Recent reports have suggested a significant change in the causes of blindness in children in low-income countries cataract becoming the leading cause. We aimed to investigate the presentations and surgical outcomes in children with cataract operated at different ages in Tanzania.We conducted a prospective study of 228 children aged ≤192 months at three tertiary centres, 177 with bilateral cataracts and prospectively followed them for 1-year postsurgery. We collected demographic, surgical, preoperative and postoperative clinical characteristics using the standard childhood cataract surgical assessment questionnaire. Families were encouraged to return for follow-up by phone with travel reimbursement where necessary.Preoperatively, 76% bilateral children were blind in the better eye. 86% of children were followed up at 1 year and 54% bilateral children achieved visual acuity of 0.48 logMAR or better in the better eye and 5% were blind. 33% of unilateral children achieved visual acuity of 0.48 logMAR or better and 17% were blind. Preoperative blindness (adjusted OR (AOR) 14.65; 95% CI 2.21 to 97.20), preoperative nystagmus/strabismus  and aphakia  predicted poor visual outcome in bilateral cases. 9% of 342 refracted eyes had initial postoperative cylinder of 1.5 D or more, as did a similar proportion (11%) of 315 eyes refracted 1 year after surgery. Acute fibrinous uveitis occurred in 41 (12%) eyes.Three-quarters of children were blind preoperatively whereas over half had good vision 1-year postoperatively. Preoperative blindness, nystagmus/strabismus and aphakia predicted poor visual outcome, suggesting that cataract density determines density of amblyopia. Successful measles immunisation and vitamin A supplementation have resulted in a fall in the prevalence of blindness in children in Sub-Saharan Africa (SSA), from approximately 1 per 1000 to 0.6 per 1000.Visual outcomes are poorer following surgery for bilateral cataract in SSA, than in high-income countries. Studies in SSA show that 8%–60% of children achieve best-corrected visual acuity of 0.48 logMAR or better after surgeryThis was a prospective, longitudinal hospital-based observational study of children undergoing cataract surgery who were recruited between November 2016 and August 2017. Children aged <16 years were recruited from three tertiary facilities in Tanzania. All children underwent preliminary evaluation for study eligibility by paediatric ophthalmologists . We excluded children with traumatic cataracts and minor lens opacities not requiring surgery. Sociodemographic and clinical details were recorded by investigating clinicians using a questionnaire. Further data were collected to investigate risk factors for cataract. Weight and haemoglobin at surgery were compared with published national averages.Visual acuity in children 3 years and below was assessed with the Teller Acuity Cards. Children aged 4–7 years were initially assessed usingHOTV matching method, and if this was not possible, Lea Symbols were used, and failing this, Teller acuity cards were used. Children aged 8 years and above were tested using Snellen Charts. All results were converted to logMAR values. Cataracts were examined by direct ophthalmoscopy and slit lamp through dilated pupils. Cataract free lens and the total cataract were subjectively graded as grade 0 and 10, respectively. Cataracts with static morphologiesBiometry was performed in the operating room after induction of general anaesthesia. Intraocular lens (IOL) power was chosen to be approximately 20% less than that predicted to achieve emmetropia in children younger than 2 years; a 10% under correction for children from 2 to 8 years of age and emmetropia for older children.Four surgeons conducted surgeries; posterior capsulotomy and anterior vitrectomy were performed for children less than 7 years of age using an Alcon Accurus vitrectomy machine via an anterior approach or through a pars plana incision. In children above 1 year of age, the main corneal wound and paracenteses sites were sealed with hydroinflation; in children under 1 year both were closed with 9–0 nylon sutures. Individual surgeons used their standard technique.IOLs were routinely implanted under Aurogel  for children aged 4 months and above, with exceptions being a corneal diameter of <9.5 mm; or an axial length of <17 mm or other ocular abnormalities, which precluded implantation. Alcon AcrySoft single-piece and multi-piece IOLs  were used routinely according to availability for all children during the study period. At the end of the procedure, intracameral ceftriaxone (1 mg), and subconjunctival dexamethasone (2 mg) and gentamycin (10 mg) were administered. Subconjunctival triamcinolone-acetate (20 mg) was administered to patients at high risk of uveitis.All children were examined on the first day and stayed in hospital for 1 week. They were then followed up at 2 weeks, 1 month, 3 months, 6 months and 1 year postoperatively and visual acuity, refractive error and intraocular pressure (IOP) were measured at each follow-up and postoperative complications were recorded. Refraction was first performed 1 week postoperatively and when needed, spectacles were given to all children regardless of age. IOP was measured using I-Care and a standard proforma was used to record all postoperative findings. Parents were counselled at discharge and at all other visits about the importance of follow-up. Contact details were recorded to allow for reminders of subsequent follow-up and travel expenses were provided, if required.Statistical analysis was conducted using STATA V.14. Descriptive analysis to determine the frequency of postoperative refractive errors and visual acuity improvement over time was performed. All plausible predictors of visual outcome were tested by univariate analyses and those found to have association with the outcome  were further analysed in a multivariate model.There was an opportunity to discuss and ask questions. Finally, if the parent or guardian agreed to allow the child to be enrolled into the study, this was documented on a consent form in Kiswahili, and witnessed by a third person.A total of 228 children (177 (78%) with bilateral cataracts and 51 (22%) with unilateral cataracts, 405 eyes total) aged ≤192 months  were recruited. One hundred and forty-one (61.8%) were male; 111 (62.7%) with bilateral cataracts and 30 (58.8%) with unilateral cataracts). Eighty-seven (38%) were younger than 1 year at presentation and 164 (72%) were younger than 6 years. Sixty-nine out of 177 (38.9%) bilateral children were younger than 1 year old and were the subject of a separate case control study on risk factors. Description of patients by laterality according to age, sex, cataract types and tertiary care facility are shown in Body weight at surgery was lower  kg) in cataract patients compared with the age-matched census data for normal babies and teenagersPreoperative findings are shown in 10.1136/bjophthalmol-2020-316042.supp1Supplementary dataThe mean was 21.0 months , with 115 (52.5%) children having ≥12 months. Of 177, 127 (71.8%) bilateral children had lag time of 6 months and above compared with 30/51 (58.8%) children (p=0.04) with unilateral cataracts. There was no significant difference in lag time by gender .There was a change of surgical technique for two surgeons (FGM and SJV) during the study, from 3 mm superior scleral tunnel incision (sutured) to 3 mm  superior corneal incision and corneal paracenteses at 3 and 9 o’clock; no wound leaks, endophthalmitis or shallow anterior chambers developed. A total of 249 (61.5%) surgeries were done through corneal incisions and 61.8% of all surgeries were completely sutureless. All wounds in children less than 1 year, and scleral-tunnels and sclerostomies in any age were sutured.IOLs were inserted in 346 of 405 (85.4%) eyes operated: AcrySoft single-piece 255 (62.9%) and three-piece lenses 91 (22.5%). Intracapsular fixation of the IOL was achieved in 290 (71.4%) eyes and 56 (13.8%) were sulcus fixated. A total of 390 (96.1%) eyes underwent posterior capsulotomy and anterior vitrectomy, in 142 (34.9%) eyes via a pars plana approach and 259 (63.8%) eyes via an anterior approach (missing data in five eyes).One hundred and fifty-four out of 177 (87.0%) children with bilateral cataracts and 42 out of 51 (82.4%) children with unilateral cataracts were followed up at 1 year postoperatively. Two children died before 1-year follow-up, one after a month and one after 6 months follow-up. No child died during the perioperative period.Postoperative complications and reoperation rates by laterality are shown in A total of 342/392 (87.2%) eyes that had 1-year follow-up  were refracted at 1 month or less postoperatively and 315 (80.4%) eyes were refracted at 1 year postoperatively. A total of 90/342 (26.3%) eyes that were refracted at initial follow-up (1 month or less) had astigmatism and 68/315 (21.6%) eyes that were refracted 1 year after surgery had astigmatism. A total of 32/342 (9.4%) eyes that were refracted at initial follow-up had astigmatism of 1.5 D or more. 34/315 (10.8%) eyes that were refracted 1 year after surgery had astigmatism of magnitude of 1.5 D or more. Against the rule astigmatism of 1.5 D or more rates were 20/90 (22.2%) initially and 16/68 (23.5%) after 1 year. Children with corneal incisions were more likely to have postoperative astigmatism (OR=2.6: p=0.004) than those with scleral at 1 year. Children with refractive error of ≥2.0 D  were corrected and any other residual refractive errors were corrected with an appropriate near vision addition. However, children whose parents were unable to pay for spectacles and those under 5 years who had postoperative myopia and were in focus for near were not given spectacles. One hundred and twenty-six out of 196 (64.3%) children with 1-year follow-up were given glasses. One hundred and nine out of 125 (87.2%) children given glasses were wearing them at follow-up. Refractive outcomes  are shown in Children with postoperative hypermetropia ≥3 DS were younger (p=<0.001) and had shorter eyes (p<0.001) than those without. During the first postoperative year, there was a mean myopic shift magnitude of 1.34 D . For every unit (month) decrease in age at surgery there was increase in mean myopic shift by 0.018 D; 95% CI 0.013 to 0.021; (p<0.001). Myopic shift vs age at surgery is shown in A total of 154 of 177 (87%) bilateral children had a quantitative postoperative visual acuity assessment after 1-year follow-up. Eighty-three (53.9%) of these achieved visual acuity of 0.48 logMAR or better in their better eye; 39 (25.3%) had best-corrected vision between 0.50–1.00 logMAR; 24 (15.6%) had best-correct vision 1.00–1.3 logMAR and 8 (5.2%) were worse than logMAR 1.3, 1 year postoperatively. The proportion of better eyes with 1-year best-corrected visual acuity worse than 1.00 logMAR was lower (p<0.001) for less dense (grade <5) cataracts (3.12%) compared with denser (grade 8–9) cataracts (84.38%). 