Purpose. To study epidemiology, clinical findings and visual prognosis of patients with Fuchs' Heterochromic Iridocyclitis (FHI). Methods. A retrospective analysis was performed on 158 patients with FHI. Thirty-five patients were observed only once; the remaining 123 had a mean follow-up of 30.7 months (50 of them had a mean follow-up of 63.5 months) and in those we assessed complications, medical and surgical treatment, and long-term visual prognosis. Results. Average age at uveitis diagnosis was 27.2 years and 18.3% of patients were children. Blurred vision (54.5%) and floaters (40.5%) were the most frequent presenting symptoms. Small to medium-sized keratic precipitates (95.6%), iris atrophy (86.8%), and vitreous opacities (91.2%) were the most common signs; the prevalence of cataract and IOP increase was 63.5% and 20.1%, respectively, and their incidence was 0.1 and 0.06 eye/year. Significant risk factor for visual loss was IOP increase at presentation (p = 0.02). At final examination 98% of the eye had a visual acuity ≥ 0.6, and topical (p < 0.001) and systemic (p < 0.001) corticosteroids therapy were used less frequently than before referral. Conclusions. FHI has a good visual prognosis, despite the significant incidence of cataract and glaucoma. A correct and prompt diagnosis might avoid unnecessary therapies and provide excellent visual outcomes. Ernst Fuchs was the first in 1906 to report both the clinical and pathologic features of a consistent number of patients with a chronic low grade anterior chamber inflammation, heterochromia, and cataract –4. UsualThe purpose of the present study was to evaluate the clinical and epidemiological findings, the prevalence and incidence of complications, and the long-term visual prognosis of Italian patients with FHI.A retrospective analysis of the clinical charts of patients referred to the Ocular Immunovirology Service of Sapienza University of Rome, Rome, Italy, from January 2003 to December 2012 was performed. The study was undertaken in accordance with the tenets of the declaration of Helsinki.Inclusion criteria was a diagnosis of FHI, which has been made upon several of the following clinical features: (i) small to medium-sized keratic precipitates involving the whole endothelial surface; (ii) a chronic inflammation in anterior chamber, usually ≤2+ according to SUN criteria ; (iii) dOne-hundred and fifty-eight patients, 80 females (50.6%) and 78 males (49.4%), fulfilled the criteria and were included in the study. One patient had a bilateral involvement.After recording a detailed ocular and medical history, each patient underwent a full ophthalmological examination including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, bilateral indirect ophthalmoscopy and biomicroscopy of the fundus, and Goldmann applanation tonometry. In some unclear cases, in order to exclude other forms of uveitis, we performed additional laboratory examinations, including a complete blood cell count, erythrocyte sedimentation rate, tuberculin skin tests or quantiFERON-TB Gold, syphilis serology, serum biochemical analysis, chest X-ray, and angiotensin converting enzyme determination. Toxoplasma serology was done only in patients with chorioretinal scars.For all the patients, we have recorded the following: age at uveitis diagnosis, age at FHI diagnosis, age at presentation at referral center, unilateral or bilateral involvement, clinical features at presentation, clinical course, forms of treatment, ocular complications at our first examination or occurring during the follow-up (when available), and visual prognosis.Thirty-five patients were observed only once, while 123 subjects (124 eyes) were followed up for more than 3 months . Ocular complications and the need for medical and surgical treatment were evaluated on those last patients. A further evaluation to assess the long-term visual prognosis was done on 50 patients who had a follow-up longer than 36 months .t-test and the χ2 test. p values ≤ 0.05 were considered statistically significant. Kaplan-Meier curves were used to compare eye complication rates. All the analyses were performed using SPSS 19.0 statistical software (LEAD Technologies).The statistical analysis was performed using the Student's The epidemiologic findings of 158 patients with FHI are reported in t = 0.64; p = 0.52).The average age at uveitis diagnosis was 27.19 ± 10.61 years (range 7–61 years), while that of FHI was 29.22 ± 11.31 years (range: 8–61 years). The average age at our first examination was 32.69 ± 10.97 years (range: 8–64 years). The mean interval from uveitis diagnosis to examination in our referral center was 2.12 ± 1.7 years. There was no significant difference between the average age at uveitis onset between males  and females  (In 29 patients (18.35%) FHI was diagnosed in children (before 16 years of age) and in 1 of those before 7 . FHI was diagnosed after 60 years of age in one patient only, during a routine eye examination.Fifty-five patients (34.8%) had a positive history of rubella, while seventy-three patients (46.2%) had no history of rubella and were not investigated serologically. Thirty patients (18.98%) had no history of rubella and were serologically tested: all (100%) were positive for rubella IgG antibody.Blurred vision and floaters were the most frequent presenting symptoms . Other symptoms recalled by the patients included hyperemia , photophobia , and pain . Thirty-six patients were asymptomatic (23%), and the diagnosis was made during a routine eye examination.The clinical findings of patients with FHI at our first observation are reported in One hundred and thirty-six eyes (86%) showed a BCVA ≥ 0.6, 16 (10.1%) between 0.2 and 0.5, and 6 eyes (3.8%) ≤ 0.1. Glaucoma was the leading cause of a severe visual loss in 50% of those cases , followed by cataract, severe vitreous opacities, and corneal scar in 1 eye each (0.6%).The most common clinical findings were small to medium-sized keratic precipitates (95.6% of the eyes). According to SUN criteria  no to moFourteen eyes (8.8%) had undergone cataract surgery with intraocular lens (IOL) implantation elsewhere. Among the remaining 144 patients (145 eyes), 83 eyes presented a posterior subcapsular cataract (57.24%) and 4 eyes (2.75%) a white cataract. The prevalence of cataract was 63.5%. Vitreous opacities were found in 145 eyes (91.2%), where in 72 eyes (45.28%) they were ≥ 2+. Optic disc changes were found in 27 eyes (17%): 15 eyes (9.4%) presented a cup/disk ratio > 0.6, 7 (4.4%) a pale optic disc, 2 (1.2%) both of these changes, and 3 (1.9%) an optic disc hyperemia.Chorioretinal scars were found in 8 eyes (5%). Serum antitoxoplasma IgG antibody was positive in 2 of these patients , but none of the patients had a history of symptomatic ocular or systemic toxoplasmosis. Epiretinal membranes were found in 3 eyes (1.9%), retinal tear in 1 eye (0.6%), and a retinal hole in another one (0.6%), respectively.Four patients with FHI (2.5%) presented a systemic disease prior to uveitis onset that might confuse the diagnosis, because of their possible association with uveitis: 2 (1.25%) were affected by psoriasis, 1 (0.6%) by celiac disease, and 1 by acute rheumatic disease. Two other patients (1.25%) developed a systemic disease potentially associated with uveitis during follow-up: one, serologically positive for rubella, developed an optic neuritis in FHI unaffected  eye, 19 years after FHI diagnosis, and was diagnosed as having multiple sclerosis on a nuclear magnetic resonance results and neurologic consultation; another patient developed Hodgkin's lymphoma 2 years after FHI onset.Among 119 eyes which were followed up for a mean period of 30.74 ± 26.92 months, 29 (24.36%) which at baseline have had no cataract or an initial subcapsular cataract without significant reduction of visual acuity presented a BCVA reduction < 5/10 because of cataract onset/progression. The incidence of cataract was 0.1 eye/year. IOP increase developed in 15 of 91 eyes (16.48%), with an incidence of 0.06 eye/year. Epiretinal membranes were quite rare .Figures The overall risk for a visual acuity reduction ≤ 0.4 was 0.001 eye/year.Risk factors for visual acuity reduction are reported in p = 0.02).The only significant risk for a visual acuity reduction ≤ 4/10 was an IOP increase at presentation  had no therapy. Twenty-nine eyes (23.38%) were given a course of systemic corticosteroid therapy: 12 eyes (9.75%) to try to lower vitreous opacities and 17 (13.8%) to prevent and control postoperative (cataract and glaucoma) inflammation. Sixty-five eyes (52.4%) received topical corticosteroid therapy and 40 eyes (32.25%) mydriatics, mostly immediately after a surgical procedure . Forty-seven eyes (37.9%) received IOP lowering drops.χ2 = 23.76; p < 0.001) and systemic steroids from 58.8% to 23.38% . Eight patients (6.5%) had been previously subjected to immunosuppressive therapy elsewhere. These drugs were discontinued in all the cases during our follow-up .Comparing the therapeutic regimen given before and during our follow-up, we have observed a significant decrease in the need for medications: topical steroids from 82.2% to 52.4% of the eyes .In twenty-five patients (25 eyes) phacoemulsification and in the bag IOL implantation was performed by us (17.4% of the phakic patients at our first examination). BCVA at the end of follow-up was ≥ 0.8 in all the cases (mean 0.88 ± 0.04). Capsulotomy was performed in 13 patients : in 7 out of 25 eyes operated by us (28%) and in 6 out of 14 eyes (42.85%) operated elsewhere , in 11 cases (6.9%) by us. The incidence of trabeculectomy was therefore 0.02 eye/year. The mean BCVA at the end of follow-up of eyes undergoing trabeculectomy was 0.61 ± 0.42, in 3 eyes less than 0.5 and in 2 less than 0.1. Both of these presented a very low preoperative visual acuity .In 50 patients (50 eyes), followed up for an average period of 63.47 ± 20.38 months (range: 36–119 months), we have observed a BCVA at baseline ≥ 0.6 in 45 eyes (90%) and ≤ 0.1 in 3 eyes (6%). At the end of follow-up one eye (2%) presented a BCVA ≤ 0.1, because of a corneal scar already present at the first examination, while all the others (98%) had a BCVA ≥ 0.6. At the final examination 2 eyes (4%) presented, compared to baseline, a BCVA reduction of 0.3 (cataract) and five (10%) presented an increase of BCVA of 0.3: in three cases after cataract surgery, in one after trabeculectomy, and in 1 because of vitreous opacities reduction after anti-inflammatory therapy.FHI is a quite common type of uveitis and its diagnosis relies of clinical findings –12. ThisIn our series the diagnosis of FHI was made on average 2 years after symptoms onset. Norrsell and Sjödell reported a period of 3 years between the onset of the first ocular symptoms and the diagnosis, while Fearnley and Rosenthal reported a delay of 6.7 years , 10. ThiThe mean age of uveitis diagnosis was found to be 27 years, lower than reported by other authors 29.5 to 44.5 years) 4.5 years–11, 16, Toxoplasma gondii) agents were suggested. Quentin and Reiber detected the presence of anti-rubella antibodies, using the Goldmann-Witmer index, in 100% of FHI patients [ Toxoplasma gondii was also described, but it is controversial [FHI etiology remains unknown. Several theories have been proposed and, among the possible causes, some viral  and parasitic , similar to Turkish population , 10. AltTwenty-three percent of Italian patients with FHI was completely asymptomatic, and the diagnosis was made during a routine eye examination.A bilateral involvement was found in one of our patients (0.6%) only, while this frequency varies in the literature from 0% to 21% . NorrselSmall to medium-sized keratic precipitates are typical of FHI –11 and hCataract becomes mature on average 8 years after first subcapsular opacities have been detected but can also develop very rapidly. In our study, a posterior subcapsular cataract was observed in 57.2% of phakic eyes at the first examination, while the overall prevalence was 63.5%, similar to Turkish patients (69%) . The higThe prevalence of an increased IOP and/or secondary glaucoma in patients with FHI is variable, with literature data ranging between 6.3% and 59% of cases , 10. Thep = 0.02), similar to Al-Mansour et al.'s experience [The visual prognosis of FHI is usually considered good. Our study has demonstrated that the incidence of visual decrease ≤ 0.4 is very low in medium term follow-up (0.001 per eye/year). Al-Mansour et al. reported a worsening of visual acuity only in 10% of the eyes compared to baseline, while most of the eyes had a visual acuity unchanged or improved . In our perience .p < 0.001 for both topical and systemic route of administration) and of immunosuppressive drugs (p = 0.012). These might potentially reduce the incidence of cataract and glaucoma, which are typical side effects of such a therapy, and, more importantly, of immunosuppressives-related systemic side-effects.In follow-up longer than 5 years we have observed a final visual acuity > 0.6 in 98% of the patients, with one patient only presenting a poor visual acuity related to a previous corneal scar. FHI is often misdiagnosed and patients are treated with topical, systemic, and peribulbar steroids. Peribulbar or topical steroid treatment has a minimal effect on this inflammation and it might promote the onset of posterior subcapsular opacity and elevated IOP. The referral of patients in tertiary eye care center can significantly lower the amount of corticosteroids therapy (In conclusion in Italian patients the average age at presentation is lower than in other countries, and 18% of patients are aged 16 or less. Therefore in children with unilateral, chronic anterior uveitis, it is essential to exclude FHI to avoid the incidence of therapy-related side-effects. The clinical findings of FHI do not differ from those reported in other countries, but particular attention should be paid for iris atrophy and vitreous opacities, which resulted in being more frequently encountered than heterochromia. Our study confirmed that FHI has a good long-term visual prognosis, despite the significant incidence and prevalence of cataract and glaucoma; the only significant risk factor for visual loss is IOP increase. During cataract management it is important to remove all cortical residuals and follow adequately the patient in the postoperative period to reduce the incidence of posterior capsule opacification. A correct and prompt diagnosis allows to avoid unnecessary and potentially dangerous therapy. A proper uveitis, and its complications, management can lead to a final excellent visual outcome.


