To analyze, in aged obese patients, the weight loss, comorbidity control, and safety postoperative complications of bariatric surgery by Roux-en-Y gastric bypass technique. Twenty-seven patients who underwent laparoscopic weight-reducing gastroplasty with Roux-en-Y gastric bypass to treat obesity were included. All patients were ≥ 60 years old at the time of surgery. The Wilcoxon test was used for statistical analysis, and a p-value ≤0.05it was considered significant. Ten (90.9%) patients with dyslipidemia were cured (p < 0.001). Nine (81.8%) patients with type 2 diabetes mellitus had total improvement and 2 (18.2%) had partial improvement (p = 0.003). In 23 patients with systemic arterial hypertension, 9 (39.1%) achieved total improvement and 14 (60.9%) partial improvement (p = 0.140). Five (71.4%) patients with obstructive sleep apnea syndrome were cured (p = <0.001). For other comorbidities, no partial improvement or cure was shown. Roux-en-Y gastric bypass surgery in obese elderly patients can be performed safely and with low morbidity and mortality rates. The benefits of weight loss and reduced comorbidities are promising and like those of the younger population. In 2014, the World Health Organization (WHO) estimated that approximately 1.9 billion adults worldwide were overweight and at least 600 million were obese2. The major medical concern regarding obesity is the large number of associated diseases, especially cardiovascular disease, diabetes, and malignant neoplasms3. Several long-term epidemiological studies have been able to demonstrate this strong association, as well as evidence of reduced quality of life and increased mortality in these patients6.Obesity, given the significant associated morbidity and mortality rates, is considered a worldwide epidemic with high costs for society and health systems7. The gastric pouch has considerably smaller volume (60 ml), which facilitates the lower consumption of food and calories. In addition, there is less assimilation of calories and nutrients.Although clinical treatment shows good results, the Roux-in-Y gastric bypass (RYGB) procedure is considered the gold standard for weight loss, and it has been the most widely performed bariatric procedure worldwide. Nevertheless, nowadays, vertical gastrectomy is considered the most frequently performed operation8. Due to duodenum bypass, RYGB has the potential to cause vitamin deficiencies, as well as deficiencies in minerals such as iron, copper, selenium, zinc, calcium and phosphorus9.The premature existence of ingested foods that pass into the distal small intestine may stimulate secretion of substances such as glucagon-1 peptide, leading to improved insulin sensitivity, increased insulin production and decreased resistance to insulin. This improvement in insulin sensitivity has proven to be an independent factor of weight loss10. The population over 60 years old already corresponds to 23% of all surgical procedures performed in the world. However, the number of elderly people undergoing surgery is increasing more than the elderly in the general population11. A significant portion of elderly patients present higher risks of morbidity and mortality in emergency and even elective procedures when compared to patients of other age groups12.The elderly population represents a growing share of the world’s population. It is estimated that 8% of people worldwide are over 75, and by 2025, this percentage is estimated to reach 10%13. Increased waist circumference was present in 47.6% of people13. The sarcopenic obesity, defined as the coexistence of sarcopenia and obesity, significantly affects the exercise of daily activities, affecting the quality of life and even the number of hospitalizations14. In addition, another problem of immobility and high body mass index in the elderly is the increased incidence of pressure ulcers. A retrospective cohort study found that hospitalized and intensive care patients with grade III obesity (BMI ≥ 40kg/m2) had significantly more pressure ulcers than other patients, as well as a higher mortality rate15.The prevalence of obesity among the elderly is increasing, and it is estimated in 17.9% on 65 years old17. The majority of the studies advocates in favor of the safety and efficiency of bariatric surgery; however, a deeper knowledge is needed to examine the outcome in elderly patients. The perioperative morbidity and mortality in elderly patients are the central concern for bariatric surgery in this population. This issue associated with the lack of studies, contributes for medical care centers to deny bariatric surgery coverage to patients over the age of 60 years16.As a result of this scenario, surgical procedures to treat obesity in the elderly are increasing and represent about 10% of the total bariatric surgeries performed in academic centers18. Thus, due to the increase in obese elderly and the lack of consensus on the efficacy and safety of bariatric surgery for these patients, we consider it important to analyze the results of gastric bypass surgery in ≥ 60 year-old obese patients.The approach to combating obesity in the geriatric population still lacks solid information and well-established methods because it is a recent research area and many doubts are still observed in this practiceThe aim of the present study was to analyze the results of comorbidity control before and after 2 years of laparoscopic RYGB in ≥ 60 year-old obese patients and to identify possible postoperative complications of this procedure in this population.The research protocol for this study was approved by the Research Ethics