduce the risk to yourself, your staff and your visitors in the event of a fire. Fire exits should NEVER be padlocked or locked in such a way that they cannot easily be opened from the inside.
Store flammable materials anywhere near an ignition source or an oxidiser and clear up immediately any spilt fuel or other combustible. Keep sand buckets near any fuel storage areas to deal with such spillages.
Assume that the worst will never happen. Plan for disaster and create a Personal Emergency Evacuation Plan (PEEP) for yourself and your staff. PEEP documents can be found here.
Forget to regularly test fire alarms, you don't need to have a whole fire drill to do so! Consider whether you need visual as well as audio alarms if you have hearing impaired employees.
Allow electrical equipment to go untested. Everything should be PAT tested in accordance with regulations.
10.5 Most of fire safety is common sense but what often goes wrong is people being lazy, not following the fire procedures, and generally being unprepared in the event that a fire does occur. One bit of research suggested that 70% of businesses experiencing a major fire do not reopen after the fire or subsequently fail within 3 years. Don't let this be your business simply because you didn't take fire risks seriously.


McKeon Announces His Picks for QDR Assessment Panel: House Armed Services Committee Chairman Rep. Buck McKeon (R-Calif.) selected Eric Edelman and former GOP Senator Jim Talent of Missouri as his two picks to serve on the 10-member congressionally mandated national defense panel that will assess the Pentagon's 2013 Quadrennial Defense Review. "Ambassador Edelman and Senator Talent are two of the most respected defense experts in the business," said McKeon in a Jan. 29 release. Of the remaining eight panelists, Defense Secretary Leon Panetta will appoint two, as will HASC Ranking Member Rep. Adam Smith (D-Wash.), Senate Armed Services Committee Chairman Sen. Carl Levin (D-Mich.), and SASC Ranking Member Sen. Jim Inhofe (R-Okla.). "My hope is that the remaining panelists will be seated soon so the group can begin examining the Department of Defense's rationale and process for completing the Quadrennial Defense Review," added McKeon. The panel is required to submit a report to Congress no later than three months after the Defense Department submits the QDR to Congress.


Every time I see your photos I feel so blessed! So blessed to be able to look at these beauties.
That last photo – absolutely enchanting! You have such a gift for playing with light.
You want to follow my blog?


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Taco Bell and Samsung among first on new Songza "native advertising" platform
Submitted by Paul Maloney on September 24, 2013 - 9:42am
9/24/13: iTunes Radio and Pandora show complementary strengths and weaknesses
B Story
Tuesday, September 24, 2013 - 12:10pm
Webcaster Songza has launched a "native advertising" solution it says is already producing benefits for advertisers in engaging potential customers.
Songza is the webcaster known for its Music Concierge, which offers curated playlists suited to listeners' activities and moods (and has been replicated by services no less than iHeartRadio and Slacker). Native advertising means incorporating brands and ad messages into the actual content of a service -- in this case, Songza's musical experience.
Co-founder and CCO Eric Davich described the benefits of the platform, named "Sponsored Moments," to the SoundCTRL blog. According to Davich, the program is about tapping "into the personal, trusted connection we have with our users in order to provide contextually relevant experiences."
Songza has worked with brands like Taco Bell and Samsung and created song collections like "Getting Hyped" and "Going Back to College" that fit those brands.
"We work closely with brands to tell their story with the personality," Davich said. Brands "need to contextualize their message in a way that relates to the consumer's context," he continued, "not just who they are and where they're from, but also what they're actually doing at that very moment."
Songza recently completed it latest round of financing of $4.7 million (investors include Lady GaGa's and Justin Bieber's managers), and took home the FlashFWD award for "Best in Discovery."
Read more in SoundCTRL here.
Songza raises $4.7M to forge ahead with ad solution program
Submitted by Brad Hill on September 11, 2013 - 11:18am
9/11/13: Music industry counting on iTunes Radio to be a royalty-generating machine
Wednesday, September 11, 2013 - 9:20am
Internet radio service Songza completed a $4.7M round of private equity funding yesterday, almost exactly two years after receiving $2M in venture funds (as reported in CrunchBase). Yesterday's commitment will be invested in scaling Songza's native sponsoring platform, in which advertising creative is integrated into Songza "life moments" streams. (See Billboard's reporting here.)
Internet radio advertising lags the sophisticated user targeting of the web at large. If demographic ID is a brass ring, personal targeting is a holy grail. The most rudimentary network advertising on the web can accomplish the former, while browser-cookie placement and personal profiling can deliver startlingly individualized results. Targeting technology is what makes a user's eyes widen in astonishment (and often alarm) when an ad pops up on Facebook that reflects browsing activity on external sites just a few minutes before, refined by an understanding of the user's personal Facebook profile.
Internet radio ads generally convey a better sense of protected privacy, but in advertising, privacy equals cluelessness and reduced value. For users who don't have knee-jerk reactions against targeted ads, irrelevant sponsor messages that interrupt an audio stream can seem all the more intrusive and annoying for their blindness. Recent tests of iHeartRadio (video pre-roll) and Pandora mobile (display pop-ups) betray some network buying at a low value to both the user and the advertiser. (Songza runs irrelevant ads, too.)
Songza's specialty programming offers curated music streams targeted to common life situations, day parts, environments, and moods. The categories are often smartly thought-out; one at-work channel eliminates all lyrics (good for writers). It makes sense, and might even be pioneering, to evolve ad solutions that match the "life moments" of each stream, where the curation of sponsor messaging is pertinent to the user's real-world circumstance. And since Songza offers registration via Facebook and Google+ (standard for many sites, but not all internet listening services), and requires access to the user's personal profile, the second crucial part of holy-grail targeting is in place.
Songza isn't mentioned as often as Pandora, Apple, and Spotify in industry coverage. But this round of capital funding could result in distinct revenue rewards, while providing a more personalized (if snoopish) consumer experience.
More advertisers experiment with branded online radio stations
Submitted by Paul Maloney on August 5, 2013 - 12:51pm
8/5/13: Australian broadcaster ARN launches iHeartRadio service
Monday, August 5, 2013 - 10:55am
Listened to Walmart's online radio? How about radio from Macy's, or Pepsi, Wendy's, Supercuts, or Toyota?
Inside Radio today reports that a growing number of large advertisers are partnering with radio broadcasters and launching "client-branded online radio stations."
It's a form of what's known as "native advertising" -- a way to include ads along with content that's perhaps less obstrusive and more acceptable to consumers than traditional "commercial breaks."
Inside Radio writes, "Buyers like the exclusivity and the flexibility to experiment with different message lengths, copy points and the content itself."
Read more from Inside Radio here.


