Leishmania species isolated from human skin samples. A polymerase chain reaction, restriction fragment length polymorphism (PCR-RFLP) assay, was performed on skin lesion material samples from 32 patients with confirmed CL by direct microscopic examination in order to prove its usefulness and efficiency for identification of Leishmania species. Leishmania tropica (L. tropica) is confirmed as an etiologic agent of CL in this area.Cutaneous leishmaniasis (CL) is an endemic disease and a public health problem in Hama governorate located in the central region of Syria. The aim of this study was to characterize  Leishmaniasis is a parasitic endemic disease that spreads over the world in tropical and subtropical regions. Cutaneous leishmaniasis (CL) is currently endemic in 87 countries worldwide (20 countries in the new world and 67 countries in the old world), with an estimation of new infected cases from 500,000 to one million annually . L. major and anthroponotic cutaneous leishmaniasis (ACL) caused by L. tropica [In Syria, CL has two forms: zoonotic cutaneous leishmaniasis (ZCL) caused by  tropica –4. Durin Traditionally, diagnosis of leishmaniasis in Syria relies on the clinical manifestations of the disease with the detection of the intracellular stages of the parasite by direct examination of smears or biopsies of skin lesions and culturing of specimens , 6. Leishmania species identification is not possible using these methods because all Leishmania parasites are morphologically similar. Actually, isoenzyme analysis is the golden method for identification of Leishmania species and subspecies. However, this procedure is time consuming, culture dependent and requires considerable expertise [However, the xpertise –11.Leishmania parasite [Leishmania in clinical samples as well as for parasite characterization [Leishmania parasite, due to its high conservation among species [Leishmania in patient tissues, blood, or other samples preventing the use of microscopic examination and cultivation [Therefore, accurate diagnosis of cutaneous leishmaniasis, treatment, disease prevention, and controlling strategies, as well as management decisions, require identification of the causative species of parasite –12. In trization . A unive species , 15–19. tivation , 18–20. Leishmania species that caused cutaneous leishmaniasis in Hama governorate, middle region of Syria.In this study, we aimed to identify the Leishmania) centers for consultation and treatment in Hama, suffering from skin lesions for more than 3 weeks  from individuals presented to the local sanitary  was filled out for each patient. The patients were notified of all the procedures to take place, and a signed informed consent was given to each. The ethics committee of the Ministry of Health, Damascus, Syria, approved this study. After cleaning the lesion, aspirate of skin lesion was smeared, fixed (using methanol), stained (using Giemsa), and examined microscopically for the presence of μL elution buffer. DNA extracts were stored at −20°C until being used.Total DNA was extracted from human lesion smear samples using the Qiagen DNA Mini Kit , as per tissue protocol instructions, and eluted in 200 The internal transcribed region (ITS1) of the small subunit ribosomal DNA was amplified from samples by conventional PCR using the primers L5.8S: 5′-TGATACCACTTATCGCACTT-3′ and LITSR: 5′-CTGGATCATTTTCCGATG-3′; .μL. All PCR assays were optimized with regard to annealing temperature, to concentrations of primers, and to cycling protocols. For all experiments, five μL of isolated DNA was added to the PCR mixture , and each individual PCR experiment included at least one positive control: L. tropica MHOM/TR/05/EP119; L. major IPAP/EG89/SI-177 and L. infantum EP 50 (5 μL of DNA of reference strain) and one negative control (5 μL of nuclease-free water). The cycling conditions were  repeated for 37 cycles. Amplification products were subjected to electrophoresis in 2% agarose  at 100 V in 1x TAE  buffer, stained with ethidium bromide (5 μL/100 mL), and visualized and photographed using a UV transilluminator. Amplification reactions were performed in volumes of 50 μL)  without prior purification. The digested fragments were subjected to electrophoresis in 2% agarose  at 100 V in 1x TAE buffer, stained with ethidium bromide (5 μL/100 mL), and visualized and photographed using a UV transilluminator.Restriction fragment length polymorphism (RFLP) analysis of the ITS1 amplicons was performed on the ITS1 amplicons, obtained from 32 smear samples and the reference strain, using the restriction enzyme HaeIII  were males and 14 (43.8%) were females. The patients were in the age range from 2 to 70 years. None of the examined patients had been out of Hama governorate during the 6 months preceding the onset of lesions, suggesting that these cases are autochthonous. The lesions were mainly located on the upper extremities (67.5%) compared with 25.9% on the facial region and 6.5% on the legs, typical exposed fly bites areas. Most of these patients had more than one lesion (average 1–4 lesions). All patients had localized and typical lesion of CL, from crusted nodule to ulcerated lesions. The lesions diameter varied from 0.2 to 3 cm, and the duration lesion appearance varied from 15 days to 4 months.Leishmania, by ITS1-PCR. The undigested ITS1 amplicons produced a band of expected size depending on whether Leishmania species (300–350 bp), when examined by 2% Agarose gel electrophoresis (32 samples (100%) were positive for the presence of phoresis .L. tropica (MHOM/TR/05/EP119) reference strain (positive control) pattern.The ITS1-PCR was further identified by digestion with the restriction enzyme HaeIII. However, RFLP patterns for 32 positive samples analyzed presented restriction bands 60 and 200 bp  which arLeishmania species due to their homogeneous morphologies [Leishmania species, and improve therapy procedure. The diagnosis of leishmaniasis in Syria is mostly based on clinical features and direct observation of the amastigotes stage in clinical materials , 6. Manyhologies , 22, 23.Leishmania species) from different samples onto glass slides. The ITS1 fragments which are similar to those obtained with Leishmania standard strains [Leishmania parasites [L. tropica patterns [L. tropica.This study focused on diagnosis and species identification of 32 samples obtained from patients with CL in Hama governorate in Syria. We used specific primers  that amp strains , 21, 24, strains . Many starasites , 16, 25.patterns . It was In conclusion, ITS1-PCR followed by RFLP can be considered the method of chance for diagnosing and identifying the causative species of cutaneous leishmaniasis, in Syria, for accuracy treatment.


The aim was to assess time trend of mortality with musculoskeletal disorders (MSD) as underlying cause of death in Sweden from 1997 to 2013.We obtained data on MSD as underlying cause of death across age and sex groups from the National Board of Health and Welfare's Cause of Death Register. Age-standardized mortality rates per million population for all MSD, its six major subgroups, and all other ICD-10  chapters were calculated. We computed the average annual percent change (AAPC) in the mortality rates across age/sex groups using joinpoint regression analysis by fitting a regression line to the natural logarithm of the age-standardized mortality rates and calendar year as a predictor.There were a total of 7 976 deaths  with MSD as the underlying cause of death (32.5 % of these deaths caused by rheumatoid arthritis [RA]). The overall age-standardized mortality rates (95 % CI) were 16.0 (15.4 to 16.7) and 24.9 (24.1 to 25.7) per million among men and women, respectively . On average, mortality rate declined by 2.3 % per year and only circulatory system mortality had a more favourable decline than mortality with MSD as underlying cause. Among MSD the highest decline was observed in RA (3.7 % per year) during study period. Across age groups, while there were generally stable or declining trends, spondylopathies and osteoporosis mortality among people ≥ 75 years increased by 2 and 1.5 % per year, respectively.In overall, mortality with MSD as underlying cause has declined in Sweden over last two decades, with the highest decline for RA. However, there are variations across MSD subgroups which warrants further investigations. Musculoskeletal disorders (MSD) cover a wide range of disorders affecting joints, bones, muscles and soft tissues and are considered as the most common cause of severe long term pain and physical disability . MSD areIn spite of substantial burden of MSD on individuals and societies, there is a lack of adequate recognition at the level of policy-making or priority . In respAlthough, the accuracy of death certificates has been questioned –19, theshttp://www.scb.se). Data on mortality were obtained from the National Board of Health and Welfare's Cause of Death Register which includes all those who died during one calendar year and were registered in Sweden at the time of death, regardless of whether the death occurred inside or outside the country. The causes of death are coded centrally at the Statistics Sweden according to the International Classification of Diseases, the 10th revision (ICD-10). The Cause of Death Register contains a single underlying cause of death, up to 48 additional contributory causes of death, and demographic data. For this study we used publicly available data which includes only the underlying cause of death by sex, age, region, and year . MSD were identified as ICD-10 codes M00-M99. In addition, six major subcategories of MSD with higher mortality rates were identified: pyogenic arthritis (M00), RA (M05-M06), OA (M15-M19), systemic connective tissue disorders (M30-M35), spondylopathies (M45-M48), and osteoporosis (M80-M81). To compare the trend in mortality with MSD as underlying cause with trend in mortality from other diseases over the study period, we also included fifteen other ICD-10 chapters (Table 3 in Data on population across sex and age groups were collected from the Statistics Sweden (http://surveillance.cancer.gov/joinpoint). Joinpoint regression identifies points with a significant change in trend (“joinpoints”) and determined linear trends between joinpoints. In the software a series of permutation tests proposed by Kim et al. [Age-standardized mortality rates per 1 million population were calculated by means of direct standardization using the WHO Reference Population . These am et al.  is applim et al. . We usedIt has been suggested that several MSD should not be considered as underlying cause of death  were 16.0 (15.4 to 16.7) and 24.9 (24.1 to 25.7) per million among men and women, respectively. This figures corresponded to a statistically significant women/men rate ratio (95 % CI) of 1.55 (1.47 to 1.63). Across MSD subcategories, while women had statistically significantly a higher age-standardized mortality rate for RA, systemic connective tissue disorders, and osteoporosis as underlying cause compared to men, opposite was observed for pyogenic arthritis and spondylopathies  annually during the study period in Sweden . Across age groups, the oldest age group (75+ years) experienced less profound changes in mortality with MSD as underlying cause  and OA (4.9 % per year), respectively. While women experienced a statistically significant decline in mortality with systemic connective tissue disorders as underlying cause, this was relatively constant among men  among men. In addition, across age groups, the declining trend for mortality with MSD as underlying cause among people aged ≥ 75 years was no longer statistically significant . For mortality with spondylopathies as underlying cause, the exclusion of garbage codes only influenced the trend for the total population and it became no longer statistically significant .A total of 1 543 (19.3 %) of deaths with MSD as underlying cause were attributed to garbage codes , Australia (http://www.aihw.gov.au/deaths/grim-books/) and USA (http://wonder.cdc.gov/ucd-icd10.html) showed that while the proportion of MSD from all-cause mortality was similar across countries , Sweden had the lowest age-standardized mortality rate . The differences in sociodemographic status, health care system, and mortality coding practices might be potential reasons for observed difference in mortality rates across these countries.Comparing the recent (2007–2013) mortality with MSD as underlying cause in Sweden with Denmark  as underlying cause statistically significantly declined in Sweden over the study period. This finding is in line with declining trend in mortality from RA, systemic lupus erythematosus, ankylosing spondylitis and polyarteritis nodosa in France , Spain , and EngThe mortality rates of MSD and its three subcategories  as underlying cause were higher among women compared to men and this is mainly attributed to higher prevalence of these disorders among women , 34. PreThe limitations of the current study should also be considered when interpreting its findings. We only analyzed mortality due to underlying cause of death which suffers from underestimation for MSD as these are not usually considered as underlying cause of death . InaccurThe mean age-standardized mortality rate with MSD as underlying cause was 21.1 per million people per year in Sweden during 1997–2013. The present study indicated that mortality with MSD as underlying cause declined by 2.3 % per year in Sweden and this reduction was generally more favourable than other ICD-10 chapters. However, we found variations in time trends for MSD subcategories across sex and age groups. Our findings revealed that older people (aged ≥ 75 years) observed an increasing trend in mortality with spondylopathies and osteoporosis as underlying cause which warrants further investigations. Moreover, while mortality rates of MSD and its three subcategories  as underlying cause were higher among women, more Swedish men died from pyogenic arthritis and spondylopathies during the study period. Analyzing time trend in MSD mortality using multiple cause of death framework and using individual-level data are subjects for future studies.http://www.socialstyrelsen.se/statistics/statisticaldatabase/causeofdeath).All relevant raw data are freely available from the Swedish Cause of Death Register (Not applicable (publicly available data were used).