Committee of the institution.This retrospective study was performed with adult patients of both genders who underwent laparoscopic RYGB. All surgeries were performed using Roux-en-Y gastroplasty with a 60cm long biliopancreatic loop; the length of the alimentary loop was 120cm and a 3-4cm gastric pouch was created. One of the patients also received a non-adjustable silicone ring around the gastric pouch. All surgical procedures were performed at the Department of Surgery  of the Hospital do Servidor Público Estadual. Clinical and laboratory data were obtained from medical records of patients that underwent an operation between January 2011 and January 2014.2 regardless of the presence or absence of comorbidities, BMI ≥ 35 kg/m2 associated with one or more comorbidities, and acceptance of the consent form after all the benefits and risks offered by the operation were clarified. The exclusion criteria adopted were patients submitted to other modalities of bariatric operations or who underwent the same surgical procedure with an open approach.Inclusion criteria for patients in this study were age ≥ 60 years, body mass index (BMI) ≥ 40 kg/mWe studied 25 (92.6%) women and 2 (7.4%) men, regardless of ethnicity. The average age of the patients was 63.1 ± 3.6 years (60 to 75 years old).2.All patients had grade II or III obesity according to WHO criteria, whether or not it was associated with one or more of the following comorbidities: arthropathy, asthma, depression, dyslipidemia (DLP), type 2 diabetes mellitus (T2DM), gastroesophageal reflux disease (GERD), systemic arterial hypertension (SAH), hypothyroidism, and obstructive sleep apnea syndrome (OSAS)The absence of the need for medication for postoperative comorbidity control was considered a cure, and the need for medication at a lower dose than the preoperative dose was considered partial comorbidity control.The quantitative variables analyzed were age, length of hospital stay, maximum patient weight, preoperative weight, weight after 24 months of operation, percentage of excess weight loss (%EWL), maximum patient BMI, preoperative BMI, BMI 24 months after surgery, number of comorbidities, number of preoperative medications, and medications used to control comorbidities 24 months after surgery.Statistical analysis used mean with standard deviation, median and percentages. The nonparametric Wilcoxon test and confidence intervals were employed. The significance level adopted was 0.05 (5%).The average length of hospital stay was 5.67 ± 1.73 days (4 to 12 days). The average maximum weight was 116.6 kg ± 18.2 (93 kg to 180 kg) and the average weight after 24 months of follow-up was 73.1 kg ± 11.7 (50 kg to 100 kg). The mean %EWL was 74.6% ± 22.2 (31.8% to 135.6%) .2 ± 5.5 (38 kg/m2 to 60 kg/m2) and the mean preoperative BMI was 42.0 kg/m2 ± 4.3 (33.8 kg/m2 to 54 kg/m2). After 24 months of evaluation, the mean BMI was 28.3 kg/m2 ± 3.3 (22 kg/m2 to 33 kg/m2) (The average of maximum BMI was 46.6 kg/m3 kg/m2) .Before surgery, the patients used five medications per day on average to control obesity-associated comorbidities . After 24 months, there was a reduction to three medications on average per day per patient .The average number of obesity-associated comorbidities per patient was 2. Of the 27 patients, 25 (92.6%) had one or more obesity-related diseases. In this group of patients, the distribution of comorbidities is shown in Regarding comorbidities, of the 11 patients who presented with DLP, 10 (90.9%) were cured (p < 0.001). Of the 11 patients with T2DM, 9 (81.8%) had total improvement and 2 (18.2%) had partial improvement (p = 0.003). Concerning the 23 patients with SAH, 9 (39.1%) achieved total improvement (p = 0.140) and 14 (60.9%) achieved partial improvement. Regarding OSAS, of the 7 (28.0%) patients who presented this comorbidity before the operation, in 2 (8.0%), OSAS remained after 24 months (p = <0.001). For other comorbidities, no partial improvement or cure was shown.Regarding the operative complications, it was observed that among the 27 patients in the study, 1 (3.7%) had incisional hernia, 1 (3.7%) developed surgical wound infection, and 5 (18.5%) had other postoperative complications: 2 hypertensive crises, 2 bronchospasms and 1 atrial fibrillation with high ventricular response. At long-term follow-up, 1 patient presented solids dysphagia after 2 years with resolution after ring removal surgery. There were no deaths in this series.et al.19 evaluated 850 elderly patients undergoing RYGB and indicated an operative mortality rate of 0.6% and morbidity of 5.6%. The authors concluded that gastric bypass is a safe procedure in the elderly population due to low morbidity and mortality rates20. In the present study, there was no mortality, while the morbidity index was 29.6%. Yoon et al.21 compared the outcomes of RYGB and vertical gastrectomy among populations < 60 years and ≥ 60 years of age and found no significant differences between the two populations regarding unfavorable outcomes. Postoperative complication rates among the population < 60 years and ≥ 60 years were, respectively, 2.5% and 5%. Mean operative time was slightly longer in patients ≥ 60 years (210 minutes vs. 229 minutes) and readmissions at 30 days occurred more frequently in the ≥ 60 year-old group (2.5% vs. 12.5%). However, the reasons for hospital readmissions in any of the groups were not detailed in this study21. In the present series, no hospital readmissions were recorded within 30 days after the surgical procedure.The safety and efficacy of weight loss surgical procedures in the elderly is still