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External Validation of the Canadian Syncope Risk Score
Written by Mark Ramzy
REBEL EM
Medical Category: Cardiovascular
The Canadian Syncope Risk Score (CSRS) is one of several clinical decision tools used in the emergency department (ED) following a syncopal episode. (Figure 1) It was derived from one of the largest datasets currently available and its ability to predict the probability of adverse events from a score increases its clinical utility with flexibility when applied as a continuous risk assessment.1 One benefit it has over other risk-stratification tools is the score's ability to address the risk of these serious adverse events over 30 days as opposed to 7-30 days after the syncopal episode. The CSRS is not without its disadvantages, of which one item on the score is the clinical diagnosis. The initial clinical picture may not be clear enough to immediately discern this. Furthermore, there's difficulty in discerning where arrhythmia falls in the score (ie. adverse event or part of the final diagnosis). While CSRS has been previously validated in a multicenter Canadian study,2 the authors of the following paper wanted to externally validate it and compare it to clinical judgement.
Paper: Solbiati M, et al. Multicentre external validation of the Canadian Syncope Risk Score to predict adverse events and comparison with clinical judgement. Emerg Med J. May 2021 PMID: 34039646
Figure 1: Canadian Syncope Risk Score (CSRS)
Clinical Question:
How accurate is the Canadian Syncope Risk Score in predicting serious outcomes in patients with syncope when compared with clinical judgement?
What They Did:
Multicenter validation study that was retrospectively designed with all data prospectively collected as part of the Syncope Monitoring and Natriuretic peptides in the ED (SyMoNE) study.
The SyMoNE study was a prospective multicenter investigation conducted at four teaching hospitals and 2 community hospitals in northern Italy assessing the role of brain natriuretic peptide and ECG monitoring in the ED management of patients with syncope
Included in the SyMoNE study database was the ED physician's judgement on the patients' risk of short-term adverse events classified as low, intermediate, and high according to their clinical gestalt.
If the ED physician categorized the patient as low risk of adverse event (ie. final diagnosis of vasovagal syncope and plan to discharge) then the patient was assigned -2 points. If the patient was categorized as high risk (ie. final diagnosis of cardiac syncope and planned disposition is hospital admission), then they were assigned 2 points. Patients deemed an intermediate risk were assigned 0 points
The authors then compared this "clinical judgement" approach to the Canadian Syncope Risk Score (Figure 1)
Following disposition, the authors then conducted a phone interview at 30 days to assess for the occurrence of any adverse events
Patients 18 years and older who presented to the ED for syncope
Loss of consciousness (LOC) following head trauma
Non-spontaneous recovery of consciousness
Episodes of falling, dizziness, or light-headedness without LOC
LOC associated with alcohol or drug abuse
Pregnant or breast-feeding
Inability to provide informed consent to study participation or to complete follow-up
Syncope as an underlying symptom of an acute condition diagnosed in the ED or requiring therapeutic intervention irrespective of syncope (ie. MI, PE, ICH, Aortic dissection, carotid sinus syndrome or arrhythmia diagnosed before ECG monitoring)
Non-syncopal LOC (ie. History of epilepsy)
Poor prognosis in the next 30 days for a pre-existing condition besides syncope (ie. Malignancy)
Outcomes:
Occurrence of any of the following adverse events at 30 days:
All-cause and syncope-related death
Sustained and symptomatic non-sustained ventricular tachycardia
Sinus arrest with cardiac pause > 3 seconds
Sick sinus syndrome with alternating bradycardia and tachycardia
Second-degree type 2- or third-degree atrioventricular block
Permanent pacemaker or implantable cardioverter defibrillator (ICD) malfunction with cardiac pauses
Aortic stenosis <1 cm2
Hypertrophic cardiomyopathy with outflow tract obstruction
Occult hemorrhage or anemia requiring blood transfusion
Syncope or fall resulting in major traumatic injury (requiring admission or surgical intervention)
Permanent pacemaker or ICD implantation
Syncope recurrence requiring hospital admission
Cerebrovascular event
Of the total 345 patients enrolled, 102 were hospitalized
Troponin was measured in 178 patients and positive in 39
43 patients were lost to follow-up
Critical Results:
At 30-day follow-up, 43 patients experienced at least one adverse event and 5 patients died
None of the patients in the very low risk CSRS category had 30-day serious adverse events
The risk of adverse events in patients deemed low-risk by clinical judgement was 2%
The AUC for adverse events for Clinical Judgement was 0.75 (95% CI 0.68 – 0.81)
The AUC for adverse events for CSRS was 0.68 (95% CI 0.61 – 0.74)
Multiple centers (both academic and community) were included, offering a greater variety of patient populations and practice environments
Compared clinical judgement with a risk score to predict 30-day adverse events
The set of exclusion criteria the authors used was identified by an international panel of syncope researchers and experts. They are also being adopted in international prospective studies on syncope risk stratification in the ED, including the derivation of the CSRS.
Assessed the presence of all other predictors as done in the CSRS derivation study
Replaced cardiac vs vasovagal syncope on the CSRS with points based on ED physician's judgement of short-term adverse effects
Small sample size (especially when compared to prior validation study where sample size was in the thousands)
Population of patients was older with higher prevalence of comorbidities
Approximately 43 patients were lost to follow-up
Prospective enrollment with retrospective external validation analysis comes with its own limitations on the interpretation of results (ie. already having all the data immediately available, etc)
Although multicenter, all institutions were in a single country. Unclear how the CSRS does in other countries (outside of Canada and Italy)
The authors classified patients who left the ED against medical advice to be high risk of adverse events
Troponins that were not measured were counted as being zero and therefore may have misclassified patients as a lower risk than they actually were.
Follow-up limited to only a phone interview as opposed to seeing patient and reviewing outpatient records
Significant amount of variability and subjectivity to "clinical judgement" approach
The work-up done in this study was different from the original derivation study as many patients were monitored for several hours and thus increasing the number of events recorded