Relapse and diabetes mellitus (DM) are major problems for the prognosis of autoimmune pancreatitis (AIP). We examined the prognosis of type 1 AIP after corticosteroid therapy (CST)-induced remission in terms of relapse and DM.The study enrolled 82 patients diagnosed with type 1 AIP who achieved remission with CST. We retrospectively evaluated the relapse rate in terms of the administration period of CST, clinical factors associated with relapse, and the temporal change in glucose tolerance.p = 0.050 or p = 0.020). Of the 37 DM patients, 15 patients (40.5%) had pre-existing DM, 17 (45.9%) showed new-onset DM, and 5 (13.5%) developed CST-induced DM. Patients with new-onset DM were significantly more likely to show improvement (p = 0.008) than those with pre-existing DM.During follow-up, 32 patients (39.0%) experienced relapse. There was no significant clinical factor that could predict relapse before beginning CST. AIP patients who ceased CST within 2 or 3 years experienced significantly earlier relapse than those who had the continuance of CST (It was difficult to predict relapse of AIP based on clinical parameters before beginning CST. Relapse was likely to occur within 3 years after the beginning of CST and maintenance of CST for at least 3 years reduced the risk of relapse. The early initiation of CST for AIP with impaired glucose tolerance is desirable because pre-existing DM is refractory to CST. Type 1  [et al. .et al provided a treatment strategy with a clear induction regimen, dosage schedule and suggestions for when to start maintenance therapy [CST for type 1 AIP consisting of remission induction and maintenance therapy have been established to a degree by building consensuses based on several large-scale studies ,5. Hart  therapy . However therapy –6, while therapy –9. In th3 This study included patients who met the criteria for definitive or probable AIP. The medical charts were reviewed and clinical data were collected to evaluate various factors associated with the prognosis of type 1 AIP. All patient data were completely anonymized, deidentified, and aggregated before analysis.This retrospective study was approved by the Ethics Committee of Kanazawa University Hospital. Patients who were diagnosed with type 1 AIP in Kanazawa University Hospital or its affiliated institutes from January 2000 to May 2015 and were followed for more than 1 year after CST-induced remission were enrolled. The diagnosis of type 1 AIP was based on the ICDC.10 A wide variety of CST regimens were used for maintenance therapy based on each patient’s condition. In this study, maintenance therapy was defined as continuous administration for more than 6 months after the initiation of CST. The maintenance dose was defined as the daily oral prednisolone dose administered for the longest term during the follow-up period, ranging from 5 mg/day to 10 mg/day. Patients underwent cross-sectional radiological imaging at least once every six months basically. When clinical symptoms such as abdominal pain, back pain and jaundice were observed, extraordinary imaging was performed as needed. Serum IgG and IgG4 level were measured once every three to six months. Relapse was defined as the recurrence of clinical symptoms in addition to the exacerbation of pancreatic parenchymal enlargement or OOI on cross-sectional radiological imaging after CST-induced remission [In this study, CST-induced remission was defined as the improvement of clinical symptoms in addition to the resolution of pancreatic parenchymal enlargement or other organ involvement (OOI) on cross-sectional radiological imaging within 3 months after the initiation of CST.In this study, DM was diagnosed by the diagnostic criteria of the Japan Diabetes Society . We clast-test or Mann–Whitney U-test. Survival probabilities were calculated using the Kaplan–Meier method with the log-rank test to evaluate the period to relapse of AIP. Differences with p-values of less than 0.05 were considered to be statistically significant. The statistical analyses were performed using StatView .Categorical variables were compared using the chi-square test. Continuous variables were analyzed using the Student’s The study included 82 patients with type 1 AIP. The median follow-up period was 52.9 (range 13.1–180.4) months. The initiation of CST was started at 40 mg/day in 26 patients (31.7%), 35 mg/day in 3 patients (3.7%), 30 mg/day in 46 patients (56.1%), 20 mg/day in 7 patients (8.5%). The prednisolone dose was tapered gradually, by 2.5–10 mg every 1–8 weeks, until the dose reached the maintenance dose or zero in principle. In this study, all patients achieved remission while tapering CST. 76 of the 82 patients (92.7%) had maintenance therapy and 6 (7.3%) had not. Whether maintenance of CST is continued or stopped in AIP patients was decided by individual doctor’s judgement based on side effect, background disease or patient’s request. The median duration of CST was 31.8 (range 1.4–179.3) months. 68 (82.9%) of the 82 patients who were followed up had CST for more than 1 year, 31 (66.0%) of the 47 for more than 3 years, and 11 (55.0%) of the 20 for more than 5 years.The median maintenance prednisolone dose was 5 (range 2.5–10) mg/day. Of the 76 patients who had maintenance therapy, 54 (71.1%) had a maintenance dose of 5 mg/day or more and 22 (28.9%) had a dose of 2.5 to 5 mg/day. CST was stopped during follow-up in 36 patients (43.9%).p = 0.273) and young (p = 0.211) relatively tend to experience relapse. Neither the serum IgG levels (p = 0.513) nor IgG4 levels (p = 0.500) predicted relapse.During the follow-up period, relapse occurred in 32 of the 82 type 1 AIP patients (39.0%) after CST-induced remission. p = 0.231) and the continuance of CST during follow-up period (p = 0.373) had a lower incidence of relapse, although this difference was not significant.Maintenance prednisolone doses of 5 mg/day or more (p = 0.127) tended to experience early relapse, although there was no significant association. Serum IgG level of 1800 mg/dLor more (p = 0.724) and maintenance dose of 5 mg/day or more (p = 0.452) were not associated with early relapse. Grouped for the administration period of CST, there was no significant difference between the period from the initiation of CST to relapse in patients who continued CST and ceased it within 1 year (p = 0.454). However, AIP patients who ceased CST within 2 or 3 years experienced significantly earlier relapse than those who had the continuance of CST (p = 0.050 or p = 0.020). The cessation of CST after 3 years from the initiation n of CST was not a significant factor associated with the time to relapse. In 16 patients with relapse after cessation of CST, 10 and 6 received CST for more than 1and 2 years, respectively. There was no significant difference between the duration of CST and the period from cessation of CST to relapse .The median period from the initiation of CST to relapse was 24.1 (range 3.2–105.2) months. Of the 32 patients who relapsed, 8 (25.0%) relapsed within 1 year, 8 (25.0%) between 1 to 2 years, 6 (18.8%) between 2 to 3 years, 7 (21.9%) between 3–4 years, and 3 (9.4%) after 4 years. The longest period from the initiation of CST to relapse was 105.2 months, and this patient relapsed after stopping CST after about 8 years of maintenance therapy. We evaluated the change in glucose tolerance over time in 60 patients. During follow-up, 37 patients (61.7%) had DM. Of the 37 DM patients, 15 patients (40.5%) had pre-existing DM, 17 (45.9%) showed new-onset DM, and 5 (13.5%) developed CST-induced DM. i.e., starting diabetes medication, increasing the insulin injection dose, adding new oral hypoglycemic agents, or switching from oral hypoglycemic agents to insulin injection) compared with the condition before the initiation n of CST. Exacerbation was defined as an increase in the HbA1c level by more than 0.5% or no decrease despite strengthening the therapy for DM compared with the condition before the initiation of CST. The other clinical course was judged as no change. We evaluated the clinical course of DM based on the change in the HbA1c level or diabetic medications at the time that the prednisolone dose was decreased to maintenance dose or less and classified it as improvement, no change or exacerbation. Improvement was defined as a decrease in the HbA1c level by more than 0.5% without strengthening the therapy for DM (p = 0.008), and achieve the medication-free (p = 0.01) status than those with pre-existing DM.First, 5 patients with CST-induced DM were classified as exacerbation. All of them showed borderline HbA1c level (5.6–6.4%) before the initiation of CST. Of the 32 patients excluding the group with CST-induced DM, 12 (37.5%) showed improvement, 7 (21.9%) showed exacerbation, and 13 (40.6%) showed no change. Patients with new-onset DM were significantly more likely to show improvement  showed borderline HbA1c (5.6–6.4%) before the initiation of CST and only one patient showed exacerbation in glucose tolerance.et al. reported that relapse was more common in type 1 AIP (35.8%) than in type 2 AIP (15.3%) [Since the Japanese diagnostic criteria for AIP were established in 2002 , CST has (15.3%) .et al. reported that the relapse rate of AIP with CST for only 12 weeks was 60% [The importance of maintenance therapy for type 1 AIP is well known in terms of the prevention of relapse. A Japanese multicenter randomized controlled trial of long-term CST showed that the relapse rate of patients who continued maintenance therapy for 3 years was 23.3% versus 57.9% for patients who stopped it at 26 weeks . However was 60% . In our  was 60% –6,16–20.A Japanese research group recommended continuing CST possibly up to 3 years in terms of the prevention of relapse since a previous study revealed that 92% of the relapses occurred within 3 years ,21. HoweIf we can predict whether AIP will relapse before treatment, it would help us to determine the administration period of CST. Previous studies reported some clinical factors that might predict relapse, including the presence of IgG4-related cholangitis ,23, highSince AIP can progress to irreversible pancreatic insufficiency , we recoet al. [et al. [Furthermore, we must be aware that both AIP itself and CST have a risk of DM. According to previous reports, 40–80% of AIP patients have DM ,18,28–30et al.  reportedThere are some limitations to this study. First, our study design was not prospective. Second, different diagnostic criteria for AIP are used in different studies. We adopted the ICDC, whereas other studies have used the Asian criteria ,16,20,32In conclusion, we examined recent information about the prognosis of type 1 AIP focusing on CST and DM as a complication. Since some problems regarding about relapse and DM remain, further investigation is required.