controversial. Sugerman et al.22 evaluated 538 patients undergoing RYGB and found that the most frequent complications were surgical site infection (3.2%), bleeding (2.6%), and intestinal obstruction (1.1%). The main clinical complication was pulmonary thromboembolism, found in 3 (0.55%) patients. The total mortality rate of the study was 0.55% and was related to the presence of pulmonary thromboembolism and age > 65 years. Trieu et al.23 noted that the most frequent early complications in patients > 60 years of age were anastomotic dehiscence (2.2%), bleeding (1.1%), pulmonary thromboembolism (1.1%), pneumonia (1.1%), and atrial fibrillation (1.1%). Late complications included gastrojejunal anastomosis stenosis (8.6%), peptic ulcers (3.2%), intestinal obstruction (1.1%), internal hernias (1.1%), and abdominal wall hernias (1.1%). The authors did not report deaths in their clinical registries. Pajecki et al.24 in a study with morbidity and mortality results of elderly patients undergoing RYGB, had similar follow-ups to the previously mentioned studies, except that the mortality rate was 4.3% (2 patients), one death being caused by pulmonary thromboembolism and the other due to sepsis resulting from surgical wound infection. The researchers concluded that pulmonary thromboembolism and age above 65 years are predictors of mortality.Santo 26. Robert et al.27 revealed that the length of hospital stay after gastric bypass was similar in age groups < 40 years, 40-55 years, and > 60 years. Following the present clinical registry, there was an average length of hospital stay of 5.67 days, with a minimum of 4 days and a maximum of 12 days. It is important to mention that during the period of the operations, the standardized hospitalization time was 4 days for patients undergoing gastroplasty, regardless of age.Older age is a predictor of increased length of hospital stay, although there is no significant increase in mortality. This has been shown in studies that found individuals over 65 to be most likely to require prolonged hospitalizationet al.19, in a study of 80 patients aged between 60 and 66 years, weighing between 110 and 154 kg and with BMI between 42 and 56 kg/m2, followed these patients for 5 years. After 1 year, patients had weight loss between 27 and 49 kg and a reduction in BMI to 27 to 43 kg/m2. Pajecki et al.24 found that %EWL was 71.8%, similar to the results of the present study, in which an average %EWL of 74.6% was obtained after 24 months.Regarding %EWL as a result of RYGB, studies point to the effectiveness of this technique in the elderly. Sugerman et al.28 analyzed 57 patients aged ≥ 70 years undergoing various modalities of bariatric surgery and followed them for 18 months. The authors compared the results of laparoscopic gastric band (24 patients), RYGB (14 patients), and duodenal switch (15 patients). The results obtained of %EWL of BMI lost at the end of follow-up were 37.2% for gastric band, 88.4% for gastric bypass and 100.6% for duodenal switch28. Huang et al.29 observed that after performing RYGB, %EWL was 65% in elderly patients. Abbas et al.30 obtained similar results because the mean %EWL after 12 months of RYGB in patients with a mean age of 63.4 years was 65.2%.Zaveri et al.31 in a retrospective study, analyzed weight loss in 69 elderly patients who underwent laparoscopic RYGB and obtained a percentage of total weight reduction of 23.9 ± 9.3%. These authors found that the percentage of weight loss after 3 years of gastric bypass in the elderly was lower than in young adults (27.5 ± 8.6% vs. 31.8 ± 12.1%), as well as a reduction in BMI (12.7 ± 4.9 vs. 15.2 ± 6.2). In the present clinical registry, a reduction in the mean BMI after 24 months of 13.7 kg/m2 (from 42 kg/m2 to 28.3 kg/m2) was observed, which was similar to the results of the study by Thereaux et al.32Although considered effective in this population, results of RYGB in the elderly still diverge in terms of the effectiveness of weight loss.Gray et al.28 showed that in 83.3% of patients over 70 years undergoing RYGB, there was a resolution of T2DM in 60% of cases, of OSAS in 65% of cases, of SAH in 50% of cases and of GERD in 50% of cases.Regarding the improvement or resolution of comorbidities, Zaveri et al.24 studied patients aged ≥ 60 years who underwent RYGB and were followed for 39 months. The authors observed an improvement in comorbidities such as T2DM, SAH, DLP, and GERD31. In 23% of patients there was partial improvement of T2DM, while in 77%, total control of these comorbidities was achieved. Regarding SAH, in 26% of the cases, there was control with medication reduction, while in 30% the control was obtained without medication. The mean glycated hemoglobin of these patients decreased from 6.73% to 5.7%. In the lipid profile, there was a significant increase in HDL, a slight reduction in LDL, and a strong reduction in triglycerides. Ramirez et al.33 showed reduced use of antidiabetic drugs in 40% of patients, complete resolution of T2DM in 33% of cases, and decreased use of medications for SAH (56%), DLP (54%), and degenerative knee disease (50%). In the present study, there was a reduction of 47.9% in the use of medications to control comorbidities after 24 months (from 5.33 to 3.07 medications) and an improvement in DLP in 90.9% of patients.In the present study, 81.8% of patients had achieved T2DM improvement without the need for medication to control the glycemic level. Regarding hypertension, we obtained a resolution percentage of 39.1% and a reduction of 84.6% of OSAS. Pajecki 34. Nelson et al.35 analyzed 25 patients ≥ 65 years and