GLI1, PTCH1, and HHIP in the FJs. The Weishaupt grading and OARSI scores showed high positive correlation (r = 0.894) (P < 0.01). MRI Weishaupt grades showed positive correlation with GLI1 (r = 0.491), PTCH1 (r = 0.444), and HHIP (r = 0.654) mRNA levels (P < 0.05 in each case). OARSI scores were also positively correlated with GLI1 (r = 0. 646), PTCH1 (r = 0. 518), and HHIP (r = 0.762) mRNA levels (P < 0.01 in each case). Cumulatively our findings indicate that Indian HH signaling is increased in OA and is perhaps a key component in OA pathogenesis and progression.Indian Hedgehog (HH) has been shown to be involved in osteoarthritis (OA) in articular joints, where there is evidence that Indian HH blockade could ameliorate OA. It seems to play a prominent role in development of the intervertebral disc (IVD) and in postnatal maintenance. There is little work on IHH in the IVD. Hence the aim of the current study was to investigate the role of Indian Hedgehog in the pathology of facet joint (FJ) OA. 24 patients diagnosed with lumbar intervertebral disk herniation or degenerative spinal stenosis were included. Preoperative magnetic resonance imaging (MRI) and Osteoarthritis Research Society International (OARSI) histopathology grading system was correlated to the mRNA levels of  Facet joint (FJ) osteoarthritis (OA) is an important component of degenerative changes in the lumbar spine, and is a major contributing factor to low back pain23PTCH1) and Smoothened (SMO) are two transmembrane receptors that respond to Indian Hh signaling. When Indian Hh is not present, Patched1 inhibits Smoothened, and represses the downstream gene expression by suppressing the Gli zinc finger transcription factors 1518HHIP) have also been shown to bind vertebrate Hh proteins and negatively modulate Hh signalingIndian Hedgehog (Hh), sonic Hh, and desert Hh constitute the Hh family, which plays critical role in growth, patterning, and morphogenesis567810111213PTCH1, GLI1, and HHIP. The prospective relationship between the pathology of FJ OA and Hh signaling is discussed.In this study, we examined the pathological changes in the FJ OA in humans and analyzed the expression levels of Hh signaling-associated All experimental protocol were approved by the Ethical Committee of The First Affiliated Hospital of Chinese PLA General Hospital. Written informed consent was obtained from all enrolled patients. All the subsequent research analyses were carried out in accordance with the approved guidelines.en bloc at our hospital between October 2012 and April 2013.This study included 24 consecutive patients (mean age of 61.7 (range 42–75 years)), including 15 males and 9 females, diagnosed with lumbar intervertebral disk herniation or degenerative spinal stenosis. These patients were treated with FJ resection et al. was used to evaluate the FJs21Preoperative T2-weighted MRI images of the diseased FJs were obtained and independently evaluated by two experts in this field. Discrepancy between the two evaluators were solved by discussion. The morphological MRI grading system of Weishaupt en bloc and dissected into two parts through a plane perpendicular to the joint surface. For pathological analysis, half of the FJs was fixed in 4% paraformaldehyde for 48 hours, decalcified, and embedded in paraffin. The other half of the FJs were immediately put into liquid nitrogen and used for quantitative real time polymerase chain reaction (qRT-PCR). The block was cut into 4-μm sections on the coronal plane. The sections were stained with toluidine blue and hematoxylin-eosin (HE), respectively. Osteoarthritis Research Society International (OARSI) histopathology grading system was used to evaluate the sections23The diseased FJs were resected −ΔΔCt method and normalized to ACTB expression.Total RNA from the facet joints  was extracted using the Trizol method . The RNA was reversely transcribed into cDNA using random hexamers. The cDNAs were subsequently used to template qRT-PCR reactions using KAPA SYBR® FAST Universal 2X qPCR Master Mix  using primers mentioned in P-value less than 0.05 was considered statistically significant.Continuous data were expressed as mean ± SD. Correlation analysis was performed using Spearman rank coefficient with SPSS 17.0 . A The Weishaupt grades included grade 0 in 5 cases, showing normal FJ space of 2–4 mm; grade I in 8 cases, showing narrowed FJ space of <2 mm, small osteophytes, and mild articular hypertrophy; grade II in 7 cases, showing narrowed FJ space, moderate osteophytes and articular hypertrophy, mild subchondral erosion; grade III in 4 cases, showing narrowed FJ space, large osteophytes, severe articular hypertrophy, subchondral erosion and cysts .The toluidine blue and HE staining results were scored with OARSI grading system . TypicalP < 0.01 in each case) (P < 0.05) (P < 0.01) (OARSI scores were positively correlated with GLI1 (r = 0. 646), PTCH1 (r = 0. 518), and HHIP (r = 0.762) mRNA expression levels (ch case) . MRI Wei < 0.05) . Further < 0.01) .In this study, we collected FJs with OA from 24 patients and examined the mRNA levels of Hh signaling-associated genes. It was found that the mRNA levels of GLI1, PTCH1, and HHIP are positively associated with the MRI image and pathological scores of the FJs, suggesting a role of the Indian Hh pathway in the development of FJ OA.It has been shown that ablation of Indian Hh from postnatal chondrocytes leads to closure of the growth plate, loss of trabecular bone, and defective skeletal growth2527In human OA cartilage and synovial fluid, Indian Hh is upregulated and is correlated with OA progressionet al. had reported that PTCH1, GLI1, and HHIP were all overexpressed in human osteoarthritic samples, as well as in the articular cartilage from a mouse model of osteoarthritis. In addition, mice with aberrant activation of the Hh pathway showed cartilage degradation and an increased tendency to develop osteoarthritis. The severity of the disease correlated with the degree of Hh pathway activation. Furthermore, genetic or pharmacologic inhibition of the Hh pathway in a mouse model of osteoarthritis significantly decreased collagen X deposition, cartilage degradation and osteoarthritis severity. Remarkably, inhibition of Hh in explant cultures of human osteoarthritic cartilage samples blocked expression of key genetic markers of osteoarthritis, including the metalloproteinases ADAMTS5 and MMP13, the transcription factor RUNX2, and COL10A1In addition, genetically modified mice that have elevated Hh signaling in chondrocytes showed more severe OA phenotype, and OA-caused cartilage damage can be alleviated by inhibiting Hh signaling in mice or human cartilage explantsGLI1, PTCH1, and HHIP, were found to be positively correlated with FJ OA pathological scores. This is the first study demonstrating a role of Indian Hh in the pathology of FJ OA. Future endeavors will deal with defining the precise role and underlying molecular mechanism by which Indian Hh signaling promote FJ OA.In our study, the mRNA expression levels of three Indian Hh-associated genes, F.S. and S.X.H. wrote the main manuscript text, J.L.Z., Y.L. and Y.Z. collected data and carried out the experiments, C.L.Z. analyzed the data, J.G.T. designed the experiments. All author has approved the manuscript.How to cite this article: Shuang, F. et al. Indian Hedgehog signaling pathway members are associated with magnetic resonance imaging manifestations and pathological scores in lumbar facet joint osteoarthritis. Sci. Rep.5, 10290; doi: 10.1038/srep10290 (2015).