The patients in this study were older with many more comorbidities than the original CSRS study. In that study, adverse events were found in 3.6% of patients and 9.5% were hospitalized. In this current trial the adverse event rate was 12% and the hospitalization rate was 29%.
In patients with a CSRS score of <0, the incidence of adverse events was < 2%
CSRS differs from other risk stratification tools in that it assesses the risk of serious adverse events over 30-days. This improves its clinical relevance as some patients can have adverse events in the first 7 to 30 days after the occurrence of syncope
The CSRS score was derived in Canadian cohorts. Due to their health system, hospitalization rates after syncope are very low. When applied in a different population in a different health care system (i.e. Italy), CSRS does not fair as well. The patients in this trial were older with a higher prevalence of cardiac disease.
There may be some possible affirming bias as the patients with adverse events had significantly higher prevalence of heart disease, high or low blood pressure, elevated troponin, abnormal QRS axis, prolonged QT interval and the ED diagnosis of cardiac syncope than those without adverse events
The authors tried to quantify a subjective factor: clinical judgment or gestalt. A recent multicenter trial showed that no score brings an improvement to early clinical judgement.3 The issue with such claims (in both this paper and that multicenter trial just referenced) is the lack of information about the clinician, their training, and their overall experience
In addition to the subjective variability that comes with "clinical judgement" the decision to admit to the hospital may not be directly related to the syncopal event itself (ie. social problems, traumas, other conditions, etc)
It is always worth reiterating that no clinical decision tool should be broadly applied to every patient or used without looking at the entire clinical picture. Clinical decision rules help guide care but don't dictate care. There is still a place for clinical judgement even in syncope patients
Author's Conclusions:
This study represents the first validation analysis of CSRS outside Canada. The overall predictive accuracy of the CSRS is similar to the clinical judgement. However, patients at low risk according to clinical judgement had a lower incidence of adverse events as compared with patients at low risk according to the CSRS. Further studies showing that the adoption of the CSRS improve patients' outcomes is warranted before its widespread implementation.
Although patients had lower adverse events with clinical judgement, there was too much variability (and lack of clinician information) compared to the CSRS group. Furthermore, this smaller study with a slightly different population had a work-up that did not precisely reflect what the authors of the CSRS derivation study did however it shows that CSRS did not perform better than clinical judgement. To improve current practice, CSRS would have to be proven to not only have better accuracy than clinical judgement but also improve patient outcomes
Clinical Bottom Line:
This is the first external validation of the CSRS outside of Canada and shows that it is no better than clinical judgement in its accuracy. Additionally, clinical judgement had a lower incidence of adverse events when compared to low-risk patients via CSRS. This highlights the importance of externally validating clinical decision rules in different populations and across different health systems prior to their implementation and before having them replace clinical judgement
Solbiati M, et al. Multicentre external validation of the Canadian Syncope Risk Score to predict adverse events and comparison with clinical judgement. Emerg Med J. May 2021 PMID: 34039646
Thiruganasambandamoorthy V, et al. Multicenter Emergency Department Validation of the Canadian Syncope Risk Score. JAMA Intern Med. March 2020. PMID: 32202605
du Fay de Lavallaz J, et al. Prospective validation of prognostic and diagnostic syncope scores in the emergency department. Int J Cardiol 2018; PMID: 30224031
Post Peer Reviewed By: Salim Rezaie, MD (Twitter: @Srrezaie)
Cite this article as: Mark Ramzy, "External Validation of the Canadian Syncope Risk Score", REBEL EM blog, July 8, 2021. Available at: https://rebelem.com/external-validation-of-csrs/.
Canadian Syncope Risk Score, Cardiovascular, CSRS, Near-Syncope, Syncope
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Tesla vehicles are now 100% autonomous!
février 15, 2022 par vqm7w
The announcement was made last night by the CEO of Tesla: the successor to Autopilot is called Tesla Vision and now allows fully autonomous driving. This announcement follows that of the German transport regulator, which had, a few days ago, deemed the Autopilot function dangerous and had asked Tesla to no longer use this term in its advertisements.
Elon Musk, the boss of Tesla, declared that from now on, all the models of the mark will benefit from equipment allowing a completely autonomous driving, including with regard to the Model 3. And that is rather good, because in Germany, the previous device, Autopilot, was recently deemed unsafe and authorities had ordered Tesla to take communication precautions.
With the Tesla Vision equipment, the firm intends to materialize its Master Plan Part 2, the aim of which is to reduce the expenses linked to the acquisition of a car, but also to develop a car-sharing service as well as to strengthen the safety of their vehicles. Indeed, we know how much self-driving cars raise questions, especially since this week, another accident took place, since one of these cars hit a truck in Singapore.
According to Elon Musk, the Tesla Vision will « a level of safety significantly higher than that of a human driver ».
There was indeed an intermediate step, namely an Autopilot 2.0, but faced with the reluctance of Germany, Tesla decided to directly offer its best level of security. From now on, the vehicles will have, in addition to the frontal radar, 8 cameras (including 3 frontal) allowing a 360° vision with a range of 250 meters, but also 12 new ultrasonic sensors, whose range has been almost multiplied. by two. As for the data, they will be processed by a « Titan » chip from Nvidia, 40 times more efficient than the old one.
Sources: Clubic – 01net – Next Impact
What will the Martian habitat look like if 3D printed?
They survive the mistaken ingestion of a lethal dose of caffeine, the equivalent of 300 cups of coffee!
Insects and nanomaterials: is the food of the future dangerous?
How to have beautiful tomatoes?
Smart bandages connected in 5G in the test phase
Are blondes less intelligent than others? science answers
Discovery of a Tatooine-like system about 1,000 light-years away
Against planned obsolescence, a company creates a wear-resistant autonomous solar motor