Objective. Owing to a shortage of kidney donors in Israel, children with end-stage renal disease (ESRD) may stay on maintenance dialysis for a considerable time, placing them at a significant risk. The aim of this study was to understand the causes of mortality. Study Design. Clinical data were collected retrospectively from the files of children on chronic dialysis (>3 months) during the years 1995–2013 at a single pediatric medical center. Results. 110 patients were enrolled in the study. Mean age was 10.7 ± 5.27 yrs. (range: 1 month–24 yrs). Forty-five children (42%) had dysplastic kidneys and 19 (17.5%) had focal segmental glomerulosclerosis. Twenty-five (22.7%) received peritoneal dialysis, 59 (53.6%) hemodialysis, and 6 (23.6%) both modalities sequentially. Median dialysis duration was 1.46 years (range: 0.25–17.54 years). Mean follow-up was 13.5 ± 5.84 yrs. Seventy-nine patients (71.8%) underwent successful transplantation, 10 (11.2%) had graft failure, and 8 (7.3%) continued dialysis without transplantation. Twelve patients (10.9%) died: 8 of dialysis-associated complications and 4 of their primary illness. The 5-year survival rate was 84%: 90% for patients older than 5 years and 61% for younger patients. Conclusions. Chronic dialysis is a suitable temporary option for children awaiting renal transplantation. Although overall long-term survival rate is high, very young children are at high risk for life-threatening dialysis-associated complications. End-stage renal disease (ESRD) is a major cause of morbidity and mortality in children. In the pediatric population, ESRD is mainly due to congenital anomalies of the kidney and urinary tract (CAKUT) and glomerular diseases –3. The pIn children, peritoneal dialysis (PD) is preferred over hemodialysis (HD) in terms of quality of life, growth, and preservation of residual renal function . HemodiaThe life span of children with ESRD is significantly lower than that of the age- and gender-matched general population. In studies of children on dialysis from Australia and New Zealand, survival rates were 85.7% at 3 years, 79% at 10 years, and 66% at 20 years . Lower sThe aim of the present study was to evaluate the long-term outcome of a large cohort of pediatric patients on chronic dialysis in a single tertiary medical center. Attention was focused on mortality rate and causes of death. clinical parameters such as cause of ESRD, age at diagnosis, associated diseases, age at initiation of dialysis, type of dialysis , duration of dialysis, dialysis complications; laboratory parameters such as complete blood cell count and blood chemistry ; parameters related to treatment of chronic kidney disease such as weight and height standard deviation scores (SDS) at dialysis onset and study end, use of recombinant growth hormone (rGH) therapy, blood pressure percentiles and SDS by gender, age and height percentile, presence of left ventricular hypertrophy (LVH) measured by echocardiography (mass index > 51 gr/m2.7), use and number of antihypertensive drugs, administration of recombinant erythropoietin (rEPO), and need for blood transfusions throughout treatment.The study cohort included all patients with ESRD maintained on dialysis for at least 3 months in the Dialysis Unit of Schneider Children's Medical Center of Israel from January 1995 through December 2013. The following data were retrospectively recorded from the medical files of each patient: Peritonitis was diagnosed by the presence of at least 2 of the following criteria: cloudy effluent and/or abdominal pain or fever; effluent leukocyte count of >100 cells/mm3 with >50% neutrophils; bacterial growth in the peritoneal culture [ Exit site/tunnel infection was diagnosed by the presence of purulent drainage with negative peritoneal fluid culture . Periton culture .Anemia was diagnosed when hemoglobin level was less than 11 g/dL  or when Hypertension was diagnosed by either blood pressure values over the 95th percentile for age and heights at 3 visits or a need for antihypertensive therapy. Data were presented by SDS scores.Primary outcome was as follows: death or survival at the end of the study period, survival with successful kidney transplant, or continuing dialysis at the end of the study period.z scores, cardiovascular disease defined as z scores of hypertension, and LVH and anemia (percent of the population and hemoglobin level.)Secondary outcome was as follows: dialysis complications , changes in growth, recorded in Outcome was analyzed overall and by dialysis modality (PD versus HD), age at onset of dialysis (>5 years versus <5 years), and year of initiation of dialysis (1995–2003 versus 2004–2013).U test was used to analyze parameters such as number of blood pressure drugs. Comparing changes over time, we used ANOVA with repeated measures or Wilcoxon test, as appropriate. Survival curves were formulated according to the Kaplan-Meier method. Patient survival was calculated per 100 patient dialysis years. A p value of ≤0.05 was considered significant.Data were analyzed using BMDP statistical software . AnalysiThe study was approved by the Ethics Committee of Rabin Medical Center.One hundred and ten children met the study criteria, 63 boys (57.3%) and 47 girls (42.7%) of mean age 10.67 ± 5.27 years (range: 1 month–24 yrs.) at onset of dialysis. Twenty-three patients were <5 years and 87 > 5 years; Seventy-four patients (67%) were adolescents (age: over 12 years). Eighty-two patients (74%) were of Jewish and 28 (26%) were of Arab origin. Maintenance dialysis duration was as follows: median 1.46 years (range: 0.25–17.54 years) and mean 2.48 ± 3.02 years. Mean duration of follow-up was 13.5 years ± 5.84. The major causes of ESRD are shown in p < 0.001). The later period (2004–2013) was characterized by a twofold increase in the proportion of patients treated with PD .For PD, a two-cuffed peritoneal catheter was inserted by a specialized pediatric surgeon in the operating room. Prophylaxis with Cefamezine was administered in all patients during the later period of the study (2004–2013). All the caregivers were instructed for appropriate performance of the procedure emphasizing aseptic techniques and were managed by automated PD. For HD, an arteriovenous graft or fistula was used in 44 patients  [kg, 52%)  and a cekg, 52%) ) in 41 . Bacteremia was documented at least once in 19 patients on HD (22%). The average bacteremia rate was 4.4 episodes per 1000 patient-years.16 patients developed exit site infection (31%). The average peritonitis rate was 20 episodes per 1000 patient-years. Tunnel infections were 2.2 episodes per 1000 patient-years. No bacteremia episodes were noted in patients on PD.p < 0.001). The earlier treatment period was characterized by a significantly higher rate of exit site infections  and of bacteremia . The peritonitis rate in the patients on PD was also higher in the earlier period, but the difference did not reach statistical significance .The rate of total catheter-related infections was significantly higher for PD than for HD (p < 0.001) at study end. The rate of rEPO administration was 85.3% at onset of dialysis, increasing to 97.8% at study end (p = 0.01).Anemia was documented in 101 patients (92%) before onset of dialysis. Mean hemoglobin level was 9.11 ± 1.69 gr/dL at onset of dialysis and 10.66 ± 1.52 gr/dL . Respective values for height were −1.22 ± 1.11 and −1.62 ± 1.26; this difference was not statistically significant (p = 0.13). Growth parameters analyzed by dialysis modality are shown in Mean weight SDS was −0.56 ± 0.84 at dialysis onset and −0.84 ± 0.69 at study end (p < 0.001). Respective values for diastolic blood pressure SDS were 2.51 ± 1.72 and 1.36 ± 2.22 (p < 0.001). The number of medications needed to control hypertension ranged from 1 to 4 (median 1) at onset of dialysis and decreased to 0 to 5 (median 0) at study end. Seventy patients (63%) needed treatment at dialysis onset compared to 46 (42%) at study end (p < 0.001).Seventy-seven patients (70%) were hypertensive  at onset of dialysis. Mean systolic blood pressure SDS decreased from 3.35 ± 2.19 at onset of dialysis to 2.14 ± 2.83 at study end (p = 0.01). During treatment, LVH developed in 11 patients (10.5%) who had not had LVH at dialysis onset.LVH was found in 50 patients (46%) at onset of dialysis and 37 (34%) at study end (Eighty-nine patients (90.3%) received a kidney graft during the study period, of whom 79 (88.8%) had a functioning graft at study end and 10 (11.2%) lost graft function and returned to dialysis. Causes for loss of graft included 5 patients with noncompliance; 1 with FSGS recurrence; 2 with acute rejection; 1 with graft renal artery thrombosis; 1 with chronic antibody mediated rejection. Eighty-six patients had one renal transplant and 2 patients had 2 transplants. Sixty-four grafts originated from deceased donors, 15 were from living-related donors, and 9 were from living nonrelated donors. Another 8 patients (7.3%) continued dialysis; this group age was on average 11 ± 6.4 years at onset of dialysis and were on maintenance dialysis for an average of 2.85 ± 3.9 years (range: 0.25–6.64). One child with CAKUT ceased dialysis with stable kidney function.12 patients died during the study period, with a mortality rate of 10.9%. Causes of death are detailed in p = 0.56).On Kaplan-Meier analysis, the 5-year overall survival rate on dialysis was 84%: 90% in children > 5 years and 61% in children < 5 years at dialysis onset . Patientp = 0.81).Mortality rates analyzed by patient-years on dialysis were 4.3 deaths per 100 patient-years for the whole cohort, 2.39 deaths per 100 patient-years for patients > 5 years at onset of dialysis, and 11.6 deaths per 100 patient-years for patients < 5 years at onset of dialysis. The mortality rate for PD exclusively was 9 per 100 patient-years, for HD exclusively was 7.26 per 100 patient-years, and for combined treatment was 3.93 per 100 patient-years. By treatment period, 5-year survival rates were 73% in patients treated in 1995–2003 and 90% in patients treated in 2004–2013; the difference was not statistically significant , concomitant with a decrease in the need for blood transfusions . A similar positive trend was found in the annual NAPRTCS report with a hematocrit range of 29.9% to 32% at onset of dialysis, which improved after 6 months to 32.3%–33% as found in [Anemia may be caused by a multitude of factors and poses a challenging problem in patients on chronic dialysis similar to other studies. Ninety-two percent of our patients were anemic at onset of dialysis, with a mean hemoglobin level of 9.11 ± 1.69 gr%. By the end of the study, this value increased significantly to 10.66 ± 1.52 gr% (found in . It is pp = 0.01). Improvement in LVH over time on dialysis can be explained by good fluid volume control and close monitoring of cardiovascular parameters and better patient compliance and adherence to treatment.Cardiovascular disease is a major cause of death in adolescents and young adults . In theip = 0.078), in patients treated with rGH (9.4% of patients on PD and 8.7% of patients on HD) but worsened in the remainder [Growth retardation is a complication of chronic kidney disease and has a significant influence on both final adult height and quality of life , 13. In emainder . We did According to the NAPRTCS reports , 22 survThe limitation of the present study is its retrospective design, a small sample size which for a single center is relatively large but not compared with multicenter studies, and a specific population which may defer from other centers/groups.In conclusion, despite the relatively long period on maintenance dialysis, pediatric patients with ESRD in our center have a similar outcome in terms of survival and dialysis complications to that reported in other industrialized countries. We suggest that efforts be made to broaden the use of arteriovenous fistulas and minimize the use of central cuffed catheters in order to avoid infections and thrombosis. Implementation of standardized PD education programs, prophylactic antibiotics prior to insertion of PD catheters, and strict adherence to aseptic techniques may reduce the rate of PD -associated infections.The findings may have important implications for decreasing the risks of dialysis-associated complications especially for very young ESRD patients, thereby lowering hospitalization and improving survival.