Refugees are reported to experience high rates of dental disease, although there are limited data on refugee children. The aim of this study was to report on oral health in refugee-background children in Australia, and to assess their follow-up at dental services.Cross-sectional study of opportunistic oral health screening and subsequent dental service use in refugee-background children attending a refugee health clinic in Victoria, Australia, between November 2006 – November 2010.350 patients  had oral health screening; 241 (68.9%) were born overseas,  and 109 (31.1%) were born in Australia to African-background families. Parents were concerned about oral health in 65/341 (19.1%) children, with specific concern about caries in only 9/341 (2.6%). On assessment, 155/336 (46.1%) had visible caries and 178/345 (51.6%) had caries experience (dmft/DMFT > 0). Where parents were concerned about caries, they were likely to be present , however absence of parent concern about caries was not reassuring .Compared to Australian-born children of African background; African-born children were more likely to be referred for further dental care , although there was no statistically significant difference in caries prevalence. African-born children were less likely to have caries compared to other overseas-born children . Overall 187/344 (54.4%) children were referred for further dental care; 91/124 (73.4%) attended any dental appointment. Attendance rates were 90% with a phone reminder system for appointments, attendance reduced when this system lapsed.Oral health is an important public health issue in refugee-background children, despite low levels of parent concern and very few parent reported caries. Routine direct oral health assessment is important in refugee-background children and co-ordinated health systems may help improve their attendance at dental services. Poor oral health is linked with low socio-economic status and disadvantage . AvailabThe aim of this study was to provide local data on family/self reported oral health issues, dental assessment findings and dental service use in refugee-background children attending a refugee health clinic for medical review.The Royal Children’s Hospital (RCH) Immigrant Health Clinic (IHC) provides post-arrival refugee health screening and medical consultation/management for children of refugee background. The clinic does not receive referrals for oral health concerns. New patients/families attending the IHC were offered opportunistic oral health assessment and oral health promotion. The study population was therefore a convenience sample of children attending for medical review, over the period November 2006 to November 2010.The same dental therapist assessed patients throughout the study period in a standard medical outpatient room, using an overhead lamp and disposable glass mirrors. Assessment findings were documented during the consultation on a dental screening proforma based on the World Health Organization (WHO) Oral Health Assessment Form . PatientInformation collected included: patient demographics, requirement for interpreter assistance, parent/self-reported oral health concerns and dietary risk factors, findings on inspection (dentition type (primary/mixed/secondary), visible caries, caries experience, severe caries) and management plans . Visible caries was defined as the presence of a cavity, undermined enamel or softened floor or wall on a tooth surface, detected by the naked eye with the aid of a plane mouth mirror . Caries Follow-up of attendance by patients referred to RDH was collated retrospectively using the RDH electronic patient database to extract information on any scheduled appointment(s) and attendance at any scheduled appointment(s).Data were analysed using Excel,  and STATA version 11 . Proportions were calculated for the overall study population and subgroups: overseas-born  and Australian-born children of refugee background. Comparisons between overseas-born and Australian-born were restricted to children of African origin, after preliminary data analysis revealed all Australian-born children were born to African-background families. Chi-square tests of independence and two sample t-tests were used to compare demographic characteristics between subgroups, and prevalence ratios (PR) and confidence intervals (CI) were calculated. Log binomial regression was used to calculate adjusted PRs. PRs for any visible caries, any caries experience, and any referral were adjusted for sex and dentition type. PRs for specific caries experience outcomes were restricted by detention type then adjusted by sex. Age was not included in the final regression model in order to avoid over-adjustment, due to the close correlation between dentition type and age . Further, in terms of the accuracy of recorded age, it is not uncommon for birthdates to be recorded incorrectly in refugee children, although this information is rarely available on the initial visit . PositivAssessment findings were documented as part of routine clinical care, hence formal consent was not obtained. All data were de-identified for analysis and examined retrospectively; the risk to patient confidentiality was not beyond that of standard clinical care. Ethics approval was obtained from the Royal Children’s Hospital Human Research Ethics Committee (HREC reference number 31233B&C).Oral health assessments were available for 350 eligible children aged 0 – 18 years for the period November 2006 to November 2010. There were 180 (51.4%) males and 170 (48.6%) females; the mean age was 8 years 7 months (range 8 months – 17 years 11 months). Overall, 241 children (68.9%) were born overseas and 109 (31.1%) were born in Australia to refugee-background parents. There were 25 countries of birth and 25 different languages recorded, and an interpreter was required for 221/350 (63.1%) attendances. Of the 241 overseas-born children, 176 (73.0%) were from African source countries and 65 (27.0%) were from Asia, the Middle East or the Pacific region. All 109 children born in Australia were of African origin. All children’s residential postcodes were in fluoridated water regions at the time of data collection [Parent/self reported oral health concerns were present for 65/341 (19.1%) patients and dietary risk factors were reported by 78/342 (22.8%) . However, in the 271 children with no parent/self reported concern and referral status recorded, 127 were referred for further review  = 144/271 = 53.1%). Similarly, where parents reported caries they were likely to be present (PPV = 9/9 = 100%), however parents reported caries in only 9/341 (2.6%) children. Of the 319 children with no parent/self reported concern of caries and examination status recorded, 140 had caries (NPV (lack of parent concern and no caries) = 179/319 = 56.1%).In total 187/344 (54.4%) children were referred for further dental care (Table Attendance information was available for 124/148 (83.7%) patients referred to RDH. Overall, 91/124 (73.4%) attended an appointment, 66/124 (53.2%) attended their first scheduled appointment, 33 patients (26.6%) did not attend any scheduled appointments. A phone reminder system coordinated through the referring clinic was implemented in 2008, with a concurrent attendance rate of 90% during that year. Attendance reduced after this system lapsed.The median time from referral to first scheduled RDH appointment was 50 days . There was a substantial decrease in the waiting time between 2007 (median 274 days) and 2008 (median 45 days). The median waiting periods in 2009 and 2010 were 38 and 71 days respectively.t = −6.2454, p < 0.001), reflecting the clinical observation that this group comprised younger siblings born to refugee-background families , with a higher prevalence of primary dentition in Australian-born children (52.3% vs 22.3%). There was no significant difference in sex between groups . Comparisons between subgroups are shown in Table t = 0.2426, p = 0.809), mixed , t = 0.1074, p = 0.91 (DMFT)) and secondary dentition categories . Compared to Australian-born children, overseas-born African children were more likely to be referred for further dental care .The Australian-born group was significantly younger than the overseas-born African group (There was no significant difference in age (p = 0.22), dentition type (p = 0.44), or sex (p = 0.85) between the overseas-born children from Africa and overseas-born children from other countries. Overseas-born African children were less likely to have visible caries than children born in other source countries, . African children with primary dentition were less likely to have any caries experience , had a lower mean dmft score  and were less likely to have severe caries  compared to children with primary dentition born in other countries. There was no significant difference in caries experience between these groups in children with mixed or secondary dentition.This study provides the first data on oral health and dental service use in refugee-background children in Australia, and is one of few papers in the international literature examining oral health status in this group –18. OverPrevious Australian studies of adult refugees have found higher rates of dental decay compared to the general Australian population, including other disadvantaged groups , 9, 10. Other studies have found African children have fewer caries than other children , 27, 28.In the international literature, the reported prevalence of caries in resettled refugee children ranges from 15.1% - 85% , 16–18. In this study, Australian-born African children had fewer caries than their older African-born siblings. The difference in mean age between the two groups (6.4 years vs 9.5 years) is likely to be a contributing factor to this observation. Older children have had longer cumulative exposure to risk factors for dental caries, including exposure to dietary sugars and micro-organisms, and poor oral hygiene practices. Migration to, and length of residence in a developed country may confer additional benefits alongside any protective factors related to ethnicity. Children from developing countries, especially those from areas of conflict or refugee camps, typically have very limited access to dental care . Oral heAlthough parent/self reported oral health issues were infrequent, a significant proportion of children had abnormal findings on assessment, and over half were referred for further treatment; with a low negative predictive value for parent/self report. This suggests that in order to establish an accurate understanding of oral health problems in this group, history alone is likely to be inadequate, and direct assessment is important.Guidelines for post-arrival refugee health assessments include oral health screening and health promotion in addition to screening for nutritional deficiencies and communicable diseases , 38. IncFor newly arrived refugees in Australia, access to public dental health services may be limited. Davidson et al. (2007) reported variable costs for dental services and significant waiting periods, ranging from 13 to 58 months . This stThere are multiple reasons why refugee-background famillies fail to attend health or dental appointments. These include competing resettlement priorities, administrative issues, language barriers, lack of transport, traditional health beliefs or misunderstandings, and previous negative health service experiences , 40. AdmThere are several limitations to this study. Firstly, the study population was a convenience sample from a busy outpatient refugee medical service. However, previous studies have also used convenience samples from refugee camps  and refuIn this study, the prevalence of caries in (predominantly African) refugee-background children was similar to the caries prevalence in Australian children. Limited data suggest a higher prevalence of caries in refugee children from non-African source countries. Despite caries being common, parent concern about oral health was uncommon, and direct assessment of oral health is important in refugee children. Over half of this study group required further assessment at dental services, however attendance at follow-up was poor, despite comparatively short waiting periods and appointment reminders. A coordinated reminder system between health and dental services appeared to work well initially, suggesting this may be a way to improve attendance. This study provides the first Australian caries prevalence and service use data in refugee-background children, to inform public health policy and program development directed to this group.