showed 4% mortality and total complication rate in 20% of the cases. Pajecki et al.24 showed favorable results regarding weight loss and control of comorbidities in the elderly, and other studies showed adequate results of bariatric surgery in relation to weight loss and control of T2DM and hypertension in the elderly28.The National Hospital Discharge Survey and the National Inpatient Survey observed about 25,000 bariatric surgeries, with 3.2% mortality in the elderly compared with 0.2-0.7% in other age groupsWe conclude that laparoscopic RYGB is an effective method for controlling T2DM, DLP, and OSAS in obese elderly individuals (≥ 60 years) in the first 24 months of postoperative follow-up. In addition, it has been shown to be a safe procedure with low rates of minor complications that often do not require surgical intervention in this population. However, further studies with a larger sample of people involved are needed to ratify the results obtained in the present series.


P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% : 26.96–28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51–1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84  and 0.54  respectively. By day 30, 14.15% (12.45–16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67–24.89) of patients treated without PQ; AHR = 0.66 . A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21–0.35) in patients treated with PQ, compared to 0.38% (0.24–0.60) without PQ; AHR = 0.79 . In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P. vivax malaria and its associated morbidity and mortality.The widespread use of primaquine (PQ) radical cure for  Plasmodium vivax. Primaquine (PQ) is currently the only widely available drug to kill hypnozoites, but its use is hampered by concerns over haemolysis in patients with Glucose-6-Dehydrogenase (G6PD) deficiency. At a recent round table discussion of the Asia Pacific Malaria Elimination Network (APMEN) policy makers prioritised further studies to determine the risk-benefit of PQ in different endemic settings.The radical cure of vivax malaria requires killing the blood stages and the dormant liver stages (hypnozoites) of We used a large dataset of more than 26,000 patient treated in a routine care setting in Papua, Indonesia over a 9-year period to explore the risk of adverse outcomes following PQ. Even though patients were treated with PQ without G6PD testing, those patients receiving PQ had a 20% lower risk of all cause re-presentation and 50% lower risk of hospitalization than those not treated with PQ. The risk of mortality was 20% lower, although this didn’t reach statistical significance.Great emphasis is placed on the risks of PQ induced haemolysis, inhibiting its widespread use. It is critical that these risks are interpreted in the context of the substantial benefits of reducing the recurrence of episodes of malaria and associated morbidity and mortality. Our analysis provides reassuring evidence that, in an area with a high burden of malaria and low G6PD prevalence the beneficial effects of PQ outweigh its risks. P. vivax than for P. falciparum. Unlike P. falciparum, P. vivax forms dormant liver stages (hypnozoites) that can reactivate weeks to months after an initial infection, causing recurrent parasitaemia (relapses). Whereas schizontocidal drugs are effective in killing blood stage parasites and reducing acute symptoms, they have no efficacy against the dormant liver stages of the parasite. The parasite’s propensity to recur weeks or months after initial infection results in recurrent febrile illness and a cumulative risk of anaemia and associated morbidity and mortality [In the last decade major gains have been made in malaria control, but successes have been less apparent for ortality –3. Relaportality .The only widely available drug to kill hypnozoites and therefore prevent relapsing infection is primaquine (PQ), which is administered with schizontocidal treatment in a combination known as radical cure. The effectiveness of PQ is limited by the prolonged treatment course (14 days) recommended by most national malaria control programs, and concerns over its safety, particularly the risk of acute haemolysis in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency . G6PD deP. vivax malaria in Papua, Indonesia, an area endemic for P. vivax strains with a short relapse periodicity and low G6PD prevalence [We undertook a retrospective cohort study of patients with evalence . The aimThe study is a retrospective analysis that was conducted on routine data collected from a healthcare facility in Papua, Indonesia. Although individual consent was not collected from patients, all data were anonymised. Ethical approval was obtained from the Human Research Ethics Committee of the Northern Territory (HREC 10.1397) and the Health Research Ethics Committees of the University of Gadjah Mada (KE/FK/544/EC), Indonesia.The study was designed as a retrospective cohort study of routinely collected patient data to compare the morbidity and mortality of patients treated with and without PQ.P. vivax [The climate, geography, malaria endemicity and demographics of the study site have been described previously –10. In bP. vivax .Plasmodium species [P. vivax malaria. Before March 2006 the recommended total dose was 3.5mg/kg administered over 14 days. In March 2006 local guidelines were changed to recommend a total dose of 7mg/kg administered over 14 days. For patients presenting to the hospital outpatient clinic, PQ was commenced at the same time as schizontocidal treatment, whereas in inpatients, PQ was administered once