The genome was assembled using overlapping paired-end and mate pair libraries and sequenced on an Illumina HiSeq 2500 instrument.We report here the draft  This lichen-forming fungus is the type species of Arthonia (Ach.) Ach., on which the Arthoniaceae Rchb. , a large family of about 800 lichen-forming, lichenicolous, and saprobic Ascomycota, are based. Arthonia radiata is a common and polymorphic epiphyte on mainly smooth-barked deciduous trees throughout the Holarctic. It has also been reported in Africa and New Zealand . AllPaths-LG provided the best assembly, with a contig N50 value of 1.2 Mb (46 contigs), a scaffold N50 value of 2.25 Mb (17 scaffolds), and a total sequence length of 33.5 Mb. Of all BUSCO2 genes, 99% for fungi  and 94.8% for ascomycetes  were present as complete genes in the assembly. This indicates the high quality of the presented genome.The genome was assembled using overlapping paired-end (PE) and mate pair (MP) libraries (with an average insert size of 5 to 8 kb) and sequenced with Illumina HiSeq 2500 v4 chemistry (2 × 125 bp). Assemblies were created using AllPaths-LG . The besN50 value of 6.8 kb. BUSCO2 scores indicated the presence of 94% complete and 5.5% fragmented transcripts (2 out of 290 are missing) for fungal BUSCO2 genes and 92.5% complete and 5.5% fragmented transcripts for ascomycete BUSCO2 genes .Transcriptome assembly was performed using Trinity  and a code novo repeat annotation) (see http://repeatmasker.org for both programs). We found that 16.65% of the A. radiata genome constitutes repeat sequences, most of which were LTR elements (14.94% of the whole genome).Next, we annotated repeats in the best genome assembly using a combination of RepeatMasker (homology-based annotation using the Repbase database) and RepeatModeler .This whole-genome shotgun project has been deposited at GenBank (assembly number GCA_002989075), and all the data are available at NCBI  under the accession number


IntroductionIn most healthcare models, the first interaction of a patient is with a general physician. The inspection of the oral cavity is a mandatory component of the general physical examination performed by a physician. This helps detect any oral pathology and make suitable referrals. Therefore, adequate oral health awareness is essential for physicians. Our study aimed at evaluating the oral health practices among physicians working in a private teaching setup in Islamabad, Pakistan.MethodsA cross-sectional study involving 144 physicians teaching undergraduate medical students at Shifa College of Medicine and its affiliated hospital, Shifa International Hospital, was conducted. Participants were interviewed through a self-designed questionnaire. Later, each participant demonstrated their teeth brushing technique on a standard model of the oral cavity, which was assessed against a checklist conforming to the modified bass technique. A video clip showing the aforementioned brushing technique was shown at the end of the interview. The collected data was analyzed on IBM's statistical package for the social sciences (SPSS) version 21. ResultsToothpaste was the top choice (97.2%) of teeth cleaning tool with 69% participants brushing their teeth two times a day and 56.9% using toothbrushes with bristles of medium texture. The use of mouthwash (32.6%) and dental floss (11.1%) was considerably low. Dental caries and teeth discoloration were seen in 46.5% and 43.8% physicians, respectively. An alarmingly low number of physicians (31.9%) claimed to have read guidelines regarding oral health. This translated into most participants (78.5%) visiting a dentist only when needed. Only 4.9% participants performed all components of the modified bass technique to clean teeth on the oral cavity model, with up to 22.9% unable to perform a single step accurately. ConclusionThe oral health knowledge and practices of physicians were found to be suboptimal and necessitate the integration of oral health awareness in the medical curriculum. A multiprofessional approach with physicians in crucial roles is required to address the burden of dental diseases globally.  World Health Organization (WHO) defines oral health as "a state of being free from mouth and facial pain, oral and throat cancer, oral infection and sores, periodontal (gum) disease, tooth decay, tooth loss, and other diseases and disorders that limit an individual’s capacity in biting, chewing, smiling, speaking, and psychosocial well-being" . The FédOral health is a significant challenge in today's world as in 2010, the global economic burden of dental diseases was reported to be 442 billion dollars, out of which 298 billion dollars was incurred on direct treatment, and 144 billion dollars was the indirect cost of productivity losses due to caries, periodontitis, and tooth loss .Bacterial biofilm forms supragingival and subgingival plaque, which leads to periodontal diseases and dental caries. In the past, various studies have established an association of periodontal diseases with cardiovascular, respiratory, neurological, endocrine, gastrointestinal, and gestational disorders. According to a study in Spain, the modified Bass (Mod-Bass) technique was significantly more effective in removing supragingival plaque than normal toothbrushing practices, both in the buccal and lingual sites . Health A cross-sectional study was conducted on full-time physicians working in Shifa International Hospital and Shifa College of Medicine, components of Shifa Tameer-e-Millat University, a private institution in Islamabad, Pakistan. The study spanned from December 2016 to June 2017. A sample size of 150 was determined by keeping a confidence level of 95%, a prevalence of dental caries of 16.3% . FollowiThe data obtained was entered and analyzed using SPSS version 21. Descriptive statistics were calculated. The correlation coefficient was calculated between the duration of teeth brushing of the participant and the score on teeth cleaning. The chi-square test was used to determine the difference between the modified Bass technique use, the frequency of tooth brushing per day, and caries among the two groups of doctors. A t-test of Independent samples was used to determine the difference in the mean duration of teeth brushing among the two groups of physicians. P-value <0.05 was considered statistically significant. Ethical approval of the study was obtained from Shifa International Hospital's Institutional Review Board and Ethics Committee.Among the 144 participants, 36 (25%) were males while 108 (75%) were females. A total of 61 physicians (42.4%) were working in basic health sciences as opposed to 83 (57.6%) working in clinical health sciences. A majority of the physicians (140 (97.2%)) claimed to use only toothpaste as their main tool to clean teeth. Colgate and Sensodyne were popular choices with 77 (53.5%) and 19 (13.2%) of the participants, respectively. Most physicians specifically looked for fluoride (63 (43.8%)) in their toothpaste while the others (29 (20.1%)) valued a minty flavor more. An overwhelming majority of the participants brushed their teeth two times a day. The mean duration of tooth brushing was 2.5±1.6 minutes. A significant number of physicians (82 (56.9%)) used a medium brush type followed by the usage of the soft brush by 47 participants (32.6%). Most of the participants (51 (35.4%)) changed their toothbrush every three months, followed by 38 (26.4%) changing it after two months and only 28 (19.4%) changing it every month.Only 47 physicians (32.6%) claimed to use mouthwash regularly, with even fewer (16 (11.1%)) using dental floss on a regular basis. About 31 (21.5%) physicians were in the habit of brushing their teeth after the consumption of sweet food. Among the participants, only 16 (11.1%) complained of teeth sensitivity to sugar as opposed to 39 physicians (27.1%) who suggested their teeth were sensitive to hot and cold temperatures. A large number of physicians had teeth discoloration (63 (43.8%)) and dental caries (67 (46.5%)).Only 14 (9.7%) participants were smokers in addition to 10 participants (6.9%) who consumed sheesha. None of the participants consumed paan or alcohol regularly. However, soft drinks were a relatively popular choice among physicians, with the majority consuming at least two drinks (22 (15.3%)) or one drink (21 (14.6%)0 in a week.Only an alarming 46 31.9%) physicians claimed to have read guidelines regarding oral health. It is also of extreme concern to note that 113 physicians (78.5%) only visited a dentist when needed, 20 (13.9%) visited the dentist annually, 8 (5.6%) visited the dentist every six months, and only 3 (2.1%) visited the dentist every three months. This is represented in Figure .9% physiAbout 48 physicians (33.3%) held their toothbrush at a 45-degree angle while brushing teeth. While a majority (87 (60.4%)) performed brush movements in a circular motion, only 58 (40.3%) made sure the movements started from inside and moved outside. Fewer still (33 22.9%)) slid down their toothbrush after every circular movement. Only seen participants (4.9%) performed all the four steps. Most of the participants (42 (29.2%)) performed two steps correctly while 33 (22.9%) were unable to get a single step right. This is presented in Figure 2.9%) sliWhen the correlation coefficient was calculated between the duration of teeth brushing of the participant and the score on teeth cleaning, no correlation was seen; p > 0.05. The chi-square test was used to determine the difference between the BASS technique and the use and frequency of tooth brushing per day with caries among the faculty of basic health sciences and clinical health sciences; the results were not statistically significant, p > 0.05. A t-test of independent samples was used to determine the difference in the mean duration of teeth brushing among the two groups of physicians; it was not statistically significant.Recent years have seen an increase in emergency department (ED) visits owing to dental emergencies in America. In the year 2010 alone, Americans have visited EDs 2.1 million times with dental complaints, amounting to roughly $867 million to $2.1 billion [In our study participants, a significant majority 97.2%) only used toothpaste to clean teeth. This is comparable to the results obtained in a study among healthcare professionals working at King Fahad Medical Centre, Riyadh , where 97.2% onlyOur study showed an alarmingly low use of mouthwash (32.6%) and dental floss 11.1%) in physicians. However, the results are in harmony with less than 50% health professionals using mouthwash and 34.2% using dental floss in a study in Riyadh . In Nige.1% in phOur study demonstrated 69% participants brushing their teeth two times daily while 20% only brushed once a day. The average brushing time for participants was 2.5 ± 1.6 minutes. In Riyadh , most heWhile in our study 43.8% physicians valued the presence of fluoride in their toothpaste, only 1.2% health professionals in a study in Riyadh [The key indicators that can be used to monitor oral health include dental caries and tooth loss. According to the National Institute of Dental and Craniofacial Research, USA, 91% of US adults between the age of 20 and 64 have had dental caries in their permanent teeth in 2011-2012. In contrast to