Background: Atypical hemolytic uremic syndrome (aHUS) results from an inherited dysregulation of the alternative complement pathway leading to thrombotic microangiopathy consisting of hemolytic anemia, thrombocytopenia, and renal injury. The complement inhibitor eculizumab is an approved treatment, but its reported use in neonates – who have an inherently high risk of infection – is limited. Case diagnosis/treatment: A 28-day-old female presented with gross hematuria and hypertension. aHUS was suspected based on anemia with schistocytes, thrombocytopenia, low C3, and acute kidney injury requiring peritoneal dialysis. A septic work-up initiated on day 2 for hypothermia and respiratory failure was negative. There was no improvement after 6 days of plasma therapy. Despite being < 6 weeks old she was vaccinated with pneumococcal-13 conjugate, meningococcal (groups C and Y) polysaccharide, and Haemophilus b tetanus toxoid conjugate vaccines and started on penicillin prophylaxis. After 1 dose of eculizumab 300 mg, dialysis was discontinued and her hematological parameters improved. Genetic testing revealed a complement factor H mutation. After 11 months of follow-up, she remains on eculizumab and penicillin without recurrence of aHUS or any infectious complications. Conclusions: Eculizumab is a safe and effective treatment option for aHUS even in neonates at high risk for infection.  Atypical hemolytic uremic syndrome (aHUS) occurs when uncontrolled activation of the alternative complement pathway causes systemic endothelial damage via the membrane attack complex . ApproxiNeisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenza . , 5. 1, 5Because eculizumab levels are only available in one laboratory in the United States  and turn-around time can be > 1 week, there is a need for markers that can optimize dosing . In 6 chIt is also unknown if eculizumab can be discontinued in patients with aHUS. In a recent study by Ardissino et al. , 10 patiThe risks of prolonged eculizumab therapy include immunosuppression, the need for prophylactic antibiotics, repeated vascular access in a population potentially at high risk for chronic kidney disease, and the very high financial costs of therapy. The average wholesale price (AWP) of a 300 mg vial of eculizumab is currently listed at $7,196.40 . Haemophilus influenzae type b that are approved in the United States for infants ≥ 6 weeks of age  and s of age  14]. Me. MeHaemoSS participated in a dinner case presentation sponsored by Alexion. BLL is co-inventor on the following patent application, filed September 16, 2014: “Compositions and Methods for Treatment of HSCT-Associated Thrombotic Microangiopathy” application number PCT/US2014/055922. No other authors had a conflict of interest to disclose.


A number of studies based in the US, Canada, and Australia, have found evidence of associations between the built environment (BE) and mode of transport to school, and links between active travel and deprivation. Limited research in the UK compares potential BE supports for walking to school by area deprivation. Within this study, we gathered data on BE attributes previously linked to active travel, i.e., street/path connectivity, and dwelling density, created a composite ‘walkability score’ (WS) for areas around primary schools across urban Scotland, and explored whether poorer areas exhibit lower scores than more affluent areas, or vice versa. We consider this to be a novel approach as few studies have compared BE features by deprivation across a whole country.N = 937) across mainland Scotland were mapped. Schools were attributed income deprivation scores ). Catchment area (CA) boundaries, i.e., the geographic area representing eligibility for local school attendance, were drawn around schools, and WS calculated for each CA. We compared mean WS by income quintile (ANOVA), for all local authorities (LAs) combined (N = 29), and separately for the four LAs with the greatest number of schools included in the analysis.Address and road/path maps were obtained and primary schools  showed a significantly lower WS (−0.61), than quintiles 3, 4 and 5 (Q2: −0.04 (non-sig), Q3: 0.38, Q4: 0.09, Q5: 0.18); while for Glasgow the second least deprived quintile (Q2) showed significantly higher WS , than middling (Q3: 0.18) and most deprived quintiles .WS differ by deprivation with patterns varying depending on the spatial scale of the analysis. It is essential that less walkable areas are provided with the resources to improve opportunities to engage in active travel. A growing body of literature highlights the importance of the built environment (BE) in supporting physical activity (PA), and in particular the importance of ‘walkable’ neighbourhood design or ‘walkability’ in encouraging walking and active transport –5. The tA list of the addresses for all primary schools  across mainland Scotland was created using Scottish Schools online . OrdnancSchool postcodes were linked to the six fold ‘Urban Rural Classification 2011/2012’  and onlyWhen considering variables potentially linked to walking to combine in the WS, the four component walkability index  method , 26 has WS = (2 x intersection z-scores) + (dwelling density z-scores)  to the data zone area . Z-score used in ). Street used in . Maps ofIBM SPSS Statistics V.21 was used to compare mean WS by income quintile ) across quintiles. Comparisons were made by certain LAs, i.e., the LAs with the greatest number of schools/CAs included in the analysis, i.e., Glasgow: 138 schools, North Lanarkshire: 92 schools, Edinburgh: 80 schools, South Lanarkshire: 74 schools. Post-hoc tests were also carried out to explore differences between quintiles highlighted by ANOVA, using Bonferroni correction to reduce the likelihood of Type 1 errors.across the quintiles of income deprivation in mean WS (p < 0.001); the least income deprived quintile (Q1) showed the lowest mean WS (−0.61), followed by the second least deprived quintile (Q2) (−0.04), while Q3 (middling) showed the highest mean WS (0.38), followed by the most deprived (Q5) and second most deprived (Q4) quintiles  , but there were no other significant differences between other quintiles.937 primary schools across 29 LAs were included in the analysis with mean WS ranging from -4.90 to 20.26. There were significant differences p < 0.001). Within Glasgow the highest mean scores were found for Q2 and Q1, at 1.73 and 1.35 respectively, while the lowest scores were found within the most deprived quintile (−0.10), followed by the second most deprived quintile (0.06), and Q3 (0.18) .When comparing income quintiles for WS in Glasgow, Edinburgh, North Lanarkshire, and South Lanarkshire, separately, only Glasgow showed significant differences . Within one particular LA, Glasgow City, the poorest areas displayed lower WS, while Q2 showed the highest mean scores. Additional analysis (data not shown), comparing deprivation patterns of dwelling density and intersection density separately, showed that dwelling density was highest in Q2 for both Glasgow and Scotland, while connectivity was highest in Glasgow for Q2 and across Scotland in Q3; for Scotland the highest WS in Q3 was therefore driven largely by connectivity.In terms of results for primary schools across Scotland, our findings correspond to some degree with a previous study (‘Growing up in Scotland’ Study (GUS)) which looked at active travel to primary school by income deprivation quintile across Scotland . ResultsSimilarly to our results for Glasgow, the Perth study found areas around lower socio-economic schools to be less walkable, in terms of street and pedestrian connectivity and traffic exposure, than areas around higher SES schools, with findings being driven mainly by lower connectedness in the pedestrian network . Within Our research has a number of limitations. We included schools within urban areas only, and excluded rural schools; as rural CAs tend to cover much larger geographical areas. We found, when initially comparing urban and rural areas, that two-thirds of CAs in rural areas  extended beyond a ‘walkable distance’ of 2 miles around schools, while around 90 % of CAs in large urban areas are classed as ‘walkable’. It is likely that different factors should be explored when considering walkability in rural environments as walking infrastructure, public transport and commuting distance will differ considerably from urban areas . We recoDespite the limitations of this research, we believe this study to be of value as there appears to be scarce literature comparing BE features around schools by socio-economic measures such as area deprivation. Our study not only includes analysis at a national level but also at a more local level i.e., LAs; the variation in findings between urban Scotland in general, and Glasgow City specifically, highlight the importance of analyses at different geographical scales. Furthermore, we made use of robust objective measures to encapsulate walkability, using a combination of two key attributes, i.e., street/path connectivity and dwelling density, within GIS, shown to be effective in measuring walkability . PreviouResearch exploring potential inequalities in the BE supports for active travel to school is particularly valuable within the context of Scotland as over a quarter of Scottish children do not meet government recommended physical activity levels; with lower levels observed among girls, and decreasing levels as children age . Active Our study of urban areas across Scotland contributes to the limited research on potential variations in selected BE features, potentially associated with walking, around primary schools, by income deprivation. Disparities in composite walkability scores, according to deprivation, emphasize the need for specific areas to be allocated resources to improve opportunities for active transport, while the difference in findings between mainland urban Scotland and Glasgow City highlight the importance of exploring and comparing findings at different geographical scales, whether national or city wide.We welcome proposals for collaborative projects and data sharing. The raw data in excel file format could be provided via email by the corresponding author upon request for research purposes only.