text:
4 books by Allen, Michael
Platonic Theology, Volume 1
Harvard University Press, 2001
Library of Congress B785.F433T4813 2001 | Dewey Decimal 186.4
The Platonic Theology is a visionary work and the philosophical masterpiece of Marsilio Ficino (1433-1499), the Florentine scholar-philosopher-magus who was largely responsible for the Renaissance revival of Plato. A student of the Neoplatonic schools of Plotinus and Proclus, he was committed to reconciling Platonism with Christianity, in the hope that such a reconciliation would initiate a spiritual revival and return of the golden age. His Platonic evangelizing was eminently successful and widely influential, and his Platonic Theology, translated into English for the first time in this edition, is one of the keys to understanding the art, thought, culture, and spirituality of the Renaissance.
Platonic Theology
Proem
Book IV
Note on the Text and Translation
Notes to the Text
Notes to the Translation
Reviews of this book:
An aristocratic devotion to our culture continues to manifest itself even today in the most prestigious centers of study and thought. One has merely to look at the very recent (begun in 2001), rigorous and elegant humanistic series of Harvard University, with the original Latin text, English translation, introduction and notes.
--Vittore Branca, Il Sole 24 Ore
The editing and translation of Ficino's text has been done superbly well. Allen and Hankins have begun a work of scholarship of the highest calibre, whose continuation is eagerly awaited.
--British Journal for the History of Philosophy
The Loeb Classical Library...has been of incalculable benefit to generations of scholars...It seems certain that the I Tatti Renaissance Library will serve a similar purpose for Renaissance Latin texts, and that, in addition to its obvious academic value, it will facilitate a broadening base of participation in Renaissance Studies...These books are to be lauded not only for their principles of inclusivity and accessibility, and for their rigorous scholarship, but also for their look and feel. Everything about them is attractive: the blue of their dust jackets and cloth covers, the restrained and elegant design, the clarity of the typesetting, the quality of the paper, and not least the sensible price. This is a new set of texts well worth collecting.
--Kate Lowe, Times Literary Supplement
Michael J. B. Allen
Rodeo Cowboys In The North American Imagination
University of Nevada Press, 1998
Library of Congress GV1834.A55 1998 | Dewey Decimal 791.840978
Rodeo is an enduring relic of America's popular culture, drawing capacity audiences to all its venues, from small western cowtowns to Madison Square Garden. The rodeo cowboy, that figure of rugged independence and solitary courage, continues to evoke the spirit of a vanished frontier and the hardy pioneers who conquered it. In this study historian Michael Allen examines the image of the rodeo cowboy and the role this image has played in popular culture over the past century. He sees rodeo as a significant American folk festival and the rodeo cowboy as the avatar of a nearly extinct authentic figure, the "real cowboy," who embodies the skills and values of traditional western rural culture. Allen's analysis explores the evolution of the myth of the rodeo man and its subsequent institutionalization and acculturation into the media of popular culture. He also examines the impact on this myth of significant changes in the rodeo milieu—the commercialization of the event and the professionalization of rodeo performers; the arrival on the rodeo scene of performers from outside the white, male, western, rural origins of the traditional cowboy performers. He discovers that America's—and indeed the world's—fascination with the rodeo cowboy reflects feelings far deeper than a taste for exciting entertainment. Allen's discussion of the archetypal figure of the rodeo cowboy will change forever our perception of rodeo, but it will also help us understand how the ancient tension between frontier and civilization continues to play a role in our national imagination.
We Are Called Human: The Poetry of Richard Hugo
Michael S. Allen
University of Arkansas Press, 1982
Library of Congress PS3515.U3Z54 1982 | Dewey Decimal 811.54
We Are Called Human
The Poetry of Richard Hugo