this, our study showed the prevalence of dental caries among physicians to be only 46.5%. A study carried out on Chinese urban adults aged 20-69 years demonstrated that 40.7% of the subjects reported teeth sensitivity [It was concluded that an overwhelming majority (78.5%) of participants in our study visited the dentist only when needed and a very small percentage 13.9%) sought annual dental checkups. This is comparable to a study on clinical medical, dental, and paramedical students in Mangalore where the result showed that 75% medical students, 86% paramedical students, and 69% dental students only visited the dentist when they encountered a dental problem (P<0.001) [.9% soughRegular teeth cleaning is imperative to prevent periodontal diseases and dental caries. In 2014, a study was conducted to analyze the different toothbrushing techniques recommended by dental associations, dental textbooks, and toothpaste and toothbrush companies. The results demonstrated a wide difference in opinion but, overall, the most commonly recommended technique was found to be the modified Bass technique followed by the Bass technique, Fones technique, and Scrub technique [According to a study in Spain, the modified Bass (Mod-Bass) technique removed supragingival plaque more effectively than normal tooth brushing techniques. After 21 days, the normal practices did not significantly decrease the mean plaque indices compared to the scores calculated after seven days (P > 0.05) but did so with the modified Bass technique (P < 0.05). In the lingual side, the modified Bass technique was 2.9 times more effective than normal practices in reducing plaque scores (P < 0.01) . AnotherIn a study conducted on internal medicine trainees in an urban teaching hospital located in New York City, results demonstrated that 90% trainees did not receive any training about periodontal disease in medical school, 69% could not perform a standard periodontal examination comfortably, and 76% admitted to having never screened their patients for periodontal diseases. However, it was alleviating to know that 17% physicians realized that patients expect their physician to screen them for periodontal disease and a further 46% felt a periodontal examination of the patients was imperative for the physician . SimilarEven though there is not enough evidence on a general physician's oral health knowledge and practices in Pakistan, one study among medical doctors in Khyber Teaching Hospital and Hayatabad Medical Complex, Peshawar, showed an alarmingly low level of oral health care awareness among the participating physicians. This is comparable to the results of our study where only 31.9% doctors reported to have read guidelines regarding oral health.The oral health knowledge and practices of physicians in Pakistan is suboptimal and necessitates the integration of oral health awareness in the medical curriculum. A multiprofessional approach with physicians in crucial roles is required to address the burden of dental diseases globally.


The present analysis led to the characterization of 415 and 69 proteins from the isolated embryo and endosperm tissues, respectively. The role of these proteins is discussed in terms of protein evolution and physiological properties of the rudimentary, underdeveloped, Amborella embryos, notably considering that the acquisition of desiccation tolerance corresponds to the final developmental stage of mature seeds possessing large embryos. Desiccation tolerance allows plant seeds to remain viable in a dry state for years and even centuries. To reveal potential evolutionary processes of this trait, we have conducted a shotgun proteomic analysis of isolated embryo and endosperm from mature seeds  Amborella trichopoda, the eldest sister of all flowering plants, lies at the base of the phylogenetic tree of angiosperms -1-propanesulfonate  supplemented with 50 µL of the protease inhibitor cocktail Complete Mini ). Then, 15 µL of 1 M dithiothreitol , 2 µL of DNase I  and 5 µL of RNase A  were added to the sample. Following stirring for 2 h at 4 °C, protein extracts were centrifuged at 20,000 g at 4 °C for 15 min. The resulting supernatant was submitted to a second clarifying centrifugation, as above [Protein extraction was carried out from three replicates of 100 isolated embryos and three replicates of 20 endosperm portions (free of embryos). Proteins were extracted at room temperature in 400 μL thiourea/urea lysis buffer composed of 7 M urea, 2 M thiourea, 6 mM Tris-HCl, 4.2 mM Trizmaas above ,29. The as above .Amborella seed proteome exploration was performed as previously reported [n = 3 biological replicates) that had been subjected to 1D-SDS-PAGE (http://pappso.inra.fr). Protein extracts were loaded in 1X Laemmli buffer with DTT (50 mM) in a stacking gel ). After 15 min of migration at 10 mA, the gel was stained with colloidal blue  and destained in Milli-Q water. The whole band corresponding to total proteins was excised and submitted to in-gel digestion with the Progest system  according to a standard trypsin protocol. Briefly, gel pieces were washed for 1 h at 37 °C in a solution containing 25% (v/v) acetonitrile and 50 mM ammonium bicarbonate (pH 7.8), followed by dehydration in 100% acetonitrile (ACN) for 15 min. Gel pieces were rehydrated overnight at 37 °C with 1/50 (w/w) trypsin  in 20 mM ammonium bicarbonate, pH 7.8. Digestion was stopped by adding 0.4% of trifluoroacetic acid (TFA). The reported  by LC-MS−1 on a precolumn cartridge  and desalted with 0.1% methanoic acid (HCOOH). After 3 min, the precolumn cartridge was connected to the separating PepMap C18 column . Buffers used were 0.1% HCOOH in water (A) and 0.1% HCOOH in ACN (B). Peptide separation was achieved with a linear gradient from 5 to 30% B for 30 min at 300 nL/min. Including the regeneration step at 95% B and the equilibration step at 95% A, one run took 45 min. Eluted peptides were analyzed on-line with a Q-Exactive mass spectrometer  using a nano-electrospray interface . Xcalibur 2.1 interface was used to monitor data-dependent acquisition of peptide ions. This acquisition included a full MS scan covering 300 to 1400 range of mass-to-charge ratio (m/z) with a resolution of 70,000 and a MS/MS step . MS/MS step was reiterated for the eight major ions detected during full MS scan. Dynamic exclusion was set to 45 s. HPLC was performed on a NanoLC-Ultra system ). A 4-µL sample was loaded at 7.5 µL/minAmborella Genome database  and a contaminant database  were used. Identified proteins were analyzed using X!TandemPipeline [Amborella genome were then submitted to BLAST analyses against the non-redundant protein sequences at NCBI, making it possible to evaluate their role in the physiology of the seed (http://metacyc. org). These analyzes allowed us to assign a function to the majority of the identified proteins. The functional categories and sub-categories are those defined in [A database search was performed with X!Tandem  for protPipeline . Only pefined in .Amborella sensu stricto seeds are composed of a bulky albumen, an envelope, and a rudimentary embryo of small size, eccentric, and heart-shaped (ratio embryo/seed length = 0.08). Seed cuts were stained with Naphthol blue black to visualize proteins (blue) and nuclei (dark blue). This staining also contained periodic acid/Schiff reagent to reveal the presence of polysaccharides (pink) (The dry mature s (pink) . Embryons (pink) . Endospes (pink) . They cos (pink) . An exams (pink) . These oAmborella seeds displayed a water content of 12.9% (in terms of fresh weight). These seeds (after scarification) displayed a germination percentage above 90%. It was interesting to determine the level of desiccation that seeds of this rainforest shrub could tolerate in order to confirm this trait for this basal angiosperm. For this purpose, desiccation tolerance experiments were carried out on Amborella seed batches.After harvest, sensu stricto seed batches were weighed and placed in same RHs as above. No change (less than 0.1%) of sensu stricto seed mass was noted in the next seven days for batches placed in the three studied RHs, reflecting the permeability of the endocarp and the action of desiccation on sensu stricto seeds. Equilibrium of seeds in the various studied RHs was reached after four days. Water sorption isotherms were drawn using moisture content of seeds equilibrated at all the studied RHs. The water sorption isotherm, issued from three replicates, showed typical curves with two regions observed above RH 9%, one ranging from 9–80%, the second above RH 80% , namely RH 9%, RH 45%, and RH 85%, and then weighed until equilibrium was reached (data not shown). Change of mass variation with respect to control seeds for each seed batch was −8.9%, −4.9%, and +0.5%, respectively. Endocarps were then removed from seeds, and e RH 80% A. The wae RH 80% A.p < 0.05).Seed batches issued from three replicates of a desiccation experiment were put in germination in a greenhouse. Germination of seeds occurred 70 days after sowing, and the final rate of germination was obtained 140 days after sowing B. Germinsensu stricto seeds and (ii) from 20 portions of endosperms without embryos (1.2 g) also isolated from dry mature sensu stricto Amborella seeds  300 embryos isolated from dry mature ethods,” ). A shotethods,” , as is tndosperm  and 415 ndosperm . The idendosperm . Among tndosperm . Protein destination and storage category contains 19 proteins representing 85.1% of the abundance of all proteins. Eight proteins are of the Storage protein function solely representing 82.6% in total protein abundance. The Folding and stability function contains seven proteins (1.8% in abundance). Fifteen proteins are in the Disease/Defense category . The five proteins of the Stress response function represent 2.4% in abundance. The 11 proteins of the Detoxification function represent 4.6% in abundance. The 16 proteins in the Energy category represent 3.4% in abundance. These are mainly involved in three main functions: glycolysis, tricarboxylic acid (TCA) pathway cycle and fermentation. The five proteins involved in the Metabolism category represent 1% of abundance. The Cell structure category (eight proteins) represents 1.9% of abundance. These results clearly demonstrate that the endosperm is primarily a tissue for storage of seminal reserves, as highlighted by a relative abundance of storage proteins of about 82%.The 69 identified proteins identified from the endosperm correspond to 20 unique functions. They are grouped into major categories  in relatProtein destination and storage category account for 41.3% in abundance. Among them, eight are storage proteins that represent 25.5% of total abundance, which is about 3 times less than in endosperm. The Metabolism category contains 45 proteins (5.3% in abundance). Eighteen proteins are involved in the Amino acid function . Fifteen proteins are involved in the Sugars and polysaccharides function (2% of the proteins in abundance). Five proteins are involved in the Lipid and sterol function (0.9% in abundance). The functional category Energy contains 42 proteins and represents an abundance of 11.1%. In particular, the Glycolysis function contains 18 proteins (6.7% in abundance). The TCA pathway function is represented by 14 proteins . There are 52 proteins in the Protein synthesis category, which represents 6.5% of the proteins of the embryo in terms of relative abundance.The ontological classification of the 415 proteins identified in the embryo is radically different . They coIn summary, besides a storage role the proteins of the embryo are associated with cellular mechanisms .Amborella embryo is surrounded by a voluminous endosperm . Thus, the present results reveal that a loss of more than 75% of their water content (in terms of fresh weight) does not significantly affect the germination vigor of Amborella seeds, attesting to their competence to withstand intense desiccation stress.The level of seed desiccation tolerance had never been investigated in  highest . The perendocarp . The iniAmborella mature dry seed possesses a number of proteins necessary for the stabilization of the lipid storage bodies during desiccation. In particular, five oleosins were identified in the embryo, and one was present in both the endosperm and the embryo  are degraded into fatty acids which are then used for β-oxidation and then within the glyoxylate cycle [Amborella embryo  is present in the Amborella embryo , whereas the opposite is observed by underexpression [Nelumbo nucifera) seeds is at least partly due to the extraordinary accumulation of PIMT activity within seed tissues, representing the highest accumulation ever observed in the living kingdom [Amborella embryo therefore suggests that the embryo is capable of repairing its damaged proteome during dry storage [The present proteomics analysis shows that about 11% of the embryo proteins are involved in the tabolism . It is wa embryo . To our ubstrate . In planubstrate . Thus, tpression . It has  kingdom ,58,59. T storage ,60.1-pyrroline-5-carboxylate) reductase, P5C dehydrogenase, and acetylornithine deacetylase  in orthodox seeds, including (i) the ability to accumulate stored reserves, both proteins and lipids and (ii) the ability to tolerate desiccation, a process that is of paramount importance in agriculture [The present characterization of a number of proteins from the iculture ,91.