clinical recovery had begun and patients were able to take oral medication.The study was undertaken in patients presenting to the Rumah Sakit Mitra Masyarakat (RSMM) hospital, in Timika, Papua province, Indonesia, between April 2004 and December 2013. RSMM is the largest health care facility in Timika and one of two public hospitals in the district. Since March 2006 local guidelines have recommended dihydroartemisinin-piperaquine (DHP) as the first line treatment for uncomplicated malaria due to any  species . PQ radiIn Indonesia, treatment guidelines do not recommend routine testing for G6PD deficiency to guide the administration of PQ. In a cross-sectional survey in 2013, the prevalence of severe or intermediate G6PD deficiency was 2.6% and was slightly lower in individuals of highland Papuan ethnicity (2.1%) compared to lowlanders and non-Papuans (2.6% and 2.8%) respectively [Data from all patients presenting to the RSMM between 2004 and 2013 were recorded in a Q-Pro database by hospital administrators. The following data were recorded: the patients’ unique identification number, demographic details, date of visit and duration of hospital admission, clinical diagnosis and laboratory investigations. Details on prescriptions at the hospital pharmacy were recorded in a separate database and linked to the same unique hospital record number (HRN).falciparum malaria.Hospital protocols require that all patients attending the outpatient clinic with fever or symptoms consistent with malaria and all inpatients regardless of their clinical presentation, were tested for malaria by microscopic examination of Giemsa-stained blood films. In some instances, HRP2 based rapid diagnostic tests were used for additional confirmation of P. vivax malaria are associated with a cumulative risk of anaemia and both direct and indirect mortality [P. vivax, alone or mixed with another Plasmodium species, and all associated clinical events occurring within the ensuing 30 days. Pharmacy records reported the number of tablets prescribed and the actual mg per kg dose of PQ prescribed were derived for each individual patient by applying estimated mean body weights within each age, sex, and ethnicity strata derived from a cross sectional survey [The HRN was used to link clinical and laboratory data with the pharmacy records. Since recurrent episodes of ortality ,12, the l survey . The totl survey : (i) No P. vivax parasitaemia, either mono-infection or part of a mixed infection, were included in the analyses if they were treated with an artemisinin combination therapy (ACT). Patients treated with non-ACT regimens prior to policy change in 2006 were excluded, since chloroquine resistant P. vivax is highly prevalent in Papua and its poor efficacy is associated with a high risk of adverse events attributable to parasitological failure [P. vivax [Patients with microscopically confirmed  failure . In thisP. vivax ,17. PQ iThe analysis was conducted according to an a priori statistical analysis plan  and is rThe cumulative risks of each of the outcomes were estimated using Kaplan Meier survival curves. Patients with an event on day 1 or 2 were censored on that day under the assumption that this event was related to the initial vivax episode rather than the drug treatment. Hazard Ratios for the association between treatment with/without PQ and each of the outcomes were calculated using a Cox regression model. In view of significant changes in morbidity and mortality of malaria in this area , all mulP. vivax malaria . A total 2,140 patients were excluded because they had no matching pharmacy records and 5,575 were excluded because they received schizonticidal treatment other than ACT or injectable artesunate. A further 1,455 only received a single dose PQ and for 474 patients the PQ dose was missing  received a high dose of PQ, 2,065 (7.88%) were prescribed a low dose of PQ, and 4,872 (18.58%) received no PQ. The baseline characteristics of patients treated with or without PQ were similar . The maiOverall 24,148 (92.1%) patients were treated with DHA-Piperaquine and 1,720 (6.6%) with artesunate-amodiaquine. A total of 2,482 (9.6%) of patients were treated with intravenous artesunate alone or in combination.P. vivax , 457 (6.26%) with falciparum malaria, 17 (0.23%) with other malaria species and 6,048 (82.89%) were due to non-malarial illness. The cumulative risk of re-presentation at 30 days was 27.56% (95%CI: 26.96–28.16) for those with any PQ dose compared to 30.30% (95%CI: 29.01–31.64) in patients not treated with PQ (adjusted Hazard Ratio (AHR) = 0.84 (95%CI: 0.79–0.91); p<0.001)  patients re-presented to hospital between 3 and 30 days after their initial presentation; 774 (10.61%) of these re-presentations were associated p<0.001) , Table 2P. vivax mono-infection and those requiring hospital admission were significantly more at risk of re-presenting to hospital within 30 days ; p<0.0001), but there was no difference between treatment arms in the risk of representing with non-malarial illness (HR = 0.98 (95%CI: 0.92–1.05); p = 0.551). Females, children, those presenting with  30 days . After c 30 days . After c with PQ .a priori subgroup analyses, the risk of hospitalization in patients treated with a high dose PQ was also lower than that in patients not treated with PQ  of 23,426 patients initially treated as outpatients, required admission to hospital between days 3 and 30. The cumulative risk of hospitalization at 30 days was 1.69% (95%CI: 1.51–1.88) in those treated with any dose of PQ compared to 2.71% (95%CI: 2.25–3.27) in patients not initially treated with