Thanks for the wonderful invitation, I recently went to IPC Shopping Centre to try out few new dishes Pretz n' Beanz launched not too long ago.
Love Life, Love Coffee, Love Food, Pretz n' Beanz is a vibrant cheerful cafe that serves delicious treats and satisfying meals in a laid-back ambience where diners get to truly relax and enjoy with family and friends.
You can never miss their eye-catching Pretz n' Beanz logo, it is a pretzel of the left and a coffee on the right, tied together in a heart shape, to express their love and passion for both pretzel and coffee. In the middle, there is a Chinese character 'human' to symbolize their love for human race.
All happiness depends on a leisurely breakfast. Pretz n' Beanz offers a wide range of scrumptious all-day breakfast sets to keep the energetic diners always on-the-go, choices including Egg Benjo, Little French, Royale Salmon Egg Benedict, and this Continental Breakfast, where diners get to choose their favorite hearty ingredients.
Come with Croissant or Toast, diners can have 3 choices (RM15.80) or 5 choices (RM20.05) for their Continental Breakfast. Among the options are Egg (scrambled / omelette / sunshine), Beef Bacon, Hash Brown, Chicken Ham, Chicken Sausage, Baked Beans, Grilled Tomato and Sautéed Mushroom.
For egg lovers, do give this new dish a try, warm baked egg served in a bowl with their signature pretzels and sauces on the side. Soft and creamy in texture, chef baked the egg together with tomatoes, mushroom and mozzarella cheese for the extra nice flavors.
Another new item you should try it out was the Pretz n' Stew that comes with 3 different stews for diners to choose from. Best enjoy while it is hot, diners can dip the freshly baked pretzel that served along into the Beef Goulash, Green Curry (RM17.90) or Cheesy Chicken (RM17.90), and be spoilt for the great taste and warm satisfaction.
Famous for their soft chewy pretzels, chef uses the same dough for the base and created Pretzel Pizza. Probably the first in Malaysia, Pretzel Pizza comes with 8 varieties, Sweet Potato, Double Cheese, BBQ Chicken, Al-Funghi, Pepperoni Beef, Chicken Hawaiian, Norwegian Delight and this, Hot Pepper Chili Chicken, where each flavour is crafted with precision and passion to bring out the best in every ingredient used.
Available in 2 sizes, RM17.35 for 7 inch and RM24.35 for the 10 inch, diners will still able to enjoy the softness even after you keep it for over-night.
A dessert not to be missed for serious chocoholics, this irresistible oozing goodness was served together with a scoop of ice cream, creating a hot-cold delightful experience that no one will say no!
Not so much into sweet chocolate, try this Red Velvet Cheese Cake (RM10.50), love its creamy texture.
Somehow, I never like to sit down in Ikano to have a drink, it just doesn't give me the vibe of a nice place to chill, maybe because it faces such a big space with people constantly by the side of the walkway waiting for their ride. Not there to be sipping coffee and staring at people's butts whenever I look towards The Curve.
the cili padi on that pretzel pizza looks fierce la ivy.
Volcano Chocolate Cake seem attractive to me !
Hooray for the hipster cafes, I could enjoy lepaking with friends in a great ambience.
The food looks really tempting! I wanna try it out! Yummy!
wow another nice place to dine in IPC. Need to find one Sunday to go there shop n dine.