Renal failure is a process that expresses a loss of functional capacity of the nephrons, independently of its etiology. The most widely used technique to combat renal failure is hemodialysis. Renal failure causes various systemic alterations including oral complications such as variations in the flow and composition of the saliva. Caries is a multifactorial disease and impaired stimulated salivary flow rate and buffering capacity are the best-known risk factors. The present study aims to evaluate the salivary pH, buffering capacity and the flow rate of saliva to the DMFT status in adult hemodialysis patients among the Indian population.Twenty healthy individuals and sixty patients undergoing hemodialysis were divided into four groups based on the following criteria: Group 1: Control group; healthy individuals,Group 2: Patients before undergoing dialysis or undergoing dialysis<3 months, Group 3: Patients undergoing dialysis since 6 months-2 years, Group 4: Patients undergoing dialysis>2 years. Dental examinations were performed according to the modified WHO oral health survey 2013 criteria and DMFT index. Saliva was collected after pre-stimulation to measuring the flow rate, buffering capacity and pH.The results exhibited a decrease in the salivary flow rate and buffering capacity with the increase in the time interval of hemodialysis, but salivary pH was found to be increasing with time. A direct relationship was seen between the DMFT scores with the increasing time interval. There was a significant correlation between DMFT index, stimulated salivary flow rate, and buffering capacity in the patients.Oral health impairment can beacon to grave problems in infection-prone hemodialysis patients. Hence, the patients on hemodialysis should have regular dental examinations and treatment. Regular dental examination and instruction in patients awaiting a renal transplantation is of vital importance to ensure optimal oral health. Key words:Saliva, pH, Buffering Capacity, Flow Rate, Hemodialysis, DMFT.  Saliva is a clinically ostensive biofluid efficacious for novel conceptualization to prognosis of a disease, laboratory diagnosis, clinical diagnosis, monitoring of diseases and treatment of patients of both oral and systemic origin . Saliva Dentists encounter various systemic diseases in clinic practice, one such being chronic renal failure or end-stage renal disease. Over the last few decades, the prevalence and incidence of patients with end-stage renal disease has been increasing . HemodiaThe risk of oral infections may also aggravate the risk of septicemia and endocarditis in dialysis patients. The condition has been noted to be exacerbated by ill-fitting oral prosthesis, caries and local infections . TherefoDental caries has been advocated to be a multifactorial disease, where impaired stimulated salivary flow rate and buffering capacity are noted as the best-known risk factors . Hence ,The present study was conducted on a total of 80 individuals; 20 healthy individuals and 60 patients undergoing hemodialysis treatment in the Department of Nephrology at K.S Hegde Hospital. Ethical clearance was acquired from the Institution Ethics Committee. Patients under the age of 18 years and complete edentulous patients were excluded from the study.The patients were divided into four groups based on the following criteria:Group I: Control group [ 20 patients ] – healthy individuals., Group II: Patients undergoing dialysis < 3 months [20 patients].Group III: Patients undergoing dialysis from 6 months-2 years [20 patients] and Group IV: Patients undergoing dialysis > 2 years [20 patients].After obtaining the patient`s informed consent, the dental examinations were performed according to modified WHO oral health survey 2013 criteria and DMFT index. The teeth were isolated with cotton rolls & examined using a mouth mirror & probe under good illumination.All the individuals taking part in the study were asked to abstain from smoking, drinking, eating and performing oral hygiene procedures, 2 hours before the collection of saliva samples . The sam-Flow rate The saliva was collected into a collection cup after pre-stimulation. Whole saliva was stimulated with the aid of paraffin-wax chewing method. The saliva was collected from each subject for 5 min. For the measurement of flow rate, the collection of saliva into the collection cup was timed. It was expressed as ml/min. it was evaluated based on the following readings as per the saliva check kit: <3.5ml- very low, 3.5-5.0ml-low, >5.0ml-normal.- Buffering capacity Sufficient saliva was drawn from the collection cup using a pipette, followed by a drop of saliva each being dispensed onto the three test pads. After 2 minutes, the test pads started to change color.Depending upon the final color on the test pad, the total number of points was calculated. The combined total buffering capacity of saliva was interpreted based on the saliva buffer capacity indicator available with the kit: green – 4, green/blue-3, blue-2, red/blue-1, red-0. Depending upon the total points, the buffering ability of the saliva was deciphered based on the following scores; 0-5:very low, 6-9:low, 10-12: normal/high.-pH measurement The saliva was pipetted onto a pH test strip for 10 seconds. The color obtained on the test strip was compared against the salivary pH indicator. The salivary pH indicator is a testing chart available in the package.The data obtained was statistically analyzed Kruskal-Wallis Test and Mann -Whitney U Test.p<0.001). On pairwise comparison between the study groups, the difference in the distribution of salivary volume was found to be statistically significant between all the groups (<0.05)  salivary flow rate of 3.63 (1.32) followed by patients under dialysis for 6 months to 2 years (4.95±1.60), under dialysis for < 3months (6.55±1.69), and highest in control group (9.20±1.70). The median salivary flow rate in those subjects is 3.25, 4, 5.80 and 9 respectively. There was a significant difference in the distribution of the salivary volume among the study groups ( (<0.05) .An inverse relationship was observed between the decrease in the buffering capacity of saliva in hemodialysis patients to the increasing time intervals. Patients under dialysis for more than 2 years had the least mean (SD) salivary buffering capacity of 3.65 (1.84) followed by patients under dialysis for 6 months to 2 years (7.50±2.26), under dialysis for < 3months (8.80±2.09), and highest in control group (10.95±1.19). The median buffering capacity in those subjects is 4, 8, 10 and 11.50 respectively. Patients under dialysis for more than 2 years had the least mean (SD) salivary buffering capacity of 3.65 (1.84) followed by patients under dialysis for 6 months to 2 years (7.50±2.26), under dialysis for < 3months (8.80±2.09), and highest in control group (10.95±1.19) .p<0.001). On pairwise comparison between the study groups, the difference in the distribution of pH levels was found to be statistically significant between all the groups (<0.05)  salivary pH of 7.33(0.35) followed by patients under dialysis for 6 months to 2 years (6.75 ±0.35), under dialysis for < 3months(6.38±0.32), and lowest in control group (6.02±0.27). The median pH in those subjects is 7.45,6.80.6.25 and 6 respectively. There was a significant difference in the distribution of the pH levels among the study groups ( (<0.05) .p<0.001) On pairwise comparison between the study groups, the difference in the distribution of DMFT score was found to be statistically significant between all the groups (<0.05)  DMFT score of 16.85 (4.58) followed by patients under dialysis for 6 months to 2 years (12.65±3.33), under dialysis for < 3months (8.90±3.08), and least in control group (3.00±2.15). The median DMFT score in those subjects 15.50, 12.50, 8 and 2.50 respectively. There was a significant difference in the distribution of the DMFT score among the study groups ( (<0.05) .Earlier research has reported deteriorating oral status of patients undergoing hemodialysis in comparison to that of the general population ,14. Henc-Evaluation of pH & Buffering capacityIn the present study, there existed a direct relationship between the increase in the salivary concentration of pH with increasing time intervals whereas an indirect relationship was noted between the decrease in buffering capacity of saliva with increasing time intervals. This is an invariable finding in all the studies that have evaluated these salivary parameters, both in adults as well as in children -17. The -Evaluation of salivary volumeet al., who advocated that the salivary flow in dialysis patients remained within the normal range .In the present study, there was an inverse relationship between DMFT scores with the increase in the time interval of hemodialysis treatment. This can be attributed to the decreased salivary flow among the individuals along with decreased buffering capacity ,15. AlthResearch has advocated that in patients undergoing hemodialysis, oral home care effectuation tends to be less prevalent when they did seek dental care on a regular basis ,25.In the present study, the salivary collection and analysis was done post hemodialysis. The limitations of this study could be that it has to be further expanded by increasing the number of samples and checking the salivary parameters pre and post hemodialysis procedures at different time intervals.The present study concluded that the salivary parameters flow rate and buffering capacity decreased with increasing time intervals whereas pH increased with increasing time intervals. Owing to these results, the DMFT scores were also found to be increasing with the passage of time. Accordingly, monitoring of pH, buffering capacity and volume should certainly be considered as a part of the routine sialometric assessment in renal transplant and dialysis patients. Oral infections and manifestations can lead to serious problems in dialysis patients who are prone to infections. Therefore, regular dental examinations and treatment should be made a fundamental protocol in these patients. Future studies in much larger cohorts of transplant and dialysis patients at different time interval should be conducted to evaluate the efficacy and feasibility of salivary analysis.