65/103 (63.1%) who had Teller acuity test at follow-up achieved corrected visual acuity of 0.48 logMAR or better in their better eye and 29 out of 51 (39.2%) children who had recognition acuities achieved best-corrected visual acuity of 0.48 logMAR or better in their better eye. Preoperative and postoperative visual acuity results for children with bilateral cataracts are shown in Of 68, 22 (32.3%) children operated below 2 years achieved a corrected visual acuity of 0.48 logMAR or better in the better eye, compared with 61 out of 86 (70.9%) children operated at the age of 2 or older (p<0.001).Of 177, 169 (95.5%) had follow-up at 3 months. Of 177, 37 (20.9%) children achieved visual acuity of 0.48 logMAR or better in the better eye at 3 months follow-up which significantly increased to 83 out of 154 (53.9%) children at 1-year follow-up (p<0.001). Independent predictors of poor visual outcome (worse than 0.48 logMAR in the better eye) are shown in Forty-two of 51 (82.4%) had quantitative acuity at 1-year follow-up. Fourteen of42 (33.3%) achieved visual acuity of 0.48 logMAR or better; 10 (23.8%) had vision between <0.48 and 1.00 logMAR; 11 (26.2%) had vision <1.00–1.3 logMAR; and 7 (16.7%) were blind, 1 year postoperatively. Forty-six 0 f 51 (90.2%) were blind preoperatively. Only surgery at <24 months of age predicted poor visual outcome in a univariate analysis (OR=0.09: p=0.025).There were no significant differences between children who attended for follow-up at 1 year and non-attenders, in terms of the factors, which predicted visual outcome for bilateral and unilateral cases.This is the first prospective study reporting outcomes of childhood cataract surgery from East Africa. The majority of children with bilateral cataracts (and 1-year follow-up) achieved better eye vision of at least 0.48 logMAR. This proportion was better than some retrospective reports from SSAHalf the children had a lag time of 1 year or more. This is slightly less than that reported in 2005In our study, nystagmus was present in nearly half, higher than that previous reports from the regionThe proportion of children with congenital and developmental cataract who have low body weights and low haemoglobin levels during surgery were estimated to be 68.4% and 48.4%, respectively, more common in bilateral cases. Low haemoglobin levels in congenital and developmental cataracts have previously been reportedDelayed presentation did not predict poor visual outcome. This is surprising because in children with cataract who are visually deprived for longer period of time are thought to be more amblyopic. However, our data showed that high-grade cataracts are more likely to present much earlier than low-grade cataracts, perhaps negating the effect of lag time on vision. On multivariate analysis, preoperative blindness was found to be significant predictor of poor outcome (p=0.004) similar to previous reports from Tanzania and Kenya, suggesting that cataract density could be a more important determinant of deprivation amblyopia than delay in presentation over a certain period of time. Surgery at younger age predicted poor visual outcome. This has also been reported in FranceIn this study, aphakia also predicted poor visual outcome. This was also seen in FranceThere was a change of surgical technique during the study, from the standard 3 mm superior scleral tunnel incision to 3 mm  superior corneal incision. The aim was to reduce the rate of second general anaesthetic (GA) procedures (since nylon sutures need to be removed) and rate of astigmatism. Authors found that a well-constructed 3 mm superior corneal incision that barely nicks the limbal blood vessels and injecting intracameral air at the end of surgery with additional hydro inflation of the paracenteses in children above 1 year was sufficient; there were no wound leaks, endophthalmitis or shallow anterior chambers and repeat GA procedures were reduced, 10% vs 28% in a previous study with sutured paracenteses.There was a low rate of initial astigmatism of 1.5 D or more at 2 weeks follow-up and after 1 year of follow-up. However, the majority was against the rule and an absorbable suture for the corneal wound might reduce this tendency.Forty-three out of 71 (60.6%) eyes of children ≤1 year had hyperopia of ≥2.0 D compared with 25 out of 110 (22.7%) eyes of children greater than 1 year (p<0.001). This is probably because of deliberate under correction of younger children. Three-piece lenses were preferred in most difficult surgeries, younger children, microphthalmic eyes and sulcus fixation. These factors could therefore explain the link between three-piece lenses with more uveitis.Good visual results are achievable in this setting despite long lag times. Preoperative blindness and preoperative nystagmus/strabismus were significant predictors of poor visual outcome suggesting that cataract density determines density of amblyopia. Anaemia and low body weight seem to coexist in large proportion of children with non-traumatic cataracts in Tanzania, warranting further investigation. Sutureless surgery seems to be safe in children over 1 year old.


BackgroundEven though the treatment outcomes of childhood acute lymphoblastic leukemia (ALL) have improved recently, relapse of the disease still remains a challenge in developing countries. This study aims to analyze the incidence of relapse and survival rates in childhood ALL.MethodsA retrospective study of 156 children with de novo ALL between 2012-2018 was conducted. Data on age, gender, relapse type, and relapse time were analyzed.ResultsA total of 26 (16.7%) patients experienced relapse, with a male-to-female ratio of 2.71:1. The relapse rate in the high-risk group was 1.6 times greater than that in the standard-risk group (61.5% vs. 38.5%). The median time from diagnosis to relapse was 29.3 months . The most common relapse site was bone marrow (38.5%), followed by the isolated central nervous system  and CNS plus bone marrow (23.1%); the least common site was testicle with or without bone marrow or CNS (15.2%). The median post-relapse survival time was 7.5 months.ConclusionModification of the protocol to use escalated methotrexate dose and providing new therapies such as stem cell transplantation can improve the overall survival rates in relapsed ALL patients. Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children. It accounts for one-fourth of all childhood cancers and 72% of all cases of childhood leukemia. Its incidence is estimated to be two to five per 100,000 children. The peak incidence of ALL occurs between the ages of two to five. With the recent advances in chemotherapy, hematopoietic stem cell transplant, and supportive care, the long-term survival in childhood ALL has increased to 85-90%. The most important prognostic factors for determining post-relapse survival rate are relapse site , the timing of relapse (early or late), and the phenotype of the disease .Hue Central Hospital, one of the three biggest hospitals with 3,000 beds in Vietnam, plays a vital role in treating childhood ALL in the central region of Vietnam. Since 2008, ALL patients have been treated based on the Children's Cancer Group's (CCG) modified 1882 and 1881 protocols. We carried out this research to analyze the incidence of relapse and survival rate in childhood ALL treated at Hue Central Hospital between January 2012 and April 2018. We believe our findings will contribute to further improving the treatment outcomes in children with ALL.We reviewed the medical records of 156 new patients who were under 16 years of age and diagnosed with ALL. These patients were registered at Hue Pediatric Center, Hue Central Hospital, from January 1, 2012, to April 30, 2018. All patients had received the same treatment as per the modified CCG 1882 and 1881 protocols . Measurement data were described by rate or proportion, and enumeration data were described by means and standard deviations. The Kaplan-Meier method was used for generating survival curves for overall survival. A log-rank test was performed for comparing survival across groups.Data relating to 156 new patients with ALL between 2012 to 2018 were collected. Among them, there were 26 relapses, accounting for 16.7% of the total cases. The male-to-female ratio was 2.71:1. The relapse rate in the high-risk group was 1.6 times greater than that in the standard-risk group (61.5% vs. 38.5%); 85.5% of patients achieved remission after the induction phase , six (23.1%), four (15.4%), and two (7.7%) cases relapsed during the maintenance phase, after completing chemotherapy, at delayed intensification phase, and after induction phase (due to treatment abandonment), respectively. The most common relapse site was bone marrow (38.5%), followed by the isolated central nervous system , and CNS plus bone marrow (23.1%); the least common site was testicle with or without bone marrow or CNS (15.2%). The median post-relapse survival time was 7.5 ±8.3 months, and the three-year post-relapse overall survival rate was 26.9%  did not achieve remission, which was similar to findings by Pizzo and Poplack, which showed that an early response to induction therapy has prognostic value . Regardi% did notRegarding the relapse site, bone marrow was the leading site and accounted for 38.5%, while the testicle had the lowest rate of relapse (15.3%). Again, these results were similar to the outcomes of Ali et al. and Pizzo and Poplack . The reaAt the endpoint (April 2018), 73.1% of relapse patients had passed away while 26.9% of patients were still alive. The median time from relapse to death was 7.5 ±8.3 months, which was shorter compared to other studies. It might be due to the protocol we used. The protocol was not strong enough and was lacking in some tests, such as minimal residual disease to evaluate the response. According to Nguyen et al., overall post-relapse survival rates were higher for patients with isolated CNS relapse (58.7 ±3.2%) than for patients with either isolated (24.1 ±2.1%) or concurrent bone marrow (39.4% ±5.0%) relapses [Regarding the correlation between relapse events and survival after relapse, patients with intermediate relapse had a better survival rate than early relapse . This result appears reasonable. Time to relapse remains the strongest predictor of survival. According to Nguyen et al., estimates of five-years survival rates for isolated marrow relapse in early-, intermediate-, and late-relapsing patients were 11.5 ±1.9, 18.4 ±3.1, and 43.5 ±5.2%, respectively . Van De Recently, several studies have suggested that modification of the protocol to use escalated methotrexate dose and providing new therapies such as stem cell transplantation can improve the overall survival of relapsed patients ,12.In our study, we found that most relapse events in ALL occurred during the maintenance phase and after the completion of chemotherapy. Bone marrow and CNS were the most common relapse sites. According to several recent studies, modification of the protocol to use escalated methotrexate dose and providing new therapies such as stem cell transplantation can improve the overall survival rates in childhood ALL.