The indications for a concomitant mitral valve (MV) procedure remain controversial for patients with hypertrophic obstructive cardiomyopathy (HOCM). According to previous studies, a concomitant MV surgery was required in 11–20% of inpatient operations. Thus, we aimed to study the outcomes of an extended Morrow procedure without a concomitant MV procedure for HOCM patients who had no intrinsic abnormalities of the MV apparatus. We retrospectively reviewed 232 consecutive HOCM patients who underwent extended Morrow procedures from January 2010 to October 2014. Only 10 (4.31%) patients with intrinsic MV diseases underwent concomitant MV procedures. Of the 232 patients, 230 had no to mild mitral regurgitation (MR) postoperatively. We separated the 232 patients into two groups according to preoperative MR degree. One group is mild MR, and the other is moderate or severe MR. The three-month, one-year, and three-year composite end-point event-free survival rates had no difference between two groups (p = 0.820). When we separated the patients to postoperative no or trace MR group and mild MR group, there was also no difference on survival rates (p = 0.830). In conclusion, concomitant mitral valve procedures are not necessary for HOCM patients with MR caused by systolic anterior motion, even moderate to severe extent. Hypertrophic cardiomyopathy has been recognized as the most common heritable cardiovascular disease, which affects one in 500 individuals1However, the relative scarcity of experienced surgeons capable of performing a septal myectomy in developing countries impedes the expansion of this operationThe baseline characteristics were summarized in The preoperative echocardiographic data were also shown in The number of operations distributed unequally during five years and increased tremendously. Concomitant procedures were conducted in 69 (29.7%) patients, including coronary artery bypass grafting (CABG) (54), MV repair (3), MV replacement (6), CABG and MV replacement both (1), the reduction of right ventricular outflow obstruction (2), and others (3). An adjunctive surgical ablation of AF was conducted in only five patients with persistent AF. There were no deaths within 30 days after the operation . The interventricular septum thickness was significantly reduced from 25.5 ± 6.5 mm before surgery to 17.1 ± 4.8 mm (P < 0.001) pre-discharge. Simultaneously, the LVOT pressure gradient fell from 92.2 ± 26.4 mmHg to 15.2 ± 8.7 mmHg (P < 0.001).The postmyectomy transesophageal echocardiography intraoperatively identified iatrogenic ventricular septal defects (VSDs) that were immediately repaired in three (1.3%) patients who were discharged uneventfully. A perforation of the anterolateral free wall near the apex contiguous to the anterior septum was created in one patient. It was located promptly by the surgeon and was repaired without sequela. Neither iatrogenic injury of the MV nor iatrogenic injury of the aortic valve occurred in the 232 procedures. The mean cardiopulmonary bypass and aortic cross-clamp times were 83.4 ± 28.7 and 53.9 ± 19.0 minutes. The median, 25th, 75th percentiles for the postoperative intubation time were 15 hours, 12 hours, and 18 hours, respectively.Six (2.6%) patients received new permanent pacemakers before being discharged from the hospital because of a CAVB. Of these six patients, two had a preoperative complete right bundle branch block (CRBBB), one underwent a concomitant reduction of a right ventricular outflow obstruction, and two had an iatrogenic VSD during the operation. Almost all of the patients had no to mild MR postoperatively, except for two patients who maintained moderate MR. However, among the 101 patients with mild MR preoperatively, 51 (50.5%) patients had no or trace MR, and 49 (48.5%) had mild MR. In contrast, among the 131 patients with moderate to severe MR preoperatively, only 39 (29.8%) had no or trace MR, and 91 (69.5%) had mild MR. The patients with mild MR preoperatively had less MR postoperatively (p = 0.002).The mean clinical follow-up period was 23.8 ± 13.7 months (one to 59 months). A total of 228 (98.3%) patients accepted our telephone questionnaire. This group of patients experienced substantial symptomatic and hemodynamic improvement after the myectomy. During the follow-up, 193 (83.2%) patients remained asymptomatic or minimally symptomatic. The degree of LVOT pressure gradients decreased significant compared with the preoperative values . The left atrial dimension fell to 38.7 ± 5.9 mm (P < 0.001). Eleven (4.7%) patients had a residual maximal LVOT pressure gradient >30 mmHg, and two (0.8%) patients had a residual maximal LVOT pressure gradient >50 mmHg. These appeared to be related to a residual obstruction of an initial myectomy rather than recurrent obstruction from muscle regrowth. All of the patients are free from any cardiac reoperation to date. Of the 46 patients with preoperative AF documented by an electrocardiogram, only 26 (56.5%) had a normal sinus rhythm during the follow-up.To date, only one patient has died. The overall survival was 100% at three months, 100% at one year, and 99.0% at three years . The oneDuring the follow-up, 16 (6.9%) patients met the composite end-point . The thrWe separated the 232 patients into two groups according to the MR stage before the operation. One group included 17 patients with severe MR and 114 patients with moderate MR. The other group included 101 patients with mild MR. There were no differences in the baseline clinical characteristics between the two groups, except for the left atrial diameter, LVOT pressure gradient, and percutaneous transluminal septal myocardial ablation (PTSMA) history . The thrIn this study, the patients with moderate to severe MR preoperatively were more likely to have residual mild MR postoperatively. To identify the influence of postoperative mild MR on the outcomes, we excluded the two patients who had moderate MR postoperatively. We separated the 230 patients into two groups: 90 (39.1%) patients with no MR or trace MR and 140 (60.9%) patients with mild MR. The three-month, one-year, and three-year composite end-point event-free survival rates of the patients with mild MR were similar to those of the patients with no or trace MR  . When weIn the Cox proportional hazard models for the composite end-points, we included all 232 patients in the analysis. The data from the univariable Cox analysis are described in Dr. W. P. Cleland, a British surgeon, reported the first myotomy in 19588912The outcomes of the septal myectomy in our consecutive 232 HOCM patients were as good as those reported by other famous centersAlthough a transaortic septal myectomy has a good prognosis for HOCM patients5Both preoperative AF and postoperative AF are predictors of composite end-point events. Postoperative AF is an independent predictor of the composite end-point events. In other studies, AF was always identified as the risk factor of worse outcomesThere are still some limitations. This is a retrospective study; all of the surgeries were performed by one experienced surgical team. There was no concomitant MV procedure, such as a leaflet plication or anterior leaflet extension, conducted to eliminate SAM and MR. Nevertheless, these conclusions still may be valid and clinically relevant. As previously reported, the survival rate of the HOCM patients after surgery was excellent. However, more attention should be focus on HOCM-related rehospitalization. The question of whether surgery could abolish the risk for progression to the end-stage phase of heart failure requires further study.Our results prove that the extended Morrow procedure can successfully improve the symptoms of HOCM patients. Concomitant MV procedures are not necessary for patients who have even moderate to severe MR caused by SAM. Residual mild MR postoperatively does not influence the outcome of these patients. Old age, iatrogenic SVD, and postoperative AF are independent predictors of worse outcomes.This study was approved by the Human Research Ethics Committee of the Fuwai Hospital and was performed in accordance with the Declaration of Helsinki and the approved guidelines. Oral informed consent was obtained from all of the patients via a telephone questionnaire. We retrospectively reviewed all of the 232 consecutive HOCM patients who underwent a transaortic extended septal myectomy in the ninth department of surgery in our institution from January 2010 to October 2014. The diagnosis of HCM was based on clinical and echocardiographic features with the presence of a hypertrophied non-dilated left ventricular in the absence of other cardiac or systemic disease capable of producing the magnitude of the hypertrophy evidentAll of the patients underwent comprehensive echocardiogram examinations with commercially available instruments. All of the transthoracic echocardiography procedures were performed by the same professional doctor. Echocardiographic parameters were acquired using standard views and protocolsAn intraoperative transesophageal echocardiography is a pre-requisite for surgery because it allows the detection of the ventricular septal anatomy and its thickness, the evaluation of the MV function, and the identification of other abnormalities. The chest is opened with a complete standard median sternotomy. To sufficiently expose the subaortic septum, an oblique aortotomy much closer to the sinotubular junction than that usually performed for an aortic valve replacement is made and carried to the midpoint of the noncoronary sinusAll of the follow-up data were obtained between January and May 2015. During the follow-up, the time and cause of death were provided to the immediate families. The end-point was a composite of all causes of death, resuscitation from sudden death, syncope, documented stroke, arrhythmia or congestive heart failure requiring hospitalizationt test or analysis of variance. Categorical data were expressed as percentages and were compared with a chi-square test. A Cox proportional hazards model was used to identify the risk factors of composite end-points. A stepwise multivariable Cox proportional hazards model was developed to determine the independent risk factors. The proportional hazards assumption in the Cox model was assessed with models including time-by-covariate interactions. Cumulative event rates were calculated using a Kaplan-Meier method, and different event curves of outcomes were compared using a Log-Rank or Tarone-Ware test. All of the P values were reported two-sided, and P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 20 .Continuous data were expressed as the mean ± standard deviation and compared using a Student’s How to cite this article: Liu, Y. et al. Outcomes of an extended Morrow procedure without a concomitant mitral valve procedure for hypertrophic obstructive cardiomyopathy. Sci. Rep.6, 29031; doi: 10.1038/srep29031 (2016).