To evaluate the efficacy and toxicity of hypofractionated stereotactic body radiotherapy (SBRT) for patients with recurrent or residual hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). Between June 2008 and July 2015, thirty-three patients with HCC were treated by SBRT. There were 63 lesions in 33 patients. A total dose of 39–45 Gy/3–5 fractions was delivered to the 70–80% isodose line.P < 0.001) between the group of patients for whom AFP decreased more than 75% and the group for whom AFP decreased by less than 75%. The AFP-negative rate was 48.5% (16/33) after 6 months. Eight patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. Objective response rate (CR + PR) was 84.8% at 6 months. The overall survival rate was 87.9%, 75.8%, 57.6%, and 45.5% at 6, 12, 18, and 24 months, respectively. Median overall survival was 19 months. At 3 months, AFP decreased by more than 75% in 51.5% of patients (17/33). Overall survival was significantly different ( SBRT is a promising noninvasive and palliative treatment with acceptable toxicity for recurrent or residual HCC after TACE. There are differences between China and the Western world regarding hepatocellular carcinoma in the following ways: 1) alcoholic cirrhosis was a common aetiology of liver cancer in Europe and the United States. In China, it was more common that hepatitis B virus infection gradually developed into liver cirrhosis, with liver cancer as an end stage disease. (2) Approximately 70% of HCC patients had elevated AFP in China, whereas only 30% of European and American patients had similar findings. (3) While sorafenib was the standard treatment for advanced and recurrent hepatocellular carcinoma in Europe and the United States, fewer patients received sorafenib in China not only because of less than 10% drug efficacy but also because the drug did not enter the healthcare system in most areas. Currently, TACE is a commonly used method to treat liver cancer. However, it has difficulty reaching tumours of over 5 cm with complete ischaemia or necrosis. The hepatic mass is supplied by two blood vessels, the hepatic artery and the portal vein. Therefore, even if the tumour artery is completely embolized with TACE, the portal vein may still provide blood to residual tumour cells, thus providing a source for future recurrence and metastasis [ alcoholi3 copies/mL); (5) AFP levels greater than 400 ng/mL before the first TACE; (6) class A liver function by Child-Pugh scoring; (7) KPS ≥ 70; (8) a volume of normal liver tissue > 700 mL; (9) no invasion or lymph node metastasis; and (10) three or fewer lesions. During treatment, patients who had liver tumour surgery or used targeted drugs or systemic chemotherapy were excluded.This retrospective study included thirty-three patients with recurrent or residual HCC from the Radiotherapy Department of Ruikang Hospital of the Guangxi Traditional Chinese Medicine University who were treated with SBRT between June 2008 and July 2015. All patient medical records were carefully reviewed. Inclusion criteria were as follows: (1) diagnosed with HCC by pathology; (2) initial treatment by TACE for at least 3 months; (3) recurrent and residual diagnostic criteria: in HCC, after TACE in the CT/MR examination, it was found that the tumour disappeared, was not enhanced, or had subsequent reappearance or that the enhancement of the tumor was defined as recurrence or decreased but remained defined as residual; after TACE, lipiodol artifacts and CT/MR contrast agents are mixed together to determine the need for biopsy; (4) a history of liver cirrhosis derived from hepatitis B and, after formal review following antiviral therapy, a negative result for hepatitis B virus DNA  or residual  disease as determined by experienced radiation diagnostic physicians and radiologists. All patients underwent TACE 1–4 fraction. Cisplatin, Adriamycin, and/or mitomycin C were administered during TACE. Patient characteristics are presented in The median age of 33 patients was 55 years (range: 42–75), and 75.8% were male. All patients had either recurrent (3 (range: 36–236 cm3). Plans were devised so that the prescribed dose was the isodose line encompassing >96% of the PTV. No more than 3% of the PTV was to receive <94% of the prescribed dose. Patients were treated with the Accuray CyberKnife . Dose constraints are shown in The livers of all patients were implanted with 3-4 fiducials (99.9% pure gold particles) one week before the CT location scan. Fiducials localize to the tumour, within 2 cm, and no three gold fiducials can be coplanar. The tumour area was identified and outlined using a plain CT scan image as the basis to fuse CT/MR/DSA enhanced images. A plan was designed with 4D-CT treatment simulation using the CyberKnife® Robotic Radiosurgery System: X-sight Fiducials Tracking System . Target and critical structures  were contoured. The GTV (gross target volume) was defined as a tumour visible on the CT/MR scan. The GTV was expanded by 3–5 mm to form the PTV (plan target volume). All patients were treated with a total dose of 39–45 Gy/3–5 fractions. The mean target volume was 128 cmAn index AFP level was recorded before TACE and before SBRT. AFP levels were also recorded at 3 months and 6 months after SBRT or at 1 month before death for those with a survival time less than 6 months.Toxicity induced by SBRT was scored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Radiation-induced liver disease (RILD) was defined as an anicteric elevation in alkaline phosphatase of at least 2-fold the upper normal level (classic RILD) or elevated transaminases of at least 5-fold (nonclassic RILD), without progressive disease (PD) and the development of nonmalignant ascites [P < 0.05 was considered statistically significant.Survival rates were calculated from the date of SBRT. Kaplan-Meier survival analysis was used to estimate overall survival (OS). SPSS® software version 17.0  was used for statistical analyses. 6 months after treatment, all patients underwent CT/MR examination. According to mRECIST criteria, there were 63 lesions in 33 patients. The degree of change was as follows: CR: 7 (18. 9%), PR: 33 (56. 9%), and PD: 14 (24. 2%). Objective response rate (CR + PR) was 84.8% (28/33) at 6 months.The overall survival rates at 6, 12, 18, and 24 months were 87.9%, 75.8%, 57.6%, and 45.5%, respectively. Median overall survival was 19 months. The Kaplan-Meier curve for overall survival is presented in P ≤ 0.001) between the group of patients for whom AFP decreased more than 75% and the group for whom AFP decreased by less than 75%. The Kaplan-Meier curve for overall survival is presented in The AFP index values of all patients were more than 400 ng/mL before TACE treatment. Those decreased at various rates after TACE. In the recurrent disease group, the AFP index of 4 patients fell to normal levels after TACE . However, the levels rose again after 3 months. The remaining patients had no reduction to normal levels. In the residual disease group, no patients had their AFP index decline to the normal range after TACE. At 3 months, AFP decreased by more than 75% in 51.5% of patients (17/33). Overall survival was significantly different (8 patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. The symptoms were relieved or had disappeared after symptomatic and supportive treatment. No grade 3 or higher acute toxicities attributable to SBRT were found at 1 month . 2 patieTumour tissues could not be completely eliminated through TACE. Previous studies reported that approximately only 22%–50% of the tumour tissue was totally destroyed as determined by pathology examination. The rate of recurrence and metastasis correlated with tumour size, type, scope, biological characteristics, collateral circulation, liver function, embolization, lipiodol dosage, and deposition .P = 0.02). Su et al. similarly reported [There is no uniform suggestion for the treatment of residual cancer or recurrence of liver cancer. Surgery, TACE/TAE, radiation therapy, radiofrequency ablation, freezing, microwave, alcohol, and other methods have been reported in the literature –6. The rreported  the effereported  was carrreported , 13.In our study, the overall survival rate was 87.9% (29/33), 75.8% (25/33), 57.6% (19/33), and 45.5% (15/33) at 6, 12, 18, and 24 months, respectively. Median overall survival was 19 months. Therefore, SBRT combined with TAE/TACE may be an effective complementary treatment approach.Detection of serum alpha-fetoprotein (AFP) is used in clinical follow-up for high-risk population screening and cancer patients. Although 30% ~ 40% of patients have negative AFP detection in HCC of China , due to Expanding the boundary outside the target area directly affects the control of tumours in radiotherapy. How far can liver cancer be confined to the liver in a subclinical tumour? A study on the range of foreign invasion of subclinical foci provided the basis for us to determine the imaging needs for the targeted tumour to evaluate the extent of expansion. After research, the tumour boundary was expanded 4 mm to include most of the area of invasion. If the tumour diameter was <5 cm, then 95% of tumour lesions could be treated by a 2 mm expansion . These dIn this study, 8 patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. The symptoms were relieved or eliminated after symptomatic and supportive treatment. No grade 3 or higher acute toxicities attributable to SBRT were found at 1 month. 2 patients experienced liver failure toxicity at 3 months, and 1 patient was relieved after treatment. 1 patient with enlargement of the spleen experienced gastrointestinal haemorrhage at 6 months. 3 patients experienced anemia at 1 month and one of them with long-term gastrointestinal reactions turned worse at 6 months. Most toxicities could be related to tolerance, which could be recovered after acceptance of treatment. In this study, patients with less adverse reactions may be associated with patients who have only selected Child-Pugh A class.The liver has poor radiation tolerance. The occurrence of subacute radiation hepatitis is a standard for measurement. The total liver irradiation TD5/5 (minimum tolerance dose) is 25 Gy, and the whole liver irradiation level TD50/5 (maximum tolerated dose) is 40 Gy . TherefoThe major strengths of SBRT compared with conventional fractionated RT are as follows: (1) more intensified and accurate treatment of the tumour, (2) increased convenience for patients and technologists, and (3) minimal interference from delivery to the body itself . SBRT isAFP was significantly elevated at the time of initial treatment. For patients receiving radiotherapy for recurrence of hepatocellular carcinoma, a 75% decline in AFP levels at 3 months may be a predictor of survival prognosis.This study has several limitations. First, this was a retrospective single-center study. In this study, the short observation time, the small number of cases, and single-center study may affect the accuracy of the statistical test. Further prospective studies are needed to investigate the true effect of this novel treatment.SBRT is a promising noninvasive and palliative treatment with acceptable toxicity for recurrent or residual HCC after TACE. And a >75% decline in AFP levels at 3 months may be a predictor of survival prognosis.


Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes.n = 907) compared to 4.1%  in children with a genetic score of ≤14.4 . Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82  and 52 , respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case–control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations.The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk  for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%–6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%–4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%) in children with a merged genetic score of >14.4  participating in the TEDDY cohort study, which prospectively follows children from birth for the development of islet autoantibodies and diabetes.We found that both of the genetic scores, and a merged genetic score that combined the features of both, stratified the risk for islet autoantibodies and diabetes in the children.The upper quartile of the merged genetic score was associated with a >10% risk for the pre-symptomatic stage of multiple islet autoantibodies, and almost half the children who developed pre-symptomatic or symptomatic diabetes were identified by this score.Combining genetic information from multiple risk loci can improve the prediction of diseases such as type 1 diabetes.A genetic risk score model is proposed that could be used to recruit infants into early type 1 diabetes primary prevention trials.The model provides a new paradigm for genetic screening and selection of at-risk infants that, together with family history and HLA genotyping, could identify up to 25% of future childhood cases of type 1 diabetes from less than 1% of newborns. Precision medicine typically relies on our ability to identify individuals with precise genetic elements that define a disease. These elements may be used not only to select optimal treatment modalities, but also to identify individuals who may benefit from preventative interventions. In pediatric disease, current studies seeking to elucidate disease etiology, as well as clinical trials aimed at prevention, rely on identifying and enrolling infants with increased risk –7. The rIn type 1 diabetes, genotypes in the human leukocyte antigen (HLA) DRB1, DQA1, and DQB1 loci are sometimes used to identify at-risk infants from the general population ,9,10. RiWe previously applied logistic regression to the Type 1 Diabetes Genetics Consortium (T1DGC) case–control dataset and developed a weighted genetic score derived from HLA and 40 type 1 diabetes susceptibility loci (Winkler score) . IndepenThe Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter cohort study set in Germany, Finland, Sweden, and the US, has intensively followed several thousand HLA-selected children from birth for the development of islet autoantibodies and of diabetes . The prehttps://www.ukbiobank.ac.uk/)  girls), and 4,157 children (91.5%) remained islet autoantibody negative . Of the 386 children with islet autoantibodies, 241 children (62.4%) developed multiple islet autoantibodies . A total of 107 (2.3%) developed diabetes by age 10 years (47 [43.9%] girls). The cumulative risk for developing islet autoantibodies was 9.2%  children who had material for additional genetic analysis. The median follow-up in these children was 7.39 years. For each of the Winkler, Oram, and merged scores, the score was greater in children who developed islet autoantibodies by 6 years of age as compared to children who remained islet autoantibody negative (P < 0.001). The cumulative risk for developing multiple islet autoantibodies by 6 years of age was 11.0% (95% CI 8.7%–13.3%) in children with a score of >14.4, compared with 4.1% (95% CI 3.3%–4.9%) in children with a score of ≤14.4 (P < 0.001). The cumulative risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a score of >14.4, compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 (P < 0.001). The risks were also stratified by the Winkler and Oram scores  and the sensitivity decreased (P < 0.001) with each increment in the genetic score threshold by the 5th percentile of the cohort. The risk for multiple islet autoantibodies reached a maximum of 13.2% (95% CI 9.2%–17.1%) above a threshold of >15.1, which identified 38 of the 173 children who developed multiple islet autoantibodies by age 6 years, corresponding to a sensitivity of 22.0% (95% CI 16.4%–28.7%). Above a threshold of 14.4, representing the upper 25% of merged genetic score values and where risk for multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%), 82 of the 173 children who developed multiple islet autoantibodies by age 6 years were identified . In a population where the prevalence of HLA DR3/DR4-DQ8 and HLA DR4-DQ8/DR4-DQ8 genotypes is similar to that of the TEDDY cohort (2.9%), using the threshold of 14.4 would identify <1% of all newborns without a prior family history of type 1 diabetes.Islet autoantibody and diabetes risk appeared incremental with increasing merged genetic score. Since the efficiency of a test is measured by both sensitivity and positive predictive value (risk), we examined the relationship between sensitivity and risk at increasing thresholds for the genetic score  Tables. Genetic scores derived from logistic regression of numerous loci associated with type 1 diabetes susceptibility were able to stratify the risk for pre-symptomatic and clinical type 1 diabetes in a prospective cohort of children with high-risk HLA genotypes but no family history of type 1 diabetes. The risks of developing islet autoantibodies, multiple islet autoantibodies, and diabetes increased with each increment in the genetic score. A genetic score that would identify <1% of all newborn infants was associated with a risk for developing multiple islet autoantibodies of >10% by 6 years of age. This compares to a background population risk of around 0.4% . These fThe study was performed using a large number of children who were prospectively followed for the development of islet autoantibodies from infancy. The findings were consistent between US and European children and for 2 independently derived genetic scores that were used to develop the merged genetic score. We note, however, that the risk scores were generated using the outcome of clinical, or stage 3, type 1 diabetes. It has been previously noted in multiple studies, including TEDDY, that many, but not all of the genes associated with type 1 diabetes confer risk for islet autoantibodies ,27. For https://clinicaltrials.gov/ct2/show/NCT03364868), where DNA extraction from blood spots and typing are performed for less than US$8 per sample. Extending the strategy to individuals with other HLA genotypes is possible, but the other genotypes are less frequent in type 1 diabetes and are associated with a lower risk than that conferred by the DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 genotypes. Therefore, the inclusion of other genotypes is unlikely to further improve risk stratification.The study was performed to extend the opportunities for early identification of individuals at increased risk for disease. Previous primary prevention trials in type 1 diabetes involved HLA typing of infants with a family history of type 1 diabetes ,4,31. ThIn conclusion, a genetic score based on 3 SNPs for HLA class II genotyping and 41 SNPs in other genes identified <1% of newborn children who, in the absence of a family history of type 1 diabetes, had a >10% risk for developing multiple islet autoantibodies by 6 years of age. This greatly extends the possibilities of enrolling participants into clinical trials aimed at evaluating type 1 diabetes prevention strategies that could be applied in infancy and before the development of autoimmunity .S1 Appendix(DOC)Click here for additional data file.S1 Figy-axis) and the proportion of all cases of type 1 diabetes in each cohort (x-axis) are shown for both genetic scores (B).Genetic scores calculated using the Winkler model (left panels) and the Oram model (right panels) in the UK Biobank and Wellcome Trust Case Control Consortium (WTCCC) controls, and in WTCCC cases with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype (A). The empirically calculated risk of type 1 diabetes ((TIF)Click here for additional data file.S2 FigIslet autoantibody outcome (A); geographic location (B); sex (C). Red horizontal lines indicate the median genetic score value in each group.(TIF)Click here for additional data file.S3 Figy-axis) is shown relative to the age in years (x-axis) and was calculated using the Kaplan–Meier method. Curves are shown for children with genetic scores in the upper (orange line), lower (green line), and 2 middle (blue line) quartiles. The shaded areas represent the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.Cumulative risks of developing 1 or more islet autoantibodies , multiple islet autoantibodies , and type 1 diabetes  in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their Winkler  and Oram  genetic scores. The risk ((TIF)Click here for additional data file.S4 Figy-axis for each genetic risk score from 1 year to 10 years with increments of 100 days. (B) To obtain a distribution for each of these predicted scores, we performed 2,000 paired bootstrap analyses for each genetic risk score, with the results shown as box pots (diamonds indicate the integrated area under the curve [AUC] for the full TEDDY data). These bootstrap analyses were further used to assess statistical differences of the time-dependent receiver operating characteristic curve estimates per genetic risk score. To this end, we calculated Bayes factors of the paired estimates [Three scores are compared . (A) We calculated the integral of a time-dependent receiver operating characteristic curve , indicatstimates  of 2 risstimates .(TIF)Click here for additional data file.S5 Figy-axis) is shown relative to the age in years (x-axis) and was calculated using the Kaplan–Meier method. Curves are shown for children with merged genetic scores in the upper (orange line), lower (green line), and 2 middle (blue line) quartiles. The shaded areas represent the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.Cumulative risks of developing 1 or more islet autoantibodies , multiple islet autoantibodies , and type 1 diabetes  in TEDDY children with the HLA DR3/DR4-DQ8  or DR4-DQ8/DR4-DQ8  genotype. The risk ((TIF)Click here for additional data file.S6 Figy-axis) is shown relative to the age in years (x-axis) and was calculated using the Kaplan–Meier method. Curves are shown for children divided by geographic location  and sex . The shaded areas represent the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.Cumulative risks of the development of 1 or more islet autoantibodies , multiple islet autoantibodies , and type 1 diabetes  in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype and merged genetic score > 14.4. The risk ((TIF)Click here for additional data file.S1 GRIPS Statement(DOC)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S5 Table(DOC)Click here for additional data file.