Twenty-eight participants discontinued SGLT-2-inhibitors due to various reasons: 20 participants because of genital- or urinary tract infections. One for dysuria, seven due to reduced eGFR below 45 mL/min. This study showed a considerable reduction of HbA1c and a modest reduction of eGFR, bodyweight and systolic blood pressure under clinical routine conditions. Genital infections occurred markedly more often than in randomized controlled trials. To apply SGLT-2-inhibitors more safely in clinical routine individual risks for genital and urinary tract infections should be considered and re-evaluated during therapy.The aim of this study was to investigate the effectiveness of SGLT2 inhibitors with regard to metabolic parameters and patient safety under routine ambulatory conditions. Retrospective longitudinal study of 95 patients with type 2 diabetes  receiving SGLT-2-inhibitors. Metabolic control and adverse event profile were evaluated. The mean follow-up time was 1.2 ± 0.8 years. The following changes were observed: HbA1c −1.0% ± 1.9 ( There are numerous placebo-controlled studies that have investigated the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) in people with type 2 diabetes  . The aimThis trial was designed as a retrospective longitudinal study. Data were collected in the department of Endocrinology and Metabolic diseases of the University Hospital Jena. All people with diabetes type 2 in the period between 1 January 2015 and 31 July 2017 receiving SGLT2 inhibitors as monotherapy or in combination with other antidiabetic drugs were included. Empagliflozin (25 mg daily) and dapagliflozin (10 mg daily) were the agents used in this study. The minimal treatment duration for inclusion in the analysis was one month. Laboratory and clinical data were collected from the electronic patients record EMIL™. If the SGLT2 inhibitor was initially prescribed by the general practitioner, necessary baseline parameters were requested from the general practitioner with written consent of the patients. We excluded persons with missing follow-up data or duration of treatment less than one month and without a valid declaration of agreement. Follow-up data were obtained at the end of the observation period or if SGLT2 inhibitors were discontinued. Informed Consent Statement: All procedures followed were in accordance with the ethical standards of the committee on human experimentation of the study institutions and German national standards as well as with the Helsinki Declaration of 1975, as revised in 2008. Ethical review and approval were waived for this study, due to the retrospective design of the study. Only a retrospective analysis of data collected during routine visits was carried out. There was no study-specific intervention.Outcome parameters were HbA1c, bodyweight, blood pressure, eGFR, albuminuria, hypoglycemia and the adverse effect profile. We determined clinical and laboratory data and assessed metabolic control before start of treatment with SGLT2 inhibitor and at the end of observation. HbA1c was measured using high-performance liquid chromatography  with a normal range of 5.0–6.2%. HbA1c was adjusted according to the mean normal value of healthy people  of the Diabetes Control and Complications Trial (DCCT). Albuminuria was measured in milligram albumin per gram creatinine in the second morning spontaneous urine sample (mg/g Crea). Antihypertensive therapy was recorded in detail to evaluate the effect of SGLT-2-inhibitors on blood pressure. Classes of antihypertensive drugs such as ACE-inhibitors or angiotensin II receptor blockers (ARBs), beta blockers, calcium channel blockers, diuretics and other antihypertensive drugs to track new prescriptions of these drugs were recorded. Non-severe hypoglycemia was defined as an event with typical symptoms  disappearing quickly after carbohydrate intake or a status without typical symptoms and plasma glucose ≤ 3.9 mmol/L. Severe hypoglycemia was defined as any episode requiring assistance of another person to recover . To asseAll continuous data are shown as mean ± standard deviation (SD). Categorical data are described by absolute and relative frequencies. To compare two groups, unpaired t-test was used for continuous variables and Fisher’s exact test was performed for categorical variables. Paired t-test was used regarding the difference between baseline and follow-up in both groups. Logistic regression models were applied to assess the effect of influencing factors on the discontinuation of the treatment and especially on genital infections. The statistical analysis was performed with SPSS 25.0 . Significance was defined at the 0.05 level.A total of 170 patients were detected in the patient record. Due to the previously mentioned criteria we excluded 75 patients. The baseline data of the included 95 patients are shown in 1c by −1.0%; 11 mmol/mol (p < 0.001), eGFR by −7.0 mL/min (p < 0.001), bodyweight by −3.0 kg (p < 0.001) as well as BMI by −0.9 kg/m2 (p < 0.001) and systolic blood pressure by −6 mmHg (p < 0.001). The change of diastolic blood pressure  and albuminuria  was not statistically significant. The rate of non-severe hypoglycemia increased insignificantly by 0.01 events per week (p = 0.878).There was a significantly decrease of HbAp < 0.001). Beta blockers were the most prevalent drugs with 0.6 ± 0.5 at the beginning. However, at the end of the trial ACE-inhibitors or ARBs became the most prevalent antihypertensive drug (the mean patient took 0.9 ± 0.3 ACE-inhibitors or ARBs daily).At the beginning the average patient took 1.7 ± 1.2 antihypertensive drugs as long-term medication every day which increased at the end of the observation period to 2.3 ± 1.3  discontinued the treatment with SGLT2 inhibitors. The dropouts occurred after a mean observation time of 1.0 ± 0.7 years. Twenty patients (21.1%) discontinued due to genital infections (18 patients—18.9%) or urinary tract infections (2 patients—2.1%). Eight patients (8.4%) no longer needed the therapy because glycemic control allowed to discontinue the medication. Seven patients (7.4%) had a reduced eGFR under 45 mL/min. One patient (1.1%) each discontinued due to dysuria or allergic skin reaction. Two patients (2.1%) quit the treatment without a given reason. Two patients (2.1%) interrupted the therapy due to genital infection and one patient (1.1%) due to nausea but continued the therapy later. The distribution of the mentioned reasons to discontinue therapy are shown in p = 0.120) throughout the observation period. Genital infections occurred in four (14.8%) females and 14 (20.6%) males (p = 0.259). Two (2.9%) male participants interrupted the therapy due to a genital infection and continued it later on (p = 0.510). Urinary tract infections occurred in two (7.4%) women (p = 0.079). The participants who discontinued the therapy due to urinary tract infection or genital infection had a mean age of 64.5 years. The mean age of females in this group was 62.9 years, the mean age of males was 65.2 years. Three (11.1%) women and five (7.4%) men stopped taking SGLT2 inhibitors because the initial reason to start with the medication was not present anymore (p = 0.408). The therapy was discontinued because of a reduced eGFR under 45 mL/min in three (11.1%) females and four (5.9%) males (p = 0.314). One (3.7%) female patient discontinued SGLT2 inhibitors because of dysuria (p = 0.284) and one (3.7%) because of an allergic skin reaction (p = 0.284). There was one patient of each gender  who ended the treatment without a known reason (p = 0.490). One (3.7%) male patient interrupted the therapy because of nausea but continued later (p = 0.716).We separately analyzed the cohort by gender. The percentages refer to the total count of members of each gender, respectively. Twelve (44.4%) females and 41 (60.3%) males continued the therapy  . The risk of genital infections was lower if ACE-inhibitors/ARBs  were simultaneously part of the medication, taking into account gender, smoking status, duration of diabetes mellitus and HbA1c, whereas no significant effect was observed for diuretics.Two models of logistic regressions were performed for discontinuation of therapy. The independent factors of one model were HbAThirty-seven patients (38.9%) did not have any adjustments in their antihyperglycemic therapy, whereas the therapy of the other 58 patients (61.1%) was adjusted.1c in both subgroups improved markedly in the observation period and was not different neither at baseline nor at follow up. Also, mean eGFR at baseline and follow up was comparable in both groups. Body weight reduced in both groups but patients of subgroup 1 (with treatment adjustment) lost 1.3 kg less weight than the patients of subgroup 2 (no treatment adjustment) (p = 0.307). At the end of the observation subgroup 2 had a 4.9 kg higher mean bodyweight compared to subgroup 1 (105.5 kg vs. 100.6 kg), but this was not statistically significant (p = 0.257). Blood pressure in both subgroups differed not statistically significantly in spite of a reduction in systolic blood pressure in subgroup 1.Mean HbA2. At baseline, the observed group had a high bodyweight mean of 105.5 kg and a body mass index of 35.0 kg/m2. Obesity is a risk factor for cardiovascular complications and bad outcome for individuals with diabetes mellitus [The purpose of this study was to investigate the effectiveness and safety of SGLT-2-inhibitors in the clinical routine and detect differences between the results of clinical trials and daily healthcare. Our findings showed that SGLT-2-inhibitors were effective as an add-on therapy of diabetes mellitus type 2 treatment. As markers of effectiveness the following parameters were used: HbA1c, eGFR, albuminuria, systolic and diastolic blood pressure, bodyweight and BMI. The HbA1c as parameter for glycemic control showed a significant reduction from baseline to follow-up. eGFR represents renal function and is a common laboratory value. Albuminuria was used as a second renal parameter. SGLT-2-inhibitors are known to be renoprotective  but leadmellitus , and weiWe divided the cohort into two different subgroups in order to determine the effect if antihyperglycemic treatment was adjusted. Surprisingly, the two subgroups did not show significant differences of treatment parameters. Thus, the influence on the investigated parameters can be attributed to SGLT-2 inhibitors. The development of these parameters also corresponds to those in the literature ,15. For As safety outcome of special interest, we evaluated the discontinuation of therapy due to urinary tract and genital infections. Twenty-one point one percent of study patients discontinued the therapy due to these reasons , which is far more than in placebo-controlled trials such as EMPAREG with 6.4% of the empagliflozin groups with genital infections . The folWe found that the intake of ACE-inhibitors or ARBs was associated with fewer genital infections and could have a protective effect. The purpose of the study as well as its design did not allow further conclusions on this hypothesis and should be investigated in a prospective randomized trial.To evaluate the individual risks for future genital or urinary tract infections, the mentioned factors should be considered before initiating SGLT-2-inhibitor therapy. Severe hypoglycemia is uncommon with SGLT-2-inhibitors . Thus, wThis study showed that SGLT-2-inhibitors were effective as an add-on therapy in clinical routine of diabetes care. The results were comparable to those of placebo-controlled trials. Glycemic control was improved, presented by a lower HbA1c. There were minor reductions in albuminuria, blood pressure, bodyweight and BMI. eGFR reduced during the first year after initiation of SGLT-2 inhibition. To show long-term stabilization, we would have needed a longer study duration. In order to reduce the rate of adverse events of SGLT-2-inhibitors in clinical routine, the mentioned factors should be considered. It is essential to remind the patients to adhere to the hygienic orders. The prescription of SGLT-2-inhibitors should be done on an individual basis taking into regard BMI, sex, age, patient’s history and adherence and ability to follow the hygienic necessities.