PQ; HR = 0.62 (95%CI: 0.50–0.77), p<0.001 , Table 2 with PQ .a priori subgroup analyses, the rate of death in non-Papuans after high dose PQ was significantly lower than that in patients not treated with PQ; AHR = 0.05 (95%CI: 0.006–0.43); p = 0.006  patients died between day 3 and 30 days, of whom 18 (24.00%) were not treated with PQ, 8 (10.67%) were treated with low PQ and 49 (65.33%) were treated with high dose PQ. The median number of days before death was 8  and did not vary with PQ treatment (p = 0.887). The cumulative risk of death at 30 days was 0.27% (95%CI: 0.21–0.35) in those treated with any dose of PQ and 0.38% (95%CI: 0.24–0.60) in patients not treated with PQ; AHR = 0.79 (95%CI: 0.43–1.45); p = 0.448. The rate of death was not significantly lower in patients treated with high dose PQ; AHR = 0.77 (95%CI: 0.41–1.43); p = 0.403 , Table 2 = 0.006 .P. falciparum, 26 (52.00%) with P. vivax infection and 19 (38.00%) with had a mixed species infection. Of those who died a total of 4 (5.33%) were diagnosed with acute renal failure, three of whom had received high dose PQ and one didn’t receive any PQ. The clinical details of the 75 patients who died are summarized in At time of death 50 (66.67%) of 75 patients had represented with malaria: 5 (10.00%) with Data on full blood count were available in 8,964 (34.19%) patients at their initial presentation, of whom 20.25%  had a subsequent Hb measure between day 3 and 30. Among those a total of 253 (13.94%) patients presented with an Hb below 7g/dl at first visit. The risk of the Hb concentration falling below 7g/dl was 14.15% (95%CI: 12.45–16.05) in patients treated with any dose PQ compared to 20.43% (95%CI: 16.67–24.89) in those not treated with PQ; AHR = 0.66 (95%CI: 0.45–0.97); p = 0.033. Overall the NNT with PQ to prevent one patient dropping their Hb below 7g/dl within 30 days was 16 (95%CI: 9–183). The comparative AHR for PQ treatment versus those not treated with PQ for the Hb falling below 7g/dl before day 14 were 0.61 , and between day 15 and 30 it was 0.75  . The treA total 36 patients  had a drop in Hb greater than 25% to an absolute Hb <7g/dL within the first 30 days. These included 4.05% (29/716) of patients treated with PQ, and 3.72% (7/188) of patients not receiving PQ. In the multivariable analysis there was no difference in the rate of a clinically significant fall in Hb between those treated with PQ and those who were not administered PQ; AHR = 1.16 (95%CI: 0.43–3.10); p = 0.769 . The cliOur study quantified the morbidity and mortality in more than 26,000 patients presenting with vivax malaria treated with or without PQ in a routine healthcare setting. Although patients were prescribed PQ according to local guidelines, without prior testing for G6PD deficiency, patients treated with PQ had a significantly lower risk of re-presenting to hospital, admission to hospital and developing severe anaemia compared to those patients not treated with PQ within 30 days. The overall risk of dying was lower after high dose PQ, although confidence intervals were wide.P. vivax relapse periodicity such as East Asia and Oceania [Current WHO treatment guidelines recommend a 14 day course of PQ at 0.25mg/kg/day, but also state that a higher dose (0.5mg/kg/day) may be required in areas with high  Oceania . In PapuProviding safe and effective radical cure is important at both an individual and community level. Recurrent episodes of vivax malaria result in a cumulative risk of severe anaemia and associated morbidity and mortality ,19. TheyP. vivax re-presentations in the year following initial presentation [P. vivax relapses by the provision of effective radical cure would also reduce vulnerability to other non-malaria illnesses [Our analysis shows that in Papua, Indonesia, providing PQ radical cure without prior testing for G6PD reduced the risks of re-presentation within 30 days. A previous analysis from the same location also showed a modest, but statistically significant, reduction in entation . In the llnesses ,19,25. ROur study has a number of strengths. The very large sample size reduces the possibility of chance findings. Furthermore, the patients included in this analysis represent a sample of the population seeking treatment for vivax malaria in a real world setting as compared to carefully selected patient cohorts enrolled into comparative clinical trials. This increases the applicability of the results to the patient population of interest.a priori subgroup analysis in which only outpatients were included, the risk of re-presentation was also lower in the PQ group. The remaining a priori subgroup analyses confirmed similar trends in reduction of the primary and secondary outcomes. The subgroup of patients presenting in 2007, was to include a pharmacy stock-out of PQ which lasted for 7 months, with patients also included from 6 months intervals before and after this period. The objective was to focus on patients who didn’t receive PQ due to logistical rather than clinical reasons. Whilst the trend for reduction in re-presentation and hospital admission remained, the confidence intervals were wide due to reduced sample size.Our study also has a number of important limitations. The decision regarding whether or not to prescribe PQ was made by the attending clinician and patients were not allocated randomly to a treatment regimen. Although clinicians may have been hesitant to prescribe PQ to patients who were very unwell or had significant anaemia, discussions with senior clinicians at the hospital suggest that omission of PQ was more often related to junior doctors being less