Type 2 diabetes mellitus has well known deleterious effects on coronary artery disease (CAD). The role of milder hyperglycemic states such as prediabetes (PD) on CAD is debatable. Glycated hemoglobin (HbA1c) has recently been advocated as a diagnostic tool for diabetes mellitus (DM) and PD. This study aims to assess the cardiometabolic risk profile and coronary lesions of patients with PD undergoing coronary angiography identified either by fasting plasma glucose (FPG) or HbA1c levels.We studied 514 individuals without previously known glucose disturbances. Their glycemic status was assessed by FPG and HbA1c (HPLC) and classified according to ADA guidelines, using each parameter independently, as having normal glucose tolerance (N), PD, or DM. CAD was defined as stenosis greater than 50% in one major coronary vessel or branch. Framingham score was calculated.Subjects with PD had a similar frequency of CAD compared do N individuals by both FPG (61 vs. 59.3%) and HbA1c (55.4 vs 61.2%) (p non-significant for linear-by-linear association). PD individuals identified by FPG had worse HOMA2B (mean [95% CI] 65.4 [60.9-69.9] vs. 76.6 [71.4-81.9]) and HOMA2-IR (1.10 [0.98-1.22] vs. 0.80 [0.72-0.89]) when compared to N controls. PD individuals identified by HbA1c had higher frequency of Framingham risk above 20% (25.4 vs 11.8%), arterial hypertension (87.8 vs 72.6%), and dyslipidemia (83.8 vs 72%) compared to N individuals. PD associated with an increased number of coronary lesions only when diagnosed by HbA1c .HbA1c was more effective than FPG in identifying individuals with PD associated with high cardiovascular risk profile in a sample of individuals undergoing coronary angiography. It is well established that patients with type 2 diabetes mellitus have a higher risk of developing atherosclerosis and cardiovascular disease (CVD) than non-diabetic individuals. This condition accounts for the majority of deaths in individuals with diabetes mellitus (DM) . AccelerUndiagnosed hyperglycemia is a common finding in acute coronary syndromes and active search for this disorder in the inpatient population is warranted . Also, sMoreover, there is still a strong debate whether individuals with PD identified by different parameters would present different metabolic patterns and related cardiovascular risk. In this regard, we have several tests to identify PD such as fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), and more recently the use of hemoglobin A1c (HbA1c) levels . HbA1c hIn this study we aim to assess whether the frequency of CAD, its severity, and cardiovascular risk markers are different in patients with PD diagnosed by FPG and HbA1c classification criteria as compared to type 2 diabetes and normoglycemic subjects.A total of 813 consecutive patients who underwent coronary angiography at Hospital São Paulo  were enrolled in the present study. Individuals with previously diagnosed DM were excluded, resulting in 514 eligible patients. Study subjects, individually and/or as a group, had mixed ethnic background , reflecting the heterogeneity of the Brazilian population .A blood sample was drawn before coronary angiography, after an overnight fast for analysis of FPG, plasma insulin, HbA1c , lipid profile , TSH, and creatinine levels. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease (MDRD) study equation . InsulinPatients were referred to coronary angiography by their physicians for various reasons, including presence of stable angina, a positive stress test, or for preoperative evaluation for cardiac valvular disease or peripheral vascular disease surgeries. Clinical data as well as personal and family history of cardiovascular disease, DM, and associated diseases were obtained by interview and medical examination by one member of the research group. Patients had their glycemic statuses assessed by FPG and HbA1c levels. They were classified by both criteria according to ADA guidelines in normal (N), PD, and DM . For theArterial hypertension was defined as systolic blood pressure (SBP) ≥ 140mmHg and/or diastolic blood pressure (DBP) ≥ 90mmHg, or SBP and DBP below these values in the presence of antihypertensive medication and history of arterial hypertension. Subjects were considered to have dyslipidemia either if levels of LDL-cholesterol were ≥160mg/dL, HDL-cholesterol below 40mg/dL in men and 50mg/dL in women, triglycerides >200mg/dL, or in the presence of use of lipid lowering medications (statin/fibrates) .The Framingham score was calculated as described elsewhere . In brieBesides previous DM, exclusion criteria included a creatinine clearance lower than 50 mL/min, abnormal thyroid function, the presence of active inflammatory disease or neoplasia, or anemia (Hemoglobin < 10 g/dL), conditions that could potentially interfere in some of of the laboratory measurements performed or in the presence of CAD itself. Patients with acute coronary syndromes and ST segment elevation have been excluded because thrombotic events could overestimate stenosis.Comparisons of continuous variables among normal, PD, and DM groups were made by ANOVA. Means and 95% confidence intervals (CI) were recorded, instead of means + SD, to enable comparisons between individuals classified by both FPG and HbA1c, since these don’t represent different subgroups, but the same individuals grouped differently. Number of coronary lesions was assessed by Jonckheere-Terpstra test, p values for trend were recorded. Categorical variables were assessed by Mantel-Haenszel test and p for linear-by-linear association was recorded. A two-tailed value of p < 0.05 was considered statistically significant.When classified by the FPG criterion, individuals with PD had similar demographic and clinical characteristics such as age, BMI, abdominal circumference, blood pressure, and lipid levels compared to other groups. They had higher FPG and HbA1c levels (by definition), as well as higher insulin resistance and lower beta-cell function assessed by HOMA indexes, when compared to N individuals. DM individuals had only higher FPG and HbA1c levels, being also more insulin resistant when compared to both N and PD individuals. Beta-cell secretion of these individuals was similar to the other groups Table .Table 1When classified by the HbA1c criterion, individuals with PD had also similar demographic and clinical characteristics such as age, BMI, abdominal circumference, blood pressure, and lipid levels when compared to the other two groups. They had higher glycemic parameter levels , but HOMA indexes were not different between PD and N. DM individuals had higher FPG and HbA1c levels, and were more insulin resistant than both N and PD Table . RegardiOur study suggests that the use of HbA1c for the diagnosis of PD identifies individuals with more cardiovascular risk factors than the use of FPG in a high-risk population of individuals undergoing coronary angiography, as assessed by the Framingham score. PD individuals diagnosed by HbA1c also presented more severe CAD when compared to N subjects. This profile was not seen in PD individuals identified by FPG.As expected, glycemic variables and HOMA indexes were different in individuals divided by FPG, since this measurement itself is used in the HOMA calculations. Interestingly, even though they demonstrated worse HOMA2B and HOMA2-IR as compared to normoglycemic subjects, individuals with PD did not show other differences in cardiometabolic risk profile. In the identification of hyperglycemia, the use of FPG, 2-h postload glucose, and HbA1c are associate with distinct patterns of insulin sensitivity and insulin secretion, which could possibly explain these findings . For exaRegarding cardiovascular risk factors, Di Pino et al. found that PD according to HbA1c levels selected individuals with higher cardiovascular risk compared to those with PD detected by either FPG or OGTT . Our finThere is an ongoing controversy about whether FPG or post load glucose would have a stronger association with atherosclerosis, and also about which kind of intervention regarding these parameters would modify cardiovascular risk more effectively , 20. TheMoreover, the use of HbA1c for the diagnosis of dysglycemia is more recent. Most studies that have addressed the issue of PD and CVD have used fasting glucose and/or OGTT as definitions of diagnosis. For example, the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab) showed that the risk of death was increased in those with IFG and IGT, but the risk of CVD mortality was only significantly higher for those with IFG, but not IGT, compared with normal glucose tolerance, even after adjustment for age, sex, and other traditional CVD risk factors . The WOSThe use of HbA1c measurements have some advantages over assessments of both FPG or OGTT. Some of them are very practical concerning patients submitted to coronary angiography, since no fasting is necessary and there is less interference during periods of stress . Among tOur study has several limitations. Firstly, we studied individuals with high cardiovascular risk profile, as they had clinical indication for cardiac catheterization. Therefore, our data are not applicable to the general population. In the same way, there are differences in the hemoglobin glycation among ethnic groups, which could lead to discrepancies in the correlation between HbA1c and FPG levels . Thus thHbA1c identified individuals with PD bearing a worse cardiometabolic risk profile as assessed by the Framingham score and more severe CAD when compared to either normoglycemic subjects or subjects with PD identified by FPG, in a sample of high cardiovascular risk individuals.


Liver transplantation has received increased attention in the medical field since the 1980s following the introduction of new immunosuppressants and improved surgical techniques. Currently, transplantation is the treatment of choice for patients with end-stage liver disease, and it has been expanded for other indications. Liver transplantation outcomes depend on donor factors, operating conditions, and the disease stage of the recipient. A retrospective cohort was studied to identify mortality and graft failure rates and their associated factors. All adult liver transplants performed in the state of São Paulo, Brazil, between 2006 and 2012 were studied.+ ≥ 141.01 mg/dl [RR = 1.70 (95% CI: 1.47–1.97)], RNI ≥ 2.71 [RR = 1.64 (95% CI: 1.41–1.90)], body surface ≥ 1.98 [RR = 0.81 (95% CI: 0.68–0.97)] and donor age ≥ 54 years [RR = 1.28 (95% CI: 1.11–1.48)], male gender [RR = 1.19(95% CI: 1.03–1.37)], dobutamine use [RR = 0.54 (95% CI: 0.36–0.82)] and intubation ≥ 6 days [RR = 1.16 (95% CI: 1.10–1.34)] affected the negative outcome rate.A hierarchical Poisson multiple regression model was used to analyze factors related to mortality and graft failure in liver transplants. A total of 2,666 patients, 18 years or older,  were investigated. Outcome variables included mortality and graft failure rates, which were grouped into a single binary variable called negative outcome rate. Additionally, donor clinical, laboratory, intensive care, and organ characteristics and recipient clinical data were analyzed. The mortality rate was 16.2 per 100 person-years (py) (95% CI: 15.1–17.3), and the graft failure rate was 1.8 per 100 py (95% CI: 1.5–2.2). Thus, the negative outcome rate was 18.0 per 100 py (95% CI: 16.9–19.2). The best risk model demonstrated that recipient creatinine ≥ 2.11 mg/dl [RR = 1.80 (95% CI: 1.56–2.08)], total bilirubin ≥ 2.11 mg/dl [RR = 1.48 (95% CI: 1.27–1.72)], NaThe current study confirms that both donor and recipient characteristics must be considered in post-transplant outcomes and prognostic scores. Our data demonstrated that recipient characteristics have a greater impact on post-transplant outcomes than donor characteristics. This new concept makes liver transplant teams to rethink about the limits in a MELD allocation system, with many teams competing with each other. The results suggest that although we have some concerns about the donors features, the recipient factors were heaviest predictors for bad outcomes. Liver transplantation has gained increased attention in the medical field since the 1980s due to the introduction of new immunosuppressants and improved surgical techniques. These factors have also improved outcomes, and a huge expansion in transplants and institutions performing this procedure has occurred. Currently, liver transplantation is the treatment of choice for patients with end-stage liver disease, and this treatment has been expanded to other indications as well.et al is useful for calculating the liver graft risk based on donor variables )*0.725)*(mass [kg])0.425), gender and cause of death ;Donor clinical data: age, body mass index—BMI—(mass [kg]/height [m]+ (sodium) (mg/dl), serum GOT  (mg/dl), serum GPT (glutamic-pyruvic transaminase) (mg/dl), alkaline-phosphatase (mg/dl), glutamyl-transferase (mg/dl), total bilirubin (mg/dl), and creatinine (mg/dl);Donor laboratory data: serum NaDonor intensive care data: intensive care days; intubation days; use of dopamine, dobutamine, and noradrenaline;Organ characteristics: cold ischemia time (hours) and warm ischemia time (hours);2) and body surface ((0.007184*(height [cm])*0.725)*(mass [kg])0.425);Recipient clinical data: age (year), body mass index (mass [kg]/height [m]+ (mg/dl);Recipient laboratory data: creatinine (mg/dl), total bilirubin (mg/dl), serum international normalized ratio (INR), serum NaOther features: recipient MELD Score (0.957*ln[serum creatinine]+0.378*ln[serum bilirubin]+1.120*ln[INR]+0.643)*10 , outcome (death and graft failure) and outcome causes .Individual donor and recipient variables available in the database were grouped as follows:The origin of the organ, according to the organ collection center (OCC), was the geographical context variable available in the database. The São Paulo Transplant Center (SPTC) coordinates 10 OCCs, including 4 in São Paulo City  and 6 in countryside states  .Outcome measures included the mortality rate and graft failure rate, grouped into a single binary variable (yes/no) called the negative outcome (NO) rate. Continuous quantitative independent variables were binarized by percentile rank, with the third quartile serving as the cutoff reference.The study was reviewed and approved by the Research Ethics Committee of the Clinics Hospital, São Paulo University Medical School (Protocol Number #9949–13), in