Puccinia graminis Pers. f.sp. trtici Eriks and E. Henn., is the most damaging fungal disease of both common (Triticum aestivum L.) and durum  wheat. Continuously emerging races virulent to many of the commercially deployed qualitative resistance genes have caused remarkable loss worldwide and threaten global wheat production. The objectives of this study were to evaluate the response of a panel of 283 durum wheat lines assembled by the International Maize and Wheat Improvement Center (CIMMYT) to multiple races of stem rust in East Africa at the adult plant stage and map loci associated with field resistance. The lines were evaluated in Debre Zeit, Ethiopia and Njoro, Kenya from 2018 to 2019 in five environments (year × season). The panel was genotyped using genotyping-by-sequencing. After filtering, 26,439 Single Nucleotide Polymorphism (SNP) markers and 280 lines and three checks were retained for analysis. Population structure was assessed using principal component analysis. Genome-wide association analysis (GWAS) was conducted using Genomic Association and Prediction Integrated Tool (GAPIT). The broad-sense heritability of the phenotype data revealed that 64–83% of the variation in stem rust response explained by the genotypes and lines with multiple race resistance were identified. GWAS analysis detected a total of 160 significant marker trait associations representing 42 quantitative trait loci. Of those, 21 were potentially novel and 21 were mapped to the same regions as previously reported loci. Known stem rust resistance genes/alleles were postulated including Sr8a, Sr8155B1, SrWeb/Sr9h, Sr11, Sr12, Sr13/Sr13 alleles, Sr17, Sr28/Sr16, Sr22, and Sr49. Lines resistant to multiple races in East Africa can be utilized as parents in durum wheat breeding programs. Further studies are needed to determine if there are new alleles at the Sr13 locus and potential markers for the known Sr13 alleles.Stem rust of wheat caused by  Triticum turgidum L., ssp. Durum (Desf.) Husnot, 2n = 4× = 28; AABB genome) is among the tetraploid wheat species used for making pasta, couscous and other traditional recipes mainly consumed in the Mediterranean regions (Puccinia graminis f.sp. tritici Eriks. & E. Henn (Pgt) is the most destructive fungal disease of both common and durum wheat   while Sr13b is effective only against TTKSK and TKTTF  . As a reand Asia . Among tnd TKTTF . These rSr genes, only five confer adult plant resistance (APR), namely Sr2, Sr55 (Lr67/Yr46/Pm39), Sr56, Sr57 (Lr34/Yr18/Pm38), and Sr58 (Lr46/Yr29/Pm39)  . Adult p29/Pm39) . Convers29/Pm39) . The gen29/Pm39) . The lim29/Pm39)  and verySr25 (translocation from Thinopyrum ponticum onto chromosome 7A), 6 carry the Sr25+ Sr22 (Sr22 is a translocation from T. boeticum onto chromosome 7A), and 8 have Sr38 (a translocation from T. ventricosum onto chromosome 2A) that were developed through marker-assisted selection and represent resistances that are not present in any of the durum germplasm pools worldwide . In the Debre Zeit nursery, lines were planted in dual rows of 1 m length with 0.2 m inter-row spacing arranged in randomized incomplete block design with two replications. Two susceptible  and one moderately resistant (“Mangudo”) checks were repeated after every 50 plots. In addition, the 20 stem rust differential lines with known stem rust resistance genes (Sr24 (Genotype identification number (GID) = 5391050, 5391052, 5391056, 5391057, 6391059, and 5391061).A panel of 283 spring durum wheat genotypes composed of a wide collection of advanced breeding lines and some cultivars that represent the current CIMMYT durum wheat germplasm was evaluated for adult plant response to stem rust for three seasons in Ethiopia ; off-season (January to May) 2018 and 2019, main season (June to November) 2018; and two seasons in Kenya  during the main season (June to October) 2018 and 2019; hereafter abbreviated as ETOS18, ETOS19, ETMS18, KNMS18, and KNMS19, respectively. Among the 283 genotypes included in the panel, 10 harbor ce genes  were plaDisease infection was initiated by artificial inoculation of the spreader rows with a bulk of stem rust urediniospores collected at each specific location from the previous season to ensure uniform disease distribution in the trials. Spreaders were inoculated with a mixture of field collection of stem rust races TTKSK, TKTTF, JRCQC, TTTTF, and TRTTF in Debre Zeit, Ethiopia; and races TTKSK, TTKST, TTKTT, and TTTTF in Njoro, Kenya. Inoculation was done by suspension of urediniospores in distilled water and adding a drop of Tween 20 (a drop/0.5 lt) and syringe-injection of the spreader rows  at stem elongation   and repeR = 0.2, MR = 0.4, MS = 0.8 and S = 1.0, and the mean of the scale of responses was used to calculate CI in the cases where combinations of infection responses were scored for a given genotype  covered by rust pustules . Infectigenotype .The CI was used in the statistical analysis using R statistical software version 3.6.1  and ASReijk is the response of the ith line in the jth column and the kth replication, gi is the random effect of the ith line, Cj is the fixed effect of the jth column, and rk is the random effect of kth replication and εijk is the residual associated with the model.Where: yFor the main season 2018 nursery in Ethiopia, the LMM described in Eq. 2 was fitted on the square-root-transformed CI using the lmer function of the R package lme4  and extrij is the response of the ith line at the jth replication, gi is the random effect of the ith genotype (line), rj is the random effect of the jth replication, εij the residual associated with the model.Where: yij) fitted as ar1(row):ar1(column), the first order autoregressive correlation of the residuals of the row and column, as random effects, which assumes the residuals could be correlated  and genijkl is the response of the ith line in the jth row, in the kth column and lth replication, gi is the random effect of the ith line, Rj the fixed effect of the jth row, Ck is the fixed effect of the kth column, rl is the random effect of the lth replication and εijkl is the residual associated with the model.Where: yFor the main season 2019 nursery in Kenya, the MLM described in Eq. 2 was fitted on the square-root transformed CI using the lmer function of the R package lme4 and genotypic BLUPs were extracted. From the variance components estimated from each model, broad sense heritability was calculated following the method by H2 is the broad sense heritability, Vg is the variance due to the genotype (line), Vp is the variance due to the phenotype, Vp = Vg + Ve, Ve is the residual variance.Where: oC for 2 weeks. The frozen leaf samples were then lyophilized and shipped to the USDA-ARS Eastern Regional Small Grains Genotyping Laboratory in Raleigh, NC for genotyping. Genomic DNA was isolated from the lyophilized tissue samples using a sbeadex plant DNA isolation kit  according to manufacturer’s instructions. Genomic DNA was then fragmented using a PstI-MspI double restriction digest following the GBS protocol of r2 = 1), using a sliding window of 250 SNPs, advancing by 10 SNPs per step. In total, 26,439 SNPs were called in 283 lines (including three checks) and retained for genome-wide association analysis.Two cm-long young leaf tissues were collected and frozen at −80Sr2 and Lr46/Sr58. For Sr2, lines were evaluated with marker Sr2_ger93p  assays developed around SNP linked to the resistance genes 2_ger93p . For Sr5id W743R . Lines h2) by applying a sliding window of 50 markers using TASSEL software version 5  after randomly sampling 10% of the total loci pairs. A locally estimated scatterplot smoothing (LOESS) curve was fitted using “geom_smooth” in R package ggplot2  in GWAS analyses. In the current study, the presence of population structure was assessed using principal component analysis (PCA) using the R function “prcomp” and visualized for the clustering of PC scores. The extent of LD in a population is useful for determining the resolution of association mapping. The LD between pairs of markers for the 26,439 markers was calculated as the squared allele frequency correlation  plots was used to compare the models and results were interpreted from MLM and FarmCPU. Manhattan plots of −log10 p-values were generated using the R package qqman  , Compresge qqman . A linka markers . SignifiCI ≤ 18) varied from 10% in ETOS18 with a mean CI of 40–65% in KNMS18 with a mean CI of 18.3  revealed that 69% of the total number of lines evaluated were likely to carry Sr13, 46% were likely to have Lr46 (Sr58), 30% (85 lines) were likely to have both genes (Sr13 and Lr46/Sr58) and 15% (43 lines) were lacking both genes. Among the lines positive to Sr13 and Lr46/Sr58, 14.3% showed resistance (CI ≤ 18) in all the five environments, 16.7% in four environments, 32.1% in three environments 21.4% in two environments and 15.5% in a single environment .Screening of the lines with markers linked to ironment . Three lironment . None ofp < 0.001). The mean genome-wide LD (r2) for the population was 0.39. Of the total loci pairs, 1.28%  of the loci pairs were in wide range LD on different chromosomes, and 1.09% (184) of those on different chromosomes were in significant LD (p < 0.001). The LD threshold for the population estimated from the 95th percentile of the distribution of square root transformed r2 of unlinked markers (markers located on different chromosomes) was 0.16, the critical value beyond which LD was likely due to physical linkage. The decay of LD for the linked markers varied across chromosomes in both sub-genomes  for each of the evaluation environments. Based on the Q-Q plots and the power of FarmCPU to limit potential false positive and false negative associations, we limited the interpretation of results to those from MLM and FarmCPU models. Many of the significant MTAs identified by MLM were confirmed by FarmCPU and the unconfirmed MTAs were assessed for consistency across environments to determine if they were reliable MTAs –7. FarmCPgt races in Ethiopia and Kenya across the five testing environments. From these 14.1% were detected in all the five environments, 7.4% in four environments, 5.2% in three environments, 16.3% in two environments and 57% in only one environment  (p = 0.045) represented three QTL that explained 3.43–4.59% of the phenotypic variation  (p = 0.046)  , 5. On c = 0.04) . The thrariation –4. Sevenariation , 4. Six  (0.049) . Four MT (0.049) , 4. The = 0.046) . Three p= 0.046) , 4. The p = 0.04) (r2 = 0.46) was identified using FarmCPU in KNMS18 and ETOS18, respectively (r2 = 0.86) was consistent across four of the five testing environments  representing three QTL were detected on chromosome 3B. The MTA at 55 Mb was identified at a single environment using MLM and it explained 4.04% of the phenotypic variation. The 97 Mb region identified using MLM was consistent across four  of the five testing environments and it explained 3.91–4.81% of the phenotypic variation –6. The Q = 0.04) . Two sig = 0.04) –7. Two s = 0.04)  and expl = 0.04) , 3. The ectively . This QTectively , 3. The ronments .r2 = 0.89) with a significant marker at 4 Mb  identified using FarmCPU which explained 3.18% of the phenotypic variation. An MTA identified by FarmCPU in a single environment at 1.4 Mb explained 3.18% of the phenotypic variation (data not shown). A QTL at 28 Mb was consistently identified at two testing environments and explained 4.42% of the phenotypic variation on average while the 334 Mb region was consistent across all the five testing environments and explained 3.52–7.39% of the phenotypic variation (Sr13 marker (r2 = 0.10–0.40) (R2 = 1.62%). Twenty-three MTAs identified by MLM extending from 609 Mb to 615 Mb were consistent across two to four testing environments (p = 1.01E-07) for ETOS18, at 611 Mb  for ETMS18 (p = 8.47E-07) and ETOS19 (p = 5.61E-10), at 612 Mb  for KNMS18 (p = 3.13E-09), and KNMS19 (p = 3.71E-09). The marker at 611 Mb  was consistent across two testing environments and the two models. This MTA explained 5.31–9.49% of the phenotypic variation and this marker was in weak to strong LD (r2 = 0.12–0.75) with 22 significant markers that