aware of the need to offer PQ radical cure. The baseline characteristics between the treatment groups were generally comparable, however inpatients were less likely to receive PQ than outpatients, but are known to have a higher risk of re-presentation, hospitalization and death. In the P. vivax malaria occurred on day 2, even in patients not treated with PQ and thus is likely to be predominantly related to malaria [In our analysis, patients with an event on day 1 or 2 were censored, assuming that these are related to deterioration from clinical malaria rather than its treatment. In a recent meta-analysis the nadir Hb in patients with uncomplicated  malaria . Reports malaria ,27. HoweA further limitation of the study was that it was not possible to confirm from the hospital records whether patients took the full course of PQ treatment or not. Previously we have postulated that poor adherence to PQ treatment at the same location may limit effectiveness of radical cure . The modOur analysis included all severe adverse events within 3 to 30 days of patients’ initial presentation with vivax malaria. Hb concentration was not measured routinely, although it is hospital practice to check the Hb of inpatients and those with clinical anaemia. Our primary analysis therefore focused on all cause re-presentation and hospital admission as indirect measures of adverse outcomes rather than direct measures of haemolysis. The latter was addressed in a subgroup of patients in whom Hb was measured at presentation, and reassuringly showed similar trends to a lower risk of anaemia in patients receiving PQ compared to those who did not.P. vivax infection and its associated morbidity and mortality. Our analysis in Papua, suggests that irrespective of the aetiology, one re-presentation to hospital can be prevented by treating 24 patients with PQ even without G6PD testing. The corresponding NNT with PQ was 16 to prevent one patient dropping their Hb below 7g/dl and 81 to prevent one patient requiring admission to hospital.We were also unable to discriminate whether the reported clinical endpoints were attributable to malaria, non-malaria or drug-induced aetiologies. It is possible that some of the severe adverse events could have been due to PQ-induced toxicity in G6PD deficient individuals, and that these could have been prevented if prior G6PD testing had been offered. Whilst all efforts should be made to diagnose patients with G6PD deficiency prior to PQ administration, this is often unavailable or unreliable due to logistical, financial and infrastructural limitations in remote and inaccessible locations where the main burden of malaria resides ,5. The oThe relevance of our findings for patients with vivax malaria in other endemic regions needs to be considered with caution. In southern Papua less than 3% of the population are G6PD deficient , a likelS1 Text(PDF)Click here for additional data file.S1 Data(CSV)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.S6 Table(PDF)Click here for additional data file.


The aim of the study was to evaluate the effect of bolus-tracking ROI positioning on coronary computed tomography angiography (CCTA) image quality.In this retrospective monocentric study, all patients had undergone CCTA by step-and-shoot mode to rule out coronary artery disease within a cohort at intermediate risk. Two groups were formed, depending on ROI positioning (left atrium (LA) or ascending aorta (AA)). Each group contained 96 patients. To select pairs of patients, propensity score matching was used. Image quality with regard to coronary arteries as well as pulmonary arteries was evaluated using quantitative and qualitative scores.p = 0.619 | SNR LM 19.80 vs. 20.30; p = 0.661 | SNR RCA 24.34 vs. 24.30; p = 0.767) or qualitative scores , respectively. With regard to pulmonary arteries, we found significantly higher quantitative  and qualitative scores  for ROI positioning in the LA than for ROI positioning in the AA.In terms of the coronary arteries, there was no significant difference between both groups using quantitative (SNR AA 14.92 vs. 15.46; ROI positioning in the LA or the AA results in comparable image quality of CT coronary arteriography, while positioning in the LA leads to significantly higher image quality of the pulmonary arteries. These results support ROI positioning in the LA, which also facilitates triple-rule-out CT scanning.• ROI positioning in the left atrium or the ascending aorta leads to comparable image quality of the coronary arteries.• ROI positioning in the left atrium results in significantly higher image quality of the pulmonary arteries.• ROI positioning in the left atrium is feasible to perform triple-rule-out CTA. In CTA, image quality is strongly influenced by contrast injection timing. As heart rate and cardiac output vary greatly, it is necessary to adapt the time interval between the start of contrast injection and the start of data acquisition in order to achieve optimal contrast filling.The bolus-tracking technique is widely used for choosing the optimal starting point of data acquisition in CTA. In coronary computed tomography angiography (CCTA), the ROI to monitor contrast inflow is mostly positioned in the ascending aorta (AA), while in triple-rule-out-CTA (TRO-CTA), an examination performed to evaluate the coronary arteries, aorta, and pulmonary arteries, the ROI is usually placed in the left atrium (LA) . The effThe aim of our study was to evaluate the effect of ROI positioning on CCTA image quality, especially with regard to coronary and pulmonary arteries.This study was approved by the