accordance with Brazilian and international regulations for research with human subjects. The institutional review board (IRB) waived the individual requirement for written informed consent, and they requested written consent from the director of SPTC because this was a retrospective study. The board also requested confidentiality of the individuals’ data, which was ensured at all stages of the project. The following information was de-identified: name, address, zip code, registration, donor's name and donor registry. None of the transplant donors were from a vulnerable population and all donors or next of kin provided written informed consent that was freely given.A hierarchical multiple regression model was considered to study factors related to mortality and graft failure in liver transplants. This analysis is generally used to explain the relationship between variables in models with a set of empirical propositions already indicating the relationship strength and direction between predictors and outcomes. The order of predictor entry in the regression equation was defined by the researcher based on a pre-established conceptual framework .Building a conceptual framework requires knowledge of the biological and temporal determination affecting outcomes . Using tThe position of a specific set of variables regarding the outcome was based on the arithmetic mean of the scoring system, named the expert score (ES). Organ characteristics data were the most proximal terms (4 to 5 points). Medial terms (3 to 4.99 points) included donor clinical data, donor laboratory data, donor intensive care data and recipient clinical data. The distal terms (1 to 2.99 points) included recipient laboratory data .Data are shown as absolute frequency, means with standard deviations (SD), proportion with confidence intervals 95% CI), and medians with interquartile ranges (IQRs) unless otherwise stated 5% CI, an. Crude iTo estimate survival time until death, graft failures and negative outcomes were used based on the Kaplan-Meier method ,13. To sTo improve the different models, predictor variables were tested for collinearity with the variance inflation factor (VIF) as well as for the presence of influential values. Model accuracy was evaluated using a cross-validation system ,15.http://www.r-project.org/) for statistical treatments. All the significance levels were set to p<0.05.The database was exported to the Statistical Package for the Social Sciences (SPSS) 22 for Windows  and R-GUI version 3.0.2 , with a mean of 2.07 (SD 1.87) per person. The median follow-up duration was 1.75 years . The transplantation midpoint time was 2009 (SD 1.55). Thus, most transplants were concentrated between 2008 and 2010, as shown in We recorded 897 (33.6%) deaths and 100 (3.8%) cases of graft failure . Fig 3C + higher than 141 mg/dl and body surface lower than 1.98  and AIC  values, was IV; this model explained a greater amount of variance compared with an empty model , model I , model II  and model V . However, it was not significantly better than model III . After adjustment in the Poisson multiple regression model, most analyzed variables maintained or improved (donor body surface and dobutamine use) their statistical significance and effect. Only donor total bilirubin was lower than 0.81 mg/dl and exhibited no significant effect after the adjustment .The MELD score was implemented as an allocation system for liver transplants in the USA in February 2002 . This moThe post-transplant survival  in this Although liver transplant waiting list mortality is closely correlated with MELD score, and these advanced cirrhotic patients urgently require transplantation, extended criteria grafts in very ill patients can lead to worse post-transplant outcomes. However, survival benefit studies show that these patients benefit more from this procedure, even with some risk of a mismatch –25. ThisRecipient creatinine, bilirubin and prothrombin time are biochemical markers of liver and kidney function and were shown to be much more relevant than any other donor characteristics. These markers are part of the MELD calculation, a score that is associated with short-term survival in patients with terminal hepatic insufficiency . A high Another recipient factor associated with better outcomes in our study was the body surface of the donor above 1.98. This finding is likely related to better nutrition in these patient groups. In a situation with a high percentage of critically ill patients, malnutrition is responsible for raising morbidity and mortality indices .These results demonstrated that scores based only on donor data, such as the DRI (donor risk index)  and ECD Other studies have evaluated recipient data  or both Regarding donor gender, some authors have reported an increased risk of graft loss as high as 20% when female donor organs have been transplanted into male recipients. However, others did not find such differences . Other sDonor maintenance in many cases is not ideal in Brazil. Some hospitals do not have enough ICU beds for every patient and experience frequent staff shortages. Besides the mentioned problem, our data demonstrated that objective factors related to the donor do not have a big influence on patients outcomes. Donor liver enzymes, days in the ICU, BMI and vasoactive drugs had no negative impact on outcomes, which is in contrast with previous studies ,31,36,37The finding that a lower rate of NO was associated with dobutamine use in the maintenance of the donor was interesting. In our best study model (model IV), the probability of negative outcome was 46% lower in cases with donors using dobutamine. It is important to highlight the effect of this factor in association with other modeled variables [crude RR = 0.63 (95% CI: 0.43–0.92) vs. adjusted RR = 0.54 (95% CI: 0.36–0.82)]. Dobutamine is a catecholamine derivative with specificity for beta-1 adrenergic receptors and is commonly used as a cardiotonic agent after cardiac surgery and during dobutamine stress echocardiography . NoradrePrior to the database analysis, we performed a survey with transplant experts to evaluate the factors most significantly associated with negative outcomes following liver transplants. This analysis resulted in the theoretical framework analyzed herein . The resThese experts are familiar with the specialized literature and attend international meetings regularly; however, despite their experience in the field, their knowledge of global-scale data can obscure their recognition of the realities in their own countries. The contrast between the survey and data presented herein reinforces the need for region-specific versus internationally standardized scores.The MLG multiple model was used to assess the impact of factors on the NO rate and no survival analysis, as used in previous studies ,39,40. IThe large retrospective cohort dataset was a strength in this study . AdditioWe found results lower than expected regarding patients and graft survival, but after analyzing it we could understand that they are mailing due to recipient factors. As we could see in other countries the MELD system allocation, with many teams competing with each other for not enough organs and pushing the limits for the sicker patients is harmful and bring down the outcomes. However, instead to look for another allocation system as other authors, the present study allowed a better dealing with the MELD system. We are now, in our region, trying to avoid the futile transplant. We are paying more attention on very sick patients, with high MELD score, especially in those with many organs support or after recovering from septic treatments. These measures are improving the results.We demonstrated the greater importance of recipient disease stage vs. donor factors in predicting post-transplant results. This study leaded to a better dealing with the MELD system and it is improving the results. Future studies will be conducted with this dataset to develop a national liver transplant algorithm. We intend to use the variables that have been shown to impact on the probability of negative outcome raised in this study and intelligent computing tools to develop a model applied to the Brazilian reality.The current study confirms that both donor and recipient characteristics must be taken into consideration with respect to post-transplant outcomes and prognostic scores. Our data demonstrated that recipient health status was more important than donor status in predicting transplant outcomes. These results bring a better comprehensive of the harmful of pushing the limits of transplanting very sick patients. Moreover, it also allows us to better deal with MELD allocation system in an organs shortage reality associated with a very competitive scenario.


Increasing laboratory findings indicate that n-3 fatty acids, mainly derived from fish, inhibit cancer development and progression, but results from epidemiologic studies have been inconsistent and inconclusive.To evaluate the association of fish intake with risk of liver cancer by conducting a meta-analysis.Published case-control/cohort studies that evaluated the relationship between total fish intake and risk of liver cancer were found on PubMed and EMBASE. The pooled relative risks (RRs) with 95% confidence intervals (CIs) were obtained with the random-effects model.Five retrospective case-control studies and 5 prospective cohort studies were included in the final analysis, involving a total of 3 624 liver cancer cases. Comparing the highest with the lowest category of total fish intake, the pooled RRs of liver cancer were 0.79  for case-control studies, 0.82  for cohort studies and 0.82  for all studies combined. The protective effects of total fish intake against liver cancer were confirmed by stratified and sensitivity analyses. In addition, an increase in fish intake of 1 serving/week was estimated to be significantly associated with 6% lower risk of liver cancer .Findings from this meta-analysis suggest that a higher fish intake is associated with reduced risk of liver cancer. Liver cancer is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related death worldwide, with about 564 000 new cases occurred each year ,2. The bet al. pointed out that “mounting evidence shows that dietary n-3 PUFAs inhibit the promotion and progression stages of carcinogenesis”[Fish is a rich source of n-3 polyunsaturated fatty acid (n-3 PUFA). In a previous review addressing potential mechanisms where by n-3 PUFAs may affect cancer risk, Larsson ogenesis”. Conversogenesis”. The 200ogenesis”. Howeverogenesis”,11,12,13ogenesis”,16,17,18We searched for potentially relevant publications through December, 2013 on PubMed and EMBASE databases using the search terms “fish” in combination with “liver cancer” or “hepatocellular carcinoma” or “liver neoplasm”, without language restrictions. The reference lists of retrieved publications were also carefully reviewed for any further studies.Studies were eligible for inclusion if they met the following inclusion criteria: (1) study design was case-control or cohort; (2) exposure of interest was total fish intake; (3) outcome was incidence or mortality of liver cancer; and (4) relative risks (RRs) or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were reported (or could be estimated). Studies that investigated the effect of specific type of fish or fish prepared/cooked with specific methods  were excluded. The titles and abstracts of all potentially relevant publications were reviewed to evaluate the relevance of the information; full-texts were scrutinized if any potentially relevant information was identified in a retrieved abstract.The following data were extracted from each included eligible study using a standardized data-collection protocol: the first author’s last name, publication year, country of origin, study design, number of cases and subjects, outcomes , ascertainment of exposure and outcome, levels of fish intake, RR or OR estimates with corresponding 95% CIs for each category of fish intake and variables controlled for in the analysis. Literature search, study selection and data abstraction were performed independently by two investigators, with any disagreements resolved by discussions.et al.[et al.[RR with 95% CI is the measure of effect of interest in this meta-analysis, and ORs in the included case-control studies were considered as RR approximations because the risk of liver cancer is sufficiently low. Where possible, the risk estimates with adjustment for multivariables were used. The study by La Vecchia et al. did not l.[et al. that repl.[et al.. Stratifet al.