extended from 598 Mb to 610 Mb (r2 = 0.14–0.96) with 20 significant markers that extended from 612 to 615 Mb on chromosome 6A  . The 598ronments , whereasronments –7. One Mronments . From tho 610 Mb . The MTAo 610 Mb . This MTosome 6A .r2 = 0.33) identified using FarmCPU was consistent across two seasons in Ethiopia (r2 = 0.64) was identified using MLM in ETOS19 and explained 3.72% of the phenotypic variation on average (Six significant MTAs were detected on chromosome 6B . A QTL aEthiopia  and explEthiopia . The QTL average .r2 = 0.83) (r2 = 0.64) identified by MLM was consistent across four of the five environments and explained 3.78–5.77% of the phenotypic variation  . Five MTariation –7.The characterization and identification of widely effective resistance available in breeding program’s elite pool is valuable for addressing the stem rust problem in durum wheat. In the current study, we evaluated the reaction of a panel of 283 elite durum wheat lines and cultivars representing the CIMMYT germplasm pool to multiple races of stem rust in East Africa and mapped a number of previously reported and novel genomic regions associated with field resistance to the locally prevailing races (Lists of Pedigrees: Sr13b and Sr9e) in worldwide durum wheat germplasm and cultivars (Sr13 and Lr46 which showed resistance against multiple stem rust races in single testing environment (15.5%) and all the five testing environments (14.3%)  . This inr2 = 0.39) and B sub-genome (r2 = 0.40) was not divergent (p = 0.6961) which may indicate comparable selection pressure for important agronomic traits in the two sub-genomes of the durum panel. Chromosomes 2A and 4B had the slowest in the rate of LD decay (∼8 Mb)   indicati (∼8 Mb) , 2014 an (∼8 Mb)  on world (∼8 Mb) .The comparison of our results with previous linkage mapping and association mapping studies on resistance to multiple races in East Africa and few others from different regions of the world validated many of the significant MTAs identified in our study –8. Many IWB57448 and IWA8622 reported by wPt-734078), and markers IWA2057 and IWA5702 reported by Sr31 for resistance to TTTTF and TRTTF were not close to the markers we identified on 1A. These three markers were in linkage equilibrium. The MTAs at 95 and 485 Mb may represent novel QTL while the 144 Mb region was on the threshold line (FDR adjusted p = 0.04)  were identified on chromosome 1A . Markers = 0.04)  which mabarc61 (2.7 Mb away) reported by barc81 reported by the same author for seedling resistance to races TTTTF and TTKSK and may tag the same QTL. The MTA at 183 Mb is 3 Mb away from IWB9794 reported by p-value close to threshold (0.045) while the MTA at 587 Mb is 1.5 Mb away from IWB40197 reported by Lr46, that is tightly linked to the APR gene for stem rust, Sr58. However, one of the flanking markers to Lr46, wmc44 and the same marker reported by Lr46 (CIMwMAS0085)2 indicated that 46% of the lines are expected to carry Lr46/Sr58, however, this locus was not significant in our study. This may be because of the confounding effect of major gene resistances in our population as the lines were evaluated for field response regardless of their seedling response or the Lr46 marker may not be predictive.On chromosome 1B, four significant MTAs were detected . The marwPt-5839 (386 kb away) reported by p-value close to the threshold (0.049) is likely to be false positive  but it is unlikely to be detected due to the MAF below the threshold. Both Sr21 and Sr38 are ineffective against the Ug99 lineages (predominant in Kenya), TKTTF and JRCQC (predominant in Ethiopia)  .wmc361 reported by SrWeb/Sr9h. SrWeb/Sr9h is effective against Ug99  which may indicate unreliable association , Sr28, Sr36, and Sr16. Among the seven alleles of Sr9, five of them are ineffective against Ug99 while Sr9e is reported to be inconclusive  were identified on chromosome 3A , 4. Marknst Ug99 . Sr35 waon wheat  while Sron wheat . None ofwPt-0365 and wPt-6802 reported by Sr12 is 14 Mb away from the MTA at 724 Mb. Flanking markers of Sr12 (wPt-0544 and wPt-6047) reported by Sr12. Sr12 confers resistance to Ug99 (TTKSK) at adult plant stage when combined with other resistance loci in a QTL study of Thatcher/McNeal RIL population. Although no significant interaction was observed with any of the known Sr genes postulated in our GWAS result, significant interactions were observed between the marker at 724 Mb region and QTL on chromosome1B (at 620 Mb) (p = 0.020903) and 5B (688 Mb) (p = 0.013911) for resistance to multiple races in Ethiopia and Kenya, respectively. The MTA at 9 Mb region that was consistently identified in four of the five testing environments using MLM was not close to any of the previously reported markers suggesting that it may represent a novel locus unidentified by FarmCPU  (wmc43 (4.5 Mb away) reported by wPt-6945 reported by p-value close to the threshold (0.036) which makes this association less reliable. The short arm of chromosome 3B is known to harbor the known APR gene, Sr2 but this gene is not present in the CIMMYT durum germplasm as confirmed by the screening of the panel using KASP marker designed for Sr2  in any of the lines in greenhouse and field.Five significant MTAs were identified on chromosome 3B , 3. Mark FarmCPU . The rem (0.042)  and thiswPt -5857) of a QTL on chromosome 4AL reported by Sr7 . Sr7a confers resistance against race TKTTF (Sr7b is effective against race JRCQC (Two significant MTAs (619 and 651 Mb) were identified on chromosome 4A –7. The rce TKTTF  whereas ce JRCQC .IWA1062, IWA5040, and IWA5368 reported by IWB47184, IWA2224, IWA2836, and IWB34927 reported by barc165 reported by Two significant markers were identified on chromosome 5A at 8 and 35 Mb regions , 4. Marksun209 and sun479 flanking Sr49 which is effective against all the races in Australia. The MTA at 691 Mb co-locates with sun479 (530 kb away) while 692 Mb region co-locates with sun209 (485 kb away). These two markers (691 Mb and 692 Mb) were consistent across four of the five seasons though limited by the low MAF (0.053 on average) which indicates that this gene is rare in the panel  for APR to Ug99 in hexaploid wheat. The MTA at 581 Mb identified in KNMS19 using both models, is close to these flanking markers (∼5–6 Mb away) and was detected at the adult plant stage in Kenya only. Hence, this marker is likely tagging the same locus as wPt8604) of a QTL reported by Sr56 and an all stage resistance gene Sr49  with the 4 Mb region. However, the 592 kb region was associated with resistances to races in Ethiopia where the virulent races to Sr8155B1 (JRCQC and TTKSK) are predominant indicating that this MTA may represent a new allele at the Sr8 locus or a novel gene linked to the Sr8 locus. The high LD between these two loci may indicate limited recombination rate in the regions or the resistance alleles might be selected together. Markers wPt1742 and wPt1377 reported by IWA272, IWB64917, IWB64918, IWB5029, IWB35595, IWB43808, IWB72956 reported by Sr8a though identified in one season only. It is known that the short arm of chromosome 6A hosts the alleles of Sr8 (Sr8a and Sr8b) and Sr8a confers resistance to the predominant races in Ethiopia, TRTTF  carrying Sr13 on marker screening may indicate the wide usage of this gene in CIMMYT durum wheat breeding program. This result is proven by the higher frequency (27–85%) of the favorable alleles at the Sr13 locus. However, more than one allele is expected as indicated in the differences in allele frequencies and the LD between nearby markers  reported by IWB35697 for adult plant resistance to Ug99 in Ethiopia and Kenya, are close to the MTA at 692 Mb (229 kb–2 Mb away). Marker KASP_6BL_IWB72471 reported by Sr11 is 2 Mb away from this marker indicating that it is likely mapping the Sr11 locus. However, Sr11 is ineffective against TTKSK, JRCQC, and TRTTF at the seedling stage and is effective against TKTTF (r2 = 0.64) and represent the same QTL  indicating that they represent the same QTL in the short arm of 6B which is likely novel and the MTA at 666 Mb region could also be representing a novel locus . These three markers  were in moderate to strong LD (r2 = 0.37–0.83) indicating that these MTAs are representing the region of Sr22. This gene confer resistance to TTKSK . However, it is unlikely to identify the Sr25 locus due to MAF below the threshold (0.05). Sr25 and Sr22 come with severe yield penalties in durum wheat . So, breeders should be prepared to conduct several cycles of selection to use these gene with minimal to no performance penalties. None of the markers listed earlier including markers IWA7200 reported by barc70 and wmc479 reported by Xbarc121 reported by p-value close to the threshold  reported by r2 = 0.64) likely represent Sr17. The consistency of these two MTAs across three seasons may indicate the reliability of association although the resistance allele at this locus is rare in the population . Markers wmc182, wmc517, wPt1715, wPt4298, wPt7191, wPt4045 reported by wPt1149 reported by IWB47548 and IWB4175 reported by p-value was close to the threshold (0.047) which makes this association less reliable. We identified nine significant MTAs on an unknown chromosomal location  and can be used as sources of resistance to multiple stem rust races in East Africa. Once these lines are evaluated for agronomic performance, combining more resistance alleles and/or genes to the best performing lines may increase durability of resistance to potentially emerging races. Among a total of 160 significant MTAs identified using MLM and FarmCPU with known chromosomal locations and grouped to 42 QTL, 21 QTL are putatively novel and the remaining 21 are mapped to previously reported regions. The regions representing https://figshare.com/s/5b5378408568ead07846/10.6084/m9.figshare.12949295; https://figshare.com/s/40b2f7c7be1ce931a4d2/10.6084/m9.figshare.13203194.The datasets presented in this study can be found in online repository. The name of the repository/repositories and accession number(s) can be found below: SM, MS, and MA designed the research. KA developed and assembled the mapping population, participated in experimental design, and provided seed to each evaluation site. SM, AD, and MR conducted the field experiments. GB-G and BW carried out genotyping and SNP calling. SM conducted the data analysis and drafted the manuscript. All co-authors read and reviewed on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Probable effects of living donor liver transplantation on the wellbeing of the donor and psychological difficulties are necessary to be understood. To assess the quality of life of living donors after liver donation.140 living donors who underwent hepatectomy between 2012 and July 2015 were enrolled in this study. Donors were asked to complete the Short Form 36-question Health Survey (SF-36) through face to face or by telephone interview.2). “Mother-to-child” was the most frequent relationship . 22 (15.7%) complications were reported by participants. The mean±SD score of Physical Component Summary and Mental Component Summary were 48.8±14.6 and 50.1±6.9, respectively.The mean±SD age of donors at transplantation was 32.1±7.3 years; 83 (59.3%) of donors were female. 