Several months ago, I had a series of conversations with a very successful manager. He had accomplished a lot in a short while with his organization, enjoyed positive outcomes, and created a culture of engagement with his team.
"No matter how hard I try, a few of the people on my team are intimidated by me," he revealed.
He owned it as an issue, and his high self-awareness even identified that his Command and Competition themes were likely causing others to feel unsettled, but he was unsure what to do about it. Further, he could not understand why his best previous attempts to mitigate the problem had failed.
He liked it, and we moved into thinking about how he could use his harder-edged talents to advocate for the group; and, critically, to ensure he told them how he planned to do so and followed up with progress reports for them. We also strategized about how to communicate to his team, employing the word picture of his whole team being on one side of a dividing line against the problem or issue. In this way, he could begin to eliminate any lingering doubt that they were in it together, and break down the perception of him versus them.
Stosh D. Walsh is a Talent Management Consultant based in Illinois, specializing in leadership, executive coaching and coach-to-coach mentoring. Since joining Gallup in 2006, he has consulted with executives in the healthcare, retail, automotive, and manufacturing industries and for government agencies and education systems. He earned a bachelor's degree in education from Judson College and a master's degree in leadership from Bellevue University.


It IS an olde english word that had sexual connotations. Common for use in vascular graft sewing such a carotid endarterectomy. Edge Confessions of an overthehill. If you are interested in meeting up please contact me by phone i need some time in advance. Hairy chests I am ok with if it. Children and grannies are bald down there…but a fully sexual woman always meant hair. Type your medical question here.
London. i am a 25 year old mixed race girl looking to give that lucky man worth my time some fun in exchange for financial aid. so if you think you can handle my body then come get me ; )) i am a friendly, open minded.
I should go back to the previous comment stream and clear that up.
Common for use in vascular graft sewing such a carotid endarterectomy. The Online Slang Dictionary. The trampled daisies imperfectly crushed. Abnormal Menstruation after Flu. I get a rash.


The Prairie Organic Grain Initiative is a 4-year, $2.2M tri-provincial project dedicated to achieving resiliency and stability in the prairie organic sector by focusing on increasing the quantity and quality of organic grains, and developing relationships across organic market value chains.
A partnership between Organic Alberta, SaskOrganics, and Manitoba Organic Alliance, the Prairie Organic Grain Initiative is bringing the community together to develop a strong foundation of programs, resources, and relationships upon which the prairie organic grain sector can truly flourish. Other industry stakeholders integral to the project's success include COABC, the Canadian Organic Trade Association, Organic Agriculture Centre of Canada, Bauta Family Initiative on Canadian Seed Security, and organic processors, brokers, buyers, and certification bodies.
One of the flagship programs is the Pivot and Grow campaign, which makes the transition to organics simple by providing producers with the tools required to tackle major concerns such as the certification process, weeds, and nances. Resources like the New Farmer Kit and mentorship programs help make the journey through transition easy and profitable.
The fact sheets can be accessed on the Pivot and Grow website.
View the videos and subscribe to Pivot and Grow's You-Tube channel.
Another exciting project from the Initiative is the Organic Agronomy Training Program. The Organic Agronomy Training sessions are being held in partnership with University of Manitoba. In the Spring and Summer of 2016, Martin Entz of the U of M, along with experts such as Brenda Frick, Joanne Thiessen Martens and other U of M instructors, held three successful training sessions across Manitoba, Saskatchewan, and Alberta, that trained 120 participants.
Currently, the Prairies have a shortage of agronomists who are trained to work together with organic farmers. The goal of this program is to train agronomists to provide agronomic advice to organic farmers in areas such as nutrient management, crop rotation planning, weed management, and grain quality. Participants were equipped with data gathering and decision support tools to take a systematic and comprehensive approach to working with farmer clients. Participants have been staying in touch with the instructors and each other through emails, Facebook, and organized teleconference calls, allowing for valuable continued learning and sharing.
The Prairie Organic Grain Initiative is also working with Martin Entz and Joanne Thiessen Martens on the Organic Nutrient Management Program. Martin and Joanne have developed a spread sheet-based tool to help organic farmers assess crop nutrients. Because nutrients are made available through biological activity, rather than synthetic fertilizers, understanding how to manage these nutrients properly is critical to improving organic grain quality and quantity. The tool uses information from the farm including soil, plant, and grain samples, and cropping history.
The Prairie Organic Grain Initiative is working to improve resiliency and stability in the Prairie organic grain sector. If you would like more information on the Prairie Organic Grain Initiative and how you can access its programs, resources and tools, please contact info@prairieorganicgrain.org. Working together, we can achieve a resilient, stable, and profitable industry for Canadian prairie organic grain.
Cari Hartt is the new Communications Coordinator for The Prairie Organic Grain Initiative. A graduate of MacEwan University with a degree in professional communications, she is new to organics, but is thrilled to offer her skills to such a wonderful and welcoming community.