[A dose-response analysis was performed according to the method proposed by Greenland and Longnecker  and Orsiet al.. Becauseet al.. For eveI2 statistics[P-value of less than. 1 was considered statistically significant heterogeneity. Potential publication bias was evaluated using Egger’s test and Begg’s funnel plot[Statistical heterogeneity was assessed using Q and tatistics. For thennel plot. All staThe flow chart of literature search is shown in et al.[The 10 studies, including 5 retrospective case-control studies .The RRs for liver cancer with different fish intake categories relative to the lowest category are shown in Stratifying the analysis by study design, the summary RR was 0.79  for case-control studies and 0.82  for cohort studies. According to geographic area, the summary RR was 0.81  for 4 Asian studies and 0.77  for 5 European studies. By the number of liver cancer cases, the pooled RR was 0.76  for 5 studies with cases of ＜300 and 0.84 (0.72–0.97) for 5 studies with≥300 cases. The summary RR for liver cancer incidence was 0.81  and for cancer mortality was 0.85 (0.70–1.04). A sensitivity analysis conducted by excluding one study at each turn and pooling results from the remainder showed that the summary RR ranged from 0.79  to 0.84 , indicating that our findings were not sensitive to any individual studies.et al.[et al. [The hospital based case-control study by Kanazir et al. was an o.[et al.  that conP = 0.74, I2 = 0.0%). The inverse association remained statistically significant when restricting to prospective cohort studies .Seven studies ,15,17,18P = 0.07). Visual inspection of the Begg’s funnel plot, however, did not show considerable asymmetry , ,12, 10,1A further important consideration is the potential publication bias. It is well known that positive results have a greater chance of being published, whereas small studies with null findings tend not to be reported. Two commonly applied tests to access publication bias are Begg’s and Egger’s tests. In an overall meta-analysis of case-control and cohort studies, there was a suggestion of publication bias with Egger’s test (though not significant). However, the test may be of low statistical power when the number of studies was relatively small. Thus, wSeveral limitations in this meta-analysis warrant mention. Residual or unknown confounding cannot completely be ruled out. Those subjects with higher fish intake may also be more likely to have favorable dietary patterns, healthier lifestyles, or both. Several included studies also did not control for a variety of potential risk factors for liver cancer, such as HBV/HCV, alcohol and coffee drinking, smoking and body mass index, etc. Second, the levels of fish intake among different populations, and the methods for assessing fish and identifying liver cases were largely inconsistent. However, there was little evidence of heterogeneity either in the high vs. low, or in the dose-response analyses. Finally, we only investigated total fish, and the effects of individual fish on liver cancer risk remains to be determined in future studies. The potential limitations for observational studies to access relationship between diet and health, and the difficulty in conducting prospective studies properly accounting for multiple risk factors for liver cancer were also well addressed in the editorial by Freedman and Marrero. As theyIn sum, findings from this meta-analysis of published case-control and cohort studies suggest a significant inverse association between total fish intake and risk of liver cancer. Future well-designed prospective studies are needed to further confirm our findings.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Chronic kidney disease (CKD) is more prevalent among women and is associated with adverse cardiovascular events. Among women with symptoms and signs of ischemia enrolled in the Women’s Ischemia Syndrome Evaluation (WISE), a relatively high mortality rate was observed in those with no obstructive coronary artery disease. Coronary microvascular dysfunction or reduced coronary flow reserve (CFR) was a strong and independent predictor of adverse outcomes. The objective of this analysis was to determine if renal function was associated with coronary microvascular dysfunction in women with signs and symptoms of ischemia.The WISE was a multicenter, prospective, cohort study of women undergoing coronary angiography for suspected ischemia. Among 198 women with additional measurements of CFR, we determined the estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. We tested the association between eGFR and CFR with regression analysis.P = 0.002). This association persisted even after covariate adjustment. Each 10-unit decrease in eGFR was associated with a 0.04-unit decrease in CFR (P = 0.04).There was a strong interaction between eGFR and age (P = 0.006): in those ≥60 years old, GFR was strongly correlated with CFR . No significant correlation was noted in those <60 years old.The median eGFR was 89 ml/min. The eGFR correlated with CFR (r = 0.22; Reduced renal function was significantly associated with lower CFR in women with symptoms and signs of ischemia. Coronary microvascular dysfunction warrants additional study as a mechanism contributing to increased risk of cardiovascular events in CKD. Chronic kidney disease (CKD) is associated with adverse cardiac events and excessive cardiovascular (CV) mortality. TraditiCKD is associated with inflammation, and serum levels of the acute phase reactant C reactive protein (CRP), interleukin-6 (IL-6), and serum amlyoid A (SAA) correlate with level of renal function and all-Interestingly, CKD is associated with microvascular dysfunction in other organ systems such as the cerebral and retinal circulation,13. The We hypothesized that reduced renal function, determined by estimated glomerular filtration rate (eGFR), would be independently associated with a reduced CFR.The Women’s Ischemia Syndrome Evaluation (WISE) , a prospective cohort study initiated by the National Heart, Lung and Blood Institute to improve the understanding of pathological mechanisms and diagnostic evaluation of ischemic heart disease in women, enrolled women with symptoms and signs of ischemia referred for coronary angiography. Details of the WISE study design have been described previously. BrieflyP<0.001) with volumetric flow[Coronary reactivity testing was performed in a stenosis free area of the left anterior descending coronary artery when possible, with the left circumflex artery as a secondary choice. A Doppltric flow.2) and CFR (≥2.5 or <2.5). Data are presented as either mean ± standard deviation for continuous variables or n(%) for categorical variables. Skewed variables are reported as medians (IQR) and transformed to log base 2 to satisfy the assumptions of homogeneity, linearity, and Gaussian distribution of errors. General linear regression was applied to compute P-values for continuous variables, and logistic regression for categorical variables. All P-values for baseline variables, except age, are age-adjusted. Normality of log2CFR and eGFR were tested using the Kolmogorov-Smirnov test. Pearson’s correlation was used to check univariate correlation between log2CFR, eGFR, and demographic factors. Multivariable linear regression analysis was conducted to identify potential predictors of CFR including history of diabetes, hypertension, dyslipidemia, metabolic syndrome, body mass index (BMI), CAD severity score, double product (heart rate X systolic blood pressure), hemoglobin, ever smoker, CRP, IL-6, SAA, age, current hormone replacement therapy, and eGFR (in unit of 10). A backward selection was employed, and covariates with P-value >0.2 were sequentially removed from the model. History of diabetes, hypertension, and dyslipidemia were forced into the model. All statistical analyses were conducted using SAS 9.3 .There were 198 patients with measurements available for CFR and eGFR. Clinical characteristics were stratified by median renal function (eGFR ≥89 or <89 ml/min/1.73 m2) and CFR (≥2.5 or <2.5) are summarized in The mean age was 55±10 years, and most women were menopausal (74%) and had multiple risk factors for CAD including hypertension (56%), hyperlipidemia (51%), metabolic syndrome (45%), diabetes (22%), and smoking (20%). The baseline characteristics categorized by renal function (eGFR ≥89 or <89 ml/min/1.73 mP = 0.002), as shown in P = 0.0003, model R2 = 0.18). No other variables were significant independent predictors of CFR. Results of the multivariable regression are summarized in In univariate analysis, renal function, eGFR, was significantly correlated with CFR  even though age and renal function showed a significant interaction (P = 0.006). When age was dichotomized as < or ≥60 years, 42% of women with eGFR<89 ml/min/1.73 m2 and 48% of those with eGFR ≥89 ml/min/1.73 m2 who were <60 years old had a low CFR (<2.5). However, in those ≥60 years old, 63% of those with eGFR <89 ml/min/1.73 m2 had a low CFR compared with only 36% of those with eGFR ≥89 ml/min/1.73 m2. eGFR and CFR showed a linear correlation among those ≥60 years old , while there was no significant correlation in those <60 years old   . The int2, which is below normal. Others have found an association between CFR and renal function. Charytan et al. assessed CFR by positron emission tomography in 435 non-diabetic individuals. Although baseline CFR was significantly associated with eGFR, no significant association was found after adjusting for age and hypertension status, but on longitudinal follow up a decline in eGFR was a strong and independent predictor of a decrease in CFR[Studies examining the association of CFR with renal function have shown conflicting results. A study of 22 non-diabetic subjects found no significant differences in CFR between individuals with moderate to severe CKD and 10 healthy controls. However2 had higher CFR compared to those with eGFR <60 ml/min/1.73 m2. CFR was lower in women, the elderly, and those with hypertension. Multiple logistic regression analysis adjusted for age, sex, and hypertension showed that the association of renal function and CFR persisted. But when subjects were dichotomized into groups with eGFR ≥60 and <60 ml/min/1.73 m2, there was no discernible effect of milder degrees of renal failure on CFR, particularly in women. Bezante et al. suggested that an eGFR of <60 ml/min/1.73 m2 conferred a seven-fold higher risk of having an impaired CFR[Chade et al. assessed CFR using intracoronary adenosine in 605 patients without significant obstructive CAD. Patientaired CFR, but theP = 0.004). We have previously shown in the WISE cohort that clinical and demographic variables explain only 16% of the variance in CFR and are not independently associated with CFR. eGFR on the other hand is significantly associated with CFR, even after controlling for multiple covariates including diabetes, hypertension, dyslipidemia and severity of obstructive coronary artery disease.Our study, the only one focusing solely on women, contained the largest number of women with coronary angiographic data, and had a prospectively defined protocol requiring that angiograms and CFR recordings be read by core labs masked to all other patient data. Determination of CMD was by direct coronary blood flow measurements in response to intracoronary adenosine to measure CFR. We found that even among women with only mild renal dysfunction, CFR is linearly associated with eGFR, with each 10-unit decrease in eGFR being associated with a 0.02-unit decrease in CFR  and 30% in those over the age of 60 years (r = 0.55). This is at least in part because the WISE cohort included women who were referred for coronary angiography and thus excluded those with severe renal dysfunction. This limits generalization of results to other populations. We did not assess proteinuria at baseline or at follow up. Recent data suggest that presence of albuminuria would better stratify those at risk for vascular events, especially among those with milder degrees of CKD. We did Our results demonstrate that renal function estimated by eGFR is significantly associated with CFR, and even mild decline in renal function is associated with CMD. Treatment modalities directed at traditional risk factors for atherosclerosis have had little impact in reducing mortality and morbidity in patients with CKD. CMD deserves additional study as a contributor to increased cardiovascular morbidity and mortality associated with CKD. Understanding the mechanistic basis of CMD in women with CKD has the potential to identify targets for novel therapeutics and to improve prognosis in a high-risk cohort for whom conventional therapies have been uniformly disappointing.