134 (95.7%) were married. The mean±SD BMI was 23.8±3.5 (kg/mMost living donors sustain a near average quality of life post-donation. It seems that living donation does not negatively affect the quality of life. New surgical methods have been developed in the field of liver transplantation to overcome organ shortage such as split liver organ, living donor, and reduced size . Living A study from China showed temporary abnormalities in liver function test and blood count among many of 300 living donors. While laboratory tests could be used to identify some post-operation complications, they are not useful to detect some physical, mental, and psychological difficulties, which mostly influence the quality of life of the donors after transplantation . Nor canOne study showed the Physical Component Score (PCS) decreased immediately after donation, then returned to the baseline within 6–12 months, while the Mental Component Score (MCS) remains comparable to that of normative population throughout the procedure , 10.Living donors may experience various complications that are usually mild and have a good prognosis . The proWe retrospectively reviewed data of donors who underwent hepatectomy for liver transplantation at Shiraz Organ Transplant Center from 2012 to 2015. In census way, a total of 140 living donors underwent hepatectomy during this period. In the course of the donor evaluation process, all patients gave their informed written consent to participate in the follow-up studies. Our study was approved by the Ethical Committee of Shiraz University of Medical Sciences. The donors were asked to complete a data collecting form and the SF-36 through face to face or by telephone interview. The self-administered SF-36 survey assesses eight health domains: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). Component analyses showed that there are two distinct concepts measured by the SF-36: a physical dimension, represented by the Physical Component Summary (PCS); and a mental dimension, represented by the Mental Component Summary (MCS). The eight subscales are summarized by PCS and the MCS. The SF-36 score for each question ranged from 0 to 100 with higher score representative of better function. The general population average is 50 with a standard deviation of 10 [Most of the additional data used for analysis were obtained by chart review, anesthesia records, and the computerized hospital database. Continues variables were expressed as mean±SD; categorical variables, number (percent). Student’s t test for independent samples, one-way ANOVA, and Person’s correlation coefficient were used for data analysis. A p value <0.05 was considered statistically significant.Donor Characteristics2). “Mother-to-child”  was the most frequent relationship. More than 90% of our participants were volunteers to donate again and recommend LDLT to somebody else; to be exact, 91.8% and 91.7%, respectively (The mean±SD age of donors at transplantation time was 32.1±7.3 (range: 17–65) years; 83 (59.3%) of them were female. Most of the donors  were married. About one-third  of donors had a diploma and higher education. Among our participants, 61 (43.6%) were employed. The mean±SD for Body Mass Index (BMI) was 23.8±3.5  underwent left lateral; 24 (23.1%), left lobe; and 5 (4.8%), right hepatectomy. The mean±SD of operative time was 233.8±46.9 min. The mean±SD of hospital stay and ICU stay were 4.4±2.3 and 2.8±0.9 days, respectively. There was no death among our donors. Twenty-two (15.7%) complications were recorded among our participants. The intra-operative data of all the donors were collected retrospectively .SF-36 ResultsThe mean±SD of PCS and MCS scores were 48.8±14.6 and 50.1±6.9, respectively . ImproveMales had a significantly higher scores in physical functioning scale compared with females. However, there was no significant difference in other scales between males and females. No significant difference was found in quality of life scales between employed and non-employed donors .One of main issues in liver transplantation is shortage of deceased donors. Using living donors is one of the solutions for this problem. However, one of the main items in this field is the health of donors , 14. We Studies from different countries report various results. Post-operative complications occur in 28% of living liver donors in Brazil. The rate was 13.2 in Japan and 11.6% in Pakistan. No mortality was reported -17. The A study conducted in the US reported that of 740 LDLT (707 right lobes), 39% developed at least one complication in the first year . MajoritThe most complications of our studied donors were classified as Clavien grades 1 and 2, which was consistent with other studies , 6. We fMental health and vitality scores were below the average in our study . A studyA review article reported that physical scores of quality of life decrease in the first three months after donation; they return back to the baseline within six months in the majority of donors. Mental scores are unaffected during the donation process , 19. TheDonation experience was positive among our participants. The majority (91.8%) of our donors volunteered to donate again. Living liver donors at the University of Minnesota shared the same sentiment . A study shows that the majority of donors have a recovery time of one year . ApproxiIn conclusion, most living donors sustain a quality of life near average of the general population after donation. This means that living donation does not negatively affect the quality of life of donors in Iran.


Purpose: Antimicrobial resistant infections are common in patients on haemodialysis, often needing long courses of carbapenems. This results in a longer hospital stay and risk of iatrogenic complications. However, carbapenems can be given intermittently to allow for earlier discharge. We aim to describe the clinical outcomes of intermittent versus daily meropenem in stable, intermittently haemodialysed patients. Methods: In total, 103 records were examined retrospectively. Data collected include demographics, clinical interventions and outcomes such as hospital length of stay (LOS), 30-day readmission rates and adverse events. Findings: Mean age 61.6 ± 14.2 years, 57.3% male. Most common bacteria cultured were Klebsiella pneumoniae (16.5%). The most common indication was pneumonia (27.2%). Mean duration of therapy on meropenem was 12.4 ± 14.4 days; eight patients needed more than 30 days of meropenem. In total, 55.3% did not have intervention for source control; 86.4% received daily dosing of meropenem; 7.8% patients received intermittent dosing of meropenem only, and 5.8 patients received both types of dosing regimens. LOS of the index admission was shorter for the intermittent arm (15.5 ± 7.6 days versus daily: 30.2 ± 24.5 days), though 30-day readmission was higher (50% versus daily: 38.2%). Implications: We recommend further rigorous randomised controlled trials to investigate the clinical utility of intermittent meropenem dosing in patients on stable haemodialysis. End-stage renal failure (ESRF) patients on haemodialysis often have multiple co-morbidities and are susceptible to bacterial infections  due to aRenally adjusted meropenem in haemodialysis patients is administered once daily based on product labelling. Infections such as osteomyelitis or pyogenic abscesses require several weeks of treatment with antibiotics. This often results in prolonged hospitalisation, an admission to subacute hospital to complete the antibiotic course or the use of outpatient antibiotic therapy services. ESRF patients would receive meropenem post-dialysis on haemodialysis days and come to the hospital for administration of meropenem on non-haemodialysis days. However, intravenous access is required. As most patients on haemodialysis often present with poor venous access, for long-term antibiotics, usually, a peripherally inserted central catheter (PICC) would be used. This would also logistically be easier by reducing the need to re-site intravenous cannulas every 2 to 3 days. This may be a problem in haemodialysis patients who commonly have limited vascular access and are more susceptible to line-related sepsis. Furthermore, there is significant stress from logistics on the patient and their caregiver. An alternative meropenem regime involving intermittent thrice-weekly dosing administered post-dialysis may be feasible. There are reports demonstrating its efficacy . PharmacThe evidence for toxicity with high-dose intermittent meropenem is not clear ,8, thougTo investigate the feasibility of an intermittent meropenem dosing regime in ESRF patients, we describe clinical outcomes of intermittent versus daily meropenem in stable, intermittent haemodialysed patients in terms of length of hospital stay and 30-day readmission rates.A single-centre retrospective cohort study was conducted in the National University Hospital (NUH), Singapore. Data were obtained from the NUH’s Antimicrobial Stewardship Programme database from May 2015 to February 2017. Inclusion criteria were adult patients (≥21 years old) on stable intermittent haemodialysis who had received at least 3 days of meropenem. Our study was approved by the local ethics board .In total, 103 patient records were examined. Data collection categories were patient demographics, clinical data, meropenem regime and clinical outcomes, as detailed in As this study was conducted retrospectively and group sizes are different, descriptive analyses were used. No statistical comparisons were carried out. Results are reported to 1 decimal place.In total, 103 patient records were examined.n = 59). The ethnic distribution was comparable to the Singapore population distribution. Overall, 81.6% were from government subsidised wards (n = 89). Moreover, 56.3% were admitted under nephrology (n = 58), followed by surgery , and 41 (39.8%) were referred to the infectious disease team.Mean age was 61.6 ± 14.2 years, of which 57.3% were male (n = 78). Moreover, 17 (16.5%) had active malignancy, 6 (5.8%) were on chemotherapy and 7 (6.8%) were on long term steroids. Overall, 75.7% were not immunocompromised , followed by glomerulonephritis  and hypertensive renal disease .The majority were on dialysis due to diabetic renal disease . Around a quarter  were from wound swabs, and a minority  were from urine cultures. Around half  did not have any positive microbiological result. The most common bacteria cultured were Klebsiella pneumoniae , followed by Escherichia coli , Staphylococcus aureus , Pseudomonas aeruginosa , Enterobacter cloacae  and Streptococcus pneumoniae . When cultured, bacteria were sensitive to meropenem by EUCAST  criteria. Samples obtained were mainly from blood , followed by skin and soft tissue infections .The most common diagnosis was pneumonia . In total, 61 patients had bacteria which were resistant to third-generation cephalosporins. Nine patients had bacteria which were reported susceptible to cephalosporins, but clinical decision was made to continue meropenem by the primary treating physicians despite culture result due to patient’s clinical condition. In contrast, meropenem was used for suppression of chronic infections in nine (7.9%) patients. Two were on meropenem due to hypersensitivity to other narrow-spectrum antibiotics. Mean duration of therapy on meropenem was 12.4 ± 14.4 days, with eight patients requiring more than 30 days of meropenem. The longest duration was a total of 109 days. Meropenem was largely used with curative intent . Eight (7.8%) patients received intermittent dosing of meropenem only, and six (5.8%) patients received both types of dosing regimens. All patients on intermittent dosing were on a thrice-weekly dosing regime. Dosing of meropenem varied, with eight (57.1%) patients on 2 g/2 g/3 g dosing, three (21.4%) on 2 g/2 g/2 g, two (14.3%) on 1 g/1 g/1 g and one (7.1%) on 1 g/1 g/2 g. This variation of dosing was also seen in the daily dosing regime, with a range from 500 mg once to twice daily to 1 g once to thrice daily. Comparison of variables amongst different meropenem dosing regimes is presented in The majority received daily dosing of meropenem (n = 57). Of those who received interventions, 8 (7.8%) had percutaneous drainage, 21 (20.4%) underwent major surgery and 15 (14.6%) had minor surgical procedures. In total, 55.3% did not have any intervention for source control  required ICU admission, with a mean ICU LOS of 2.1 ± 0.6 days. LOS was longer in the group with continuous meropenem (30.2 ± 24.5 days versus 15.5 ± 7.6 days), though antibiotic duration was shorter (9.0 ± 6.3 days versus 23.4 ± 17.5 days). This longer duration of antibiotics despite shorter LOS is possible as patients on intermittent meropenem dosing receive their doses as outpatients at their dialysis centres. n = 96) did not have any documented adverse events. Four patients developed Clostridium difficile colitis, two developed allergic reactions and one acquired carbapenem-resistant Enterobacteriaceae (CRE) positive on screening. In total, 41 (39.8%) were readmitted within 30 days. Moreover, 28 (27.2%) had relapses