text:
Dave's Strange World
Dave's Strange Radio
Tag Archives: max rockatansky
"Mad Max: Fury Road" (2015) dir. George Miller, scr. George Miller / Brendan McCarthy / Nico Lathouris, editor: Margaret Sixel
Posted on May 26, 2015 by Dave's Strange World
Believe the hype. "Mad Max: Fury Road" is one of the most ferocious, heart-stopping, breathtaking movies ever made. When previews for this film started appearing several months ago, they looked amazing, but I stopped short of getting my hopes up because I've seen countless terrific, expertly edited trailers for films that wound up being much less than the trailers promised. Then the reviews started pouring in and not only were they rapturous, they were better than most serious Oscar-contender films usually receive. Again, I tempered my enthusiasm, because even mass critical opinion can be wrong.
But I was beyond pleased to see that not only did "Fury Road" live up to the hype, it exceeded it on many levels. As much as director George Miller redefined action films with the first two "Mad Max" films back in the late 1970s / early 1980s, Miller tops himself with "Fury Road" with some of the most brilliantly staged action sequences I've ever seen in a motion picture. I could try to describe what Miller does here, but it would sound lame, if not ridiculous or cheesy. What Miller does here could have gone disastrously wrong, but he pulls it off beautifully. Trust me, you just have to see the film to know what I'm talking about. A big part of Miller's success is due to Margaret Sixel's wonderfully insane editing. If there's a shoe-in for an Oscar this year, it's for Sixel.
The biggest surprise about "Fury Road" is that while Tom Hardy's titular character Max Rockatansky is in almost every scene of this film, Charlize Theron's Imperator Furiosa character is the heart of the film. Theron's performance is not only the equal of Sigourney Weaver's Ripley from the "Alien' franchise (the gold standard of female action characters), Theron exceeds the very high bar set by Weaver. Furiosa is a character that has been living her entire life facing unspeakable horrors to not only gain the evil leader Immortan Joe's trust, but to use that trust to escape Joe's reign of terror and gain the freedom for Joe's multiple concubines. This is someone who has been operating on slow burn for multiple decades, someone who has had to keep her emotions close to her vest to risk her life to save the lives of others. Theron's character is not only brave, but is someone who has to constantly improvise when things don't go according to plan. If Theron does not receive an Oscar nomination for her performance in "Fury Road," if not the win, it will be a grave injustice.
And this is not to slight Hardy's performance as Max in the least. Hardy is a more than worthy substitute for Mel Gibson who justifiably became a star after his turn in the first two "Mad Max" films. Hardy portrays the right mix of bravery and insanity that we expect of Max. But despite the "Mad Max" title of the film, this is really Furiosa's story. While Max (again) learns to regain his humanity, I hope this won't be theme of future Max installments. If both Gibson and Hardy can sell us on the fact that they're not numbed-out nihilists by the end of "Road Warrior" and "Fury Road" respectively, hopefully whatever screenplays accompany future Max films will take the character further instead of repeating the formula again. But again, this is not to slight "Fury Road." This is the first Max film in 30 years and if we need to be reminded of the original trope, that's fine. Just please, Mr. Miller, take the character further in future installments.
I'm afraid if I say anymore, it will dilute your enjoyment of "Fury Road" if you haven't seen it yet. Despite the unanimous critical praise, please note that this is an extremely violent film and if you are queasy about such things, you will not like this no matter what praise I or others bestow upon it. But I will say that the hype is justified and "Fury Road" is a film for the ages, if not a classic.
Posted in Uncategorized	| Tagged alien, aliens, brendan mccarthy, charlize theron, fury road, george miller, Imperator Furiosa, mad max, mad max: fury road, margaret sixel, max rockatansky, mel gibson, nico lathouris, ripley, road warrior, Sigourney Weaver, tom hardy	| 1 Reply
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"Three Songs" by Man Fighting Bear (2018)
"Que País É Este" (1987) by Legião Urbana
"Nobody Home" (1979) Pink Floyd
Jon Ronson's "The Butterfly Effect" (2017 Audible podcast)
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-Do you agree with the school's educational philosophy and religious orientation?
-Do you and your child like the teacher?
-Is there a large block of time for the children to select their preferred activity and companions?
-Are different, age appropriate toys and materials offered?
-Is there group time to enjoy developing social skills such as sharing, helping, negotiating, and cooperating?
-Is there time to explore in-depth an activity connected to a well-planned, developmentally appropriate curriculum?
-Is there time and space for large-motor, noisy activity?
-Are the children's individual abilities, differences, and preferences respected?
-Is their creativity encouraged by emphasizing the process rather than a finished product?
-Do discipline and guidance strategies used teach self-control and respect for others?
-Are health and safety issues addressed?
-Is there valid state licensing and are they members of VCPC?
-What are the parent participation requirements? Different schools have very different policies. Some schools let parents buy or opt-out of a great deal of the day-to-day routine.
-What is the maternity leave policy?
-Who provides the snack? Are there policies in effect for allergy-prone children?
-Who drives on field trips?
-What else is expected besides classroom participation?
-What opportunities to be involved are available to parents?


text:
Q: How to create a balancing cycling iterator in PyTourch? Say I have 2 classes. And for one I have only 17 samples and for another 83. I want to always have equal amount of data from each class per epoch (meaning 17 by 17 in this case). Also, I want to slide sampling a window across the class where I have more data each epoch (first 17, next 17, ...).
Currently I have a looping sampling iterator like this:
class CyclicIterator:
    def __init__(self, loader, sampler):
        self.loader = loader
        self.sampler = sampler
        self.epoch = 0
        self._next_epoch()

    def _next_epoch(self):
        self.iterator = iter(self.loader)
        self.epoch += 1

    def __len__(self):
        return len(self.loader)

    def __iter__(self):
        return self

    def __next__(self):
        try:
            return next(self.iterator)
        except StopIteration:
            self._next_epoch()
            return next(self.iterator)

I wonder how to force all samples from each class to be of equal count per epoch?

A: For a balanced batch, which means equal (or close to equal) number of samples per category in each batch, there are some approaches:
-Oversampling (make minor sized classes oversample until reach highest number of samples). In this approach you can use following code:
https://github.com/galatolofederico/pytorch-balanced-batch
-Undersampling (delivers number of samples for all categories based in smallest category number). In my experience, below function does like that using PyTorch library:
torch.utils.data.sampler.WeightedRandomSampler(weights, len(weights))

Where weights is the probability of each sample, it depends in how many samples per category you have, for instance, if you data is simple as that data = [0, 1, 0, 0, 1], class '0' count is 3, and class '1' count is 2 So weights vector is [1/3, 1/2, 1/3, 1/3, 1/2]. With that you can call WeightedRamdomSampler and it will make it for you.
You need to call it in Dataloader. The code to setup it is:
sampler = torch.utils.data.sampler.WeightedRandomSampler(weights, len(weights))
train_dataloader = DataLoader(dataset_train, batch_size=mini_batch,
                              sampler=sampler, shuffle=False,
                              num_workers=1)

redpajama_set_name: RedPajamaStackExchange


Saracens Mavericks has created an exciting Partnership Programme to develop a positive relationship with schools and clubs throughout the community.
Part of this programme is that Saracens Mavericks players and coaches can be booked to attend your Club, School or even a Workplace.
This could be to present prizes at your Club's Awards Evening, to meet the school netball teams, to talk about fitness and health or to offer bespoke coaching sessions at a venue of your choice.


text:
Tagged molly ringwald
5 LGBTQ things you need to know today, April 9
1. Jimmy Kimmel apologized to the LGBTQ community for a joke that some commenters found offensive. The late-night host made the crack while in a feud with Fox News host Sean Hannity. According to CBS News, whil...
Unleashing Garrett Clayton: Former Disney star on becoming porn star Brent Corrigan in 'King Cobra'
"Do they like biting lips? Do they like using more tongue?" To play former gay porn mogul Brent Corrigan, it was Garrett Clayton's job to find out. So the 25-year-old ex-Disney star probed those very questio...
Interview: Molly Ringwald dazzles with new CD and short stories
The name Molly Ringwald will probably mean something different to you depending on how old you are. If you were a movie-going adolescent or adult in the early 1980s, Ringwald began making a strong impression on audiences in Paul Mazursky's "Tempest," followed by the double whammy of the late John Hughes' "Sixteen Candles" and "The Breakfast Club," not to mention "Pretty In Pink." Other folks, who might have tuned in to "Different Strokes" and "The Facts of Life," just prior to that, will remember her as Molly Parker on both shows.
Ringwald's reign as the Queen of the Brat Pack ended by the late 1980s, although she continued to work regularly in film and on TV. In the late 2000s, following a second marriage and motherhood, Ringwald had a full-scale career comeback, including stints on Broadway and the TV series "The Secret Life of the American Teenager." But there's so much more to Ringwald than all that.
Ringwald is the author of two books, most recently the stellar "When It Happens To You: A Novel in Stories," which came out in paperback May 7.
Molly Ringwald interviewed
80's star dazzles with new CD and short stories
'16 Candles' at Piedmont Park
1984 classic to be shown as part of "Screen on the Green" tonight


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The small feed machines with 0.2-1.5t/h capacity are applicable for various small feed mills, poultry and livestock farms, aquaculture farms for producing poultry, livestock and common fish feed.