within the year, while 34 (33.0%) died within 1 year of discharge. Of the 20 patients with known cause of death, 7 died from cardiac-related causes, 3 from ESRF and 10 from infection-related causes, mostly secondary to pneumonia. In total, 93.2% (To our knowledge, this is the first study to describe clinical outcomes of intermittent versus daily dosing of meropenem in patients on a stable haemodialysis regime. There is evidence that intermittent dosing of beta lactams is safe and effective for severe infections . Whilst There were few adverse events in patients treated with both intermittent and daily meropenem, in line with previous reports on the tolerability of meropenem .Our data reveal that there is much variation in meropenem dosing for both daily and intermittent dosing. This lack of standardisation highlights the need for interventional trials to clearly determine the optimal dosing regimen. In our small cohort, intermittent dosing appears to be a feasible approach to reduce healthcare utilisation, with comparable clinical efficacy to the more widely used daily dosing. The trend where patients on intermittent dosing had reduced hospital stay without major adverse events is encouraging.There is much impetus to adopt intermittent dosing of meropenem in ESRF patients on haemodialysis. Patients on haemodialysis tend towards developing depression and poor quality of life , which hWe believe that our small study would help to pave the way towards use of intermittent dosing in our haemodialysis population, with the potential to reduce hospital costs and improve the quality of life of our patients.As this was an exploratory retrospective study, our sample size was small and dosing arms were unequally distributed. We did not have a control cohort. Hence, our study was limited to being descriptive, with no statistical analysis. We were unable to conclude non-inferiority in both approaches or draw conclusions on causality. To increase the sample size, we included a small number of patients on renal replacement therapy secondary to sepsis-induced renal failure. Information on time to resolution of symptoms and clearance blood culture were inconsistently present in our record review and hence were not included in our results. Our study’s findings are preliminary. We recommend for further rigorous randomised controlled trials to investigate the clinical utility of intermittent meropenem dosing in patients on stable haemodialysis. Ethics approval and consent to participate: Domain Specific Review Board under National Healthcare Group, reference number 2018/00578


Background and Aim: Real world evidence on long term treatment of patients with familial hypercholesterolemia (FH) is important. We studied the effects of intensive lipid lowering medication (LLM) and optimized lifestyle in the study TTTFH–Treat To Target FH.Materials and Methods: Adults with a first known total cholesterol of mean (95% CI) 9.8 mmol/L  were included consecutively in their routine consultation during 2006. Of the patients 86.4% had a pathogenic FH-mutation and the remaining were clinically diagnosed. We included 357 patients and 279 met for follow-up after median 10.0  years.Results: Mean (95% CI) low density lipoprotein (LDL-C) was reduced from 3.9  to 3.0 . More men than women used high intensity statin treatment, 85.2 and 60.8%, respectively. Women (n = 129) had higher LDL-C; 3.3 mmol/L , than men; (n = 144) 2.8 mmol/L , p = 0.004. Add-on PCSK9 inhibitors (n = 25) reduced mean LDL-C to 2.0  mmol/L. At enrollment 57 patients (20.4%) had established atherosclerotic cardiovascular disease (ASCVD), and 46 (80.4%) of them experienced a new event during the study period. Similarly, 222 (79.6%) patients had no detectable ASCVD at enrollment, and 29 of them (13.1%) experienced a first-time event during the study period.Conclusion: A mean LDL-C of 3.0 mmol/L was achievable in FH, treated intensively at a specialized clinic with few users of PCSK9 inhibitors. LDL-C was higher (0.5 mmol/L) in women than in men. In patients with ASCVD at enrollment, most (80.7%) experienced a new ASCVD event in the study period. The FH patients in primary prevention had more moderate CV risk, 13% in ten years. The introduction of statins in the early 1990s dramatically improved treatment options for patients with heterozygous familial hypercholesterolemia (FH). However, apart from the introduction of ezetimibe, no important new drugs were developed for these patients until the approval of Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in 2015. Effect and safety of statins is very well documented through large cardiovascular (CV) endpoint studies . No suchThe aim of the present study was to reduce LDL-C to treatment goals as recommended in guidelines in the period 2006–2018, using statins, ezetimibe, resins and diet and lifestyle treatment at study start, and at the end of the study PCSK9 inhibitors in 7.5% of the patients.During January to July 2006, all FH patients between the age of 18–75 (n = 426) meeting for a routine consultation at the Lipid Clinic (LC) were consecutively invited to participate in the study TTTFH–Treat To Target Familial Hypercholesterolemia. Inclusion and exclusion criteria are given in c), C-reaction protein (CRP), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), Creatine kinase, Gamma GT and lipoprotein (a) (Lp (a)) was measured. In case of missing Lp (a) values the highest value was retrieved from medical records. Values for non-HDL-C and ApoB/ApoA1 ratio were calculated. Measurements at enrollment and end of study are given in Total cholesterol (TC), HDL cholesterol (HDL-C), LDL-C, triglycerides (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (apoB), glucose, Glycated hemoglobin  was an ordinary medical consultation by the MDs in the study, followed by consultations of students in clinical nutrition. We used a validated questionnaire (SmartDiet®) to evaluate the patients’ diet . Body maAdverse effects of the LLM were classified according to the likelihood of whether the effects were caused by the LLM. They were classified as definite, probable, or possible. Adverse effects were classified as definite if it disappeared after termination of the medication and in addition reoccurred at re-challenge with same medication in similar dose, and in addition to that a re-challenge procedure was repeated at least twice. Less certain adverse side effects were classified as probable or possible by clinical assessment.Patients who died (n = 12) were not included in the analysis since we did not have access to the death certificates. Of those who died, eight were male and four females. Median age (95% CI) at time of death was 64.8  years, the youngest being 38.3, and the oldest 76.1 years. From the hospital medical records, we found that cause of death was myocardial infarction in three patients. One patient died in a traffic accident, one by suicide and in the remaining 7 deaths the cause was unknown. Two of these patients had established atherosclerotic cardiovascular disease (ASCVD) and three patients had cancer.The number of ASCVD events presented in this study were retrieved from the study case report forms and from medical records. The most common events were percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) and acute myocardial infarction (AMI).th–75th percentiles (25–75p) or minimum and maximum values (min-max). Categorical variables were portrayed as number of cases and percentages. Student’s t-test, either independent or paired, were used when comparing normally distributed continuous variables, and Mann-Whitney U test or Wilcoxon signed rank test in case of non-normally distributed variables. Differences between categorical variables were tested using Chi square test for independence, or Fisher’s exact test if the assumptions for using Chi-scare test were violated. A p-value <0.05 was considered statistically significant. Analysis of variance (ANOVA) was used to test for statistical significance for three or more groups. Stratification was used as the main method to adjust for factors like sex or types of treatment. Tests were performed both with and without outliers. In case that removal of outliers affected the significance of the results, this was noted in the tables or the text.We used IBM SPSS Statistics version 25.0  for statistical analysis. Continuous variables with Normal distribution were presented as mean and 95% confidence interval (95% CI), while skewed variables were presented median and 25Measurements in the study population at enrolment and end of study are given in At enrollment 57 patients (20.4%) had established ASCVD and 46 (80.4%) of them experienced a recurrent event during the follow-up period of 8–12 years . Of thosIn those who suffered from METS during the whole observation time 68.4% had CVD, and among those who had developed METS at last visit 53.3% had CVD. In those with no METS over the ten-year period 23.3% suffered from CVD, and those who normalized their METS during the observation period 27.3% had CVD .2, but blood pressure remained unchanged during the period . The study physicians classified them as definite in 44 patients (16.5%), and 23 patients (8.3%) could not use statins at all due to adverse effects. Characteristics of those not using statins is given in p < 0.05 for all). At end of study they used less butter and/or margarine as spread on bread, less meat as cold cuts, less low-fiber bread, more fish for dinner and more vegetables, although mean score of fruits and vegetables corresponds to a maximum intake of 4 units per day, which is lower than the national recommendations. On the other hand, patients reported eating more high fat cheese (p = 0.006) than recommended. Over half of the population was physically active for at least 1.5 h per week at the end of study, and the majority had an alcohol intake between 0–7 units per week, which did not change significantly during the study period. The number of persons who smoked was reduced by 32.0% from enrolment to end of study, but the number of cigarettes smoked per smoker was not reduced.The patients improved their diet from enrolment to the last visit as measured by SmartDiet score  LDL-C 3.0  mmol/L, which is a 55% reduction compared to the untreated LDL-C of 6.6  mmol/L. As observed in other trials on treatment LDL-C is much too high in FH, Duell et al. reported 2.9 mmol/L using PCSK9 inhibitors in 30% of the patients , LangsleAge at diagnosis and treatment start is an important risk factor in FH; high age at diagnosis resulting in high lifetime LDL-C load and high risk of ASCVD . LookingThe risk of recurrent ASCVD in FH has not been much investigated previously. A Dutch study of 345 FH patients found that in patients with a history of ASCVD the event risk of was almost 30% per year under age 40 years and 15% in patients older than 60 years . The higWe observed that women had 0.5 mmol/L higher LDL-C than men , and theAdverse effects were reported in 44.1% of the patients, and 16.5% had definite side effects as classified by the study physicians. This implies that many patients accept to use statins despite side effects. However, 8.6% of the patients had stopped using statins and 6.5% did not use any kind of LLM despite having a mean (95CI%) LDL-C of 5.6  mmol/L.Routinely collected health data, obtained for administrative and clinical purposes without specific a priori research goals, are increasingly used for research . The preIn conclusion, LDL-C ≤1.8 mmol/L was achieved in no more than 8% of the patients despite the intense mostly per oral lipid treatment, with only 9% using PCSK9 inhibitors. As much as 80.7% of the patients with ASCVD at study start had recurrent ASCVD event over a period of median 10 years. The FH patients in primary prevention had a more moderate CV risk (13% in ten years). With maximally tolerated LLM without use of PCSK9 inhibitors mean (95% CI) LDL-C was reduced to 3.1 , which is much higher than the recommended levels in patients with established ASCVD or with FH, and especially in the combination of both. This illustrates the need for more extensive use of PCSK9-inhibitors among the FH-patients.


To analyze whether neoadjuvant chemoradiotherapy (nCRT) could improve the survival for patients with adenocarcinoma of the esophagogastric junction compared with neoadjuvant chemotherapy (nCT). Both neoadjuvant chemotherapy alone and chemoradiotherapy before surgery have been shown to improve overall long-term survival for patients with adenocarcinoma in the esophagus or esophagogastric junction compared to surgery alone. It remains controversial whether nCRT is superior to nCT.170 Patients with locally advanced (cT3-4NxM0) Siewert II and III adenocarcinoma of the esophagogastric junction (AEG) were treated with neoadjuvant chemotherapy consisting of capecitabine plus oxaliplatin with or without concurrent radiotherapy in the Fourth Hospital of Hebei Medical University. Intensity-modulated radiation therapy (IMRT) was used and delivered in 5 daily fractions of 1.8 Gy per week for 5 weeks . 120 Patients were included in the propensity score matching (PSM) analysis to compare the effects of nCRT with nCT on survival.With a median follow-up of 41.2 months for patients alive after propensity score matching analysis, the 1- and 3-year OS were 84.8%, 55.0% in nCRT group and 78.3%, 38.3% in nCT group . The 1- and 3-year PFS were 84.9%, 49.2% in nCRT group and 68.3%, 29.0% in nCT group . The pathological complete response (pCR) was 17.0% in nCRT group and 1.9% in nCT group (P = 0.030). No significant difference was observed in postoperative complications between the two groups.The nCRT confers a better survival with improved R0 resection rate and pCR rate compared with nCT for the patients with locally advanced AEG. Surgical resection remains the main cornerstone of the treatment for resectable advanced adenocarcinoma of the esophagogastric junction (AEG). Neoadjuvant chemotherapy alone (nCT) and chemoradiotherapy (nCRT) have been shown to improve overall long-term survival for patients with adenocarcinoma in the esophagus or esophagogastric junction compared to surgery alone –6. The MWe reviewed the data of patients with locally advanced (cT3-4NxM0) Siewert II and III AEG and treated by nCRT or nCT in our hospital between March 2012 and December 2015. It was decided by the preference of surgical oncologists and importantly by the preference of the patients if patients received nCT or nCRT. The patients were divided into nCRT group and nCT group. The Review Board of the Fourth Hospital of Hebei Medical University approved this retrospective study .2) on day 1, followed by orally administration of 1000 mg/m2 of capecitabine twice daily for 14 days. The same chemotherapy regimen was given before and after surgery. In the nCRT group, radiotherapy and chemotherapy were performed concurrently. A total radiation dose of 45 Gy by intensity-modulated radiation therapy (IMRT) was administered in 25 fractions of 1.8 Gy, with one time a day and five days per week. The liver, kidneys, spinal cord and heart were organs at risk which were needed to be protected. Surgery was given preferably 6 to 8 weeks after the end of neoadjuvant treatment. Surgical treatment include proximal subtotal gastrectomy/total gastrectomy and extended lymph node dissection (D2 resection). Proximal subtotal gastrectomy and jejunal interposition, proximal subtotal gastrectomy anastomoses with esophagogastric residues, or total gastrectomy anastomoses with Roux-en-Y was conducted through laparotomy.Patients were treated with capecitabine plus oxaliplatin for chemotherapy. The chemotherapy comprised intravenous administration of oxaliplatin , which defined as absence of tumor in the final specimen, lymphovascular invasion, nerval invasion, node positive number, node positive rate.The patients were followed up regularly. The follow-up included a complete medical history, a physical examination, chest and abdominal CT or magnetic resonance imaging, or positron emission tomography if possible and endoscopy if clinically indicated. OS was defined the time from the beginning of treatment to the time of death or follow-up deadline. PFS was defined the time from the beginning of treatment to the time of the first tumor progression time or death. The patients were not randomly assigned in our cohort. To minimize the baseline differences between the nCRT group and nCT group, the PSM analysis was conducted with age, sex, Siewert type, Eastern Cooperative Oncology Group score (ECOG), clinical T stage (cT), clinical N stage (cN) and Her-2 status included in the covariates. To evaluate the significance of differences between the two groups, Chi-square test and t-test were used. The OS and PFS were analyzed using Kaplan–Meier method. The log-rank test was used to analyse the differences in survival. P value lower than 0.05 was considered statistically significant. SPSS version 19.0 software was used for all statistical analysis.There were 170 patients with either nCT or nCRT. Eighty-one patients were in nCRT group and eighty-nine patients in nCT groups. The patients’ baseline characteristics were listed in Table The median follow-up time was 26.0 (4.5–74.2) months for all patients before PSM. The 1- and 3-year OS were 85.1% and 56.7% in nCRT group versus 79.8% and 36.5% in nCT group . The 1- and 3-year PFS rates were 83.9% and 52.7% in nCRT group versus 73.0% and 32.1% in nCT group . The median follow-up time was 41.2 (22.5–73.7) months for patients alive after PSM. Sixty-nine patients were deceased (29 in nCRT group and 40 in nCT group). The median survival, 1- and 3-year OS were 46.0 months, 84.8% and 55.0% in nCRT group versus 24.0 months, 78.3% and 38.3% in nCT group   and 47 days (range 43–58) in the nCRT group and nCT group respectively. The median number of examined lymph nodes were 29 (range 9–54) in nCRT group and 32 in nCT group (range 10–72), respectively. R0 resection and pCR were improved in nCRT group compared with nCT group (p = 0.026 and p = 0.030). Lymphovascular invasion, nerval invasion and node positive rate were decreased in nCRT group versus nCT group  , pneumonitis and esophagitis. There was no significant difference in gastrointestinal toxicities between nCRT group and nCT group (p = 0.250). There were 7 patients with ≥ grade 3 hematologic toxicities in nCRT group and 0 in nCT group (p < 0.05). And 3 of them did not receive surgery because of the hematological toxicity (thrombocytopenia) and poor general condition thereafter for a long time after chemoradiotherapy. No grade 3 esophagitis and pneumonitis occurred in nCRT group.Postoperative complications occurred in 20.8% 11/53) of the nCRT patients and 19.2% (10/52) of the nCT patients (p = 0.713). There were 10 patients with pneumonia after surgery in nCRT (one with chylothorax) and 9 patients in nCT group   patients of nCRT group and 26.9% 14/52) of nCT group (p = 0.001). Distant metastases were observed in 20.8% (11/53) patients of nCRT group and 23.1% (12/52) patients of nCT group (p = 0.774). Locoregional recurrence concurrent with distant metastasis was 3.8% (2/53) in nCRT group and 7.7% (4/52) in nCT group . And among the 8 patients in the nCT group, 3 patients developed locoregional recurrence and 2 patients were diagnosed with liver and abdominal metastasis.The purpose of this study was used ITT method to evaluate whether nCRT could improve the prognosis of the patients with locally advanced AEG compared with nCT. Because the patients were not randomly assigned in our cohort, PSM analysis was used to minimize the statistical bias. In our study, the OS and PFS were both improved in nCRT group compared with nCT group with statistical difference (55.0% and 49.2% versus 38.3% and 29.0% in 3-year OS and PFS) after PSM. The chemoradiotherapy improved 16.7% compared to chemotherapy alone in 3-year OS. The R0 resection rate were higher in nCRT compared with nCT group  and pCR . Node positive rate was decreased in the nCRT group compared with nCT group .3-4NXM0) [Whether sruvival can benefit from radiotherapy combined with preoperative chemotherapy was still controversial. Sthal et al.  compared3-4NXM0) . And in In our study, 3 patients were not given operation in nCT group because of disease progression at liver metastasis and peritoneal metastasis. Disease progression in a short period of time may be related to imperfect staging before treatment. Therefore, standard comprehensive staging is essential. Laparoscopy has become an important tool in the diagnosis, staging and treatment of patients with AEG. It was reported that diagnostic staging laparoscopy before treatment could avoid unnecessary laparotomy and let the patients to be able to receive appropriate alternative treatment . Even foFrom the patterns of failure in our study, nCRT decreased the locoregional failure significantly in nCRT group were 3.8% versus 26.9% in nCT group (p = 0.001) without significant effect on distant metastases compared with nCT (20.8% versus 23.1%) (p = 0.774), which was similar to the result from Stahl M, et al. study [CRT might increase treatment-related death , 20. ComHowever, this study had some limitations. As a retrospective study, bias may exist in evaluating the survival even with the propensity score matching analysis. Despite the advantages of nCRT over nCT, some patients may postpone or lose the opportunity to receive surgery or subsequent treatment due to the hematological toxicities. The follow-up time was not long enough to evaluate the 5-year survival precisely. Future randomized studies with big sample sizes are required to prove that adding radiotherapy to preoperative chemotherapy improves prognosis.In conclusion, neoadjuvant chemoradiotherapy might improve the overall survival and progression-free survival, increase R0 resection and pCR rate, decrease the locoregional failure over neoadjuvant chemotherapy with no significant increase of postoperative complications for the patients with locally advanced adenocarcinoma of esophagogastric junction.