local ethics committee, and due to the retrospective evaluation written informed consent was waived. Our radiology information system was searched for patients who underwent CCTA for suspected coronary artery disease between January 2015 and February 2016. Inclusion criteria were the following: patients older than 18 years; intermediate pre-test probability for the presence of coronary artery stenoses as defined by the guideline of the European Society of Cardiology [Propensity score matching  was usedBased on propensity score matching results, 96 pairs of patients were selected and included in this study   of patients were diagnosed with significant coronary stenosis using CCTA. This included 14.6% (14/96) of patients with bolus tracking in the AA and 17.7% (17/96) of patients with bolus tracking in the LA. A total of 18.2% (35/192) of patients had at least one unevaluable coronary artery segment due to artifacts, including blooming artifacts caused by calcified plaques and motion artifacts. There was one case of pulmonary embolism in our patient cohort.All examinations were performed on a third-generation dual-source CT system . Patients were examined in the supine position. An 18-G peripheral venous catheter placed in the right cubital vein was used for i.v. premedication and contrast injection.In patients with a heart rate higher than 70/min and no contraindications for beta blockers, metoprolol  was applied intravenously to achieve heart rate reduction . Then, 5The bolus-tracking technique was used to trigger the start of image acquisition, with ROI placement either in the LA or in the AA. The ROI threshold was 120 HU. The delay time between reaching the threshold and the start of the CCTA acquisition was 5 s. CCTA was performed in inspiration.In craniocaudal direction, CCTA extended from the tracheal carina to just below the diaphragm. The so-called step-and-shoot technique was used, a prospective ECG-gated, sequential CT technique .Detector collimation was 2 × 192 × 0.6 mm and rotation time was 0.25 s. The tube voltage was adapted by the scanner software CareDose4D  depending on patient physique. CCTA images were reconstructed with a slice thickness of 0.6 mm using a medium sharp kernel (Bv40) and Advanced Modeled Iterative Reconstruction (ADMIRE ) level 3To evaluate the image quality of coronary and pulmonary arteries, both quantitative measurements ) and qualitative scores were used.SNR is defined as the quotient of the mean signal intensity and the standard deviation of signal intensity. It was determined in circular ROIs in the ascending aorta, left main coronary artery (LM), proximal right coronary artery (RCA), right pulmonary artery (RPA), and left pulmonary artery (LPA). In the ascending aorta and the pulmonary arteries, the diameter of the ROI was 10 mm and in the coronary arteries it was as large as possible with the exclusion of vessel walls and plaques Figs. , 3.Fig. For generating the qualitative scores, overall image quality for coronary and pulmonary arteries was assessed independently by two radiologists with 10 and 6 years of experience in CCTA. They were blinded to the position of bolus-tracking ROI. A 5-point Likert scale with the following scores was used: 5 = perfect; 4 = very good; 3 = good; 2 = poor; 1 = insufficient. Vessel wall definition and image noise were considered in the qualitative evaluation of image quality  = 0.0167. In case of the pulmonary arteries, it was set accordingly at α = (0.05/2) = 0.025.Thus, signal intensity and SNR were compared using the Wilcoxon test. Because of multiple comparisons, the Bonferroni correction  was usedα = 0.05.Qualitative scores were compared using the Wilcoxon test, too. The significance level was set at κ) [κ ≤ 0 poor; 0.01–0.20 slight, 0.21–0.40 fair, 0.41–0.60 moderate, 0.61–0.80 substantial, and 0.81–1.00 almost perfect agreement).Regarding the qualitative analysis, interrater reliability was evaluated using weighted Cohen’s kappa (κ) , 19, whiκ)  (κ ≤ 0 pRadiation exposure was compared by the Wilcoxon test. Effective doses (in mSv) were calculated by multiplying the dose-length products provided by the scanner with a conversion factor of 18 μSv/mGycm as recommended by Huda et al .The Shapiro-Wilk test, Wilcoxon test, and the calculation of weighted Cohen’s kappa were performed using MedCalc 18.10.02 . Diagrams and tables were created using Microsoft Office Excel 2016 (Microsoft Corporation).The standardized differences for the comparison of both groups of patients pre-matching were higher than 0.1 in case of height, body weight, and heart rate as well. Post-matching, they were lower than 0.1 in all cases, so we can assume that there was no significant difference concerning these variables in the matched samples   for group A (bolus-tracking ROI in LA) was 531.64 (± 159.18) HU and for group B (bolus-tracking ROI in AA) 512.74 (± 158.27) HU. In the LM, the mean value of signal intensity for group A was 505.08 (± 155.03) HU and for group B 481.31 (± 155.83) HU. In the proximal RCA, the mean value of signal intensity for group A was 516.88 (± 164.81) HU and for group B 455.51 (± 169.88) HU.p = 0.007); in the AA (p = 0.374) and LM (p = 0.308), it was not  and for group B 15.46 (± 3.85). In the LM, the mean value of SNR for group A was 19.80 (± 8.36) and for group B 20.30 (± 8.34). In the proximal RCA, the mean value of SNR for group A was 24.34 (± 11.04) and for group B 24.30 (± 12.73).p = 0.619), LM (p = 0.661), and proximal RCA as well (p = 0.767)  Fig. .Out of 96 patients of group A, the image quality was rated 5 in 41 cases (42.7%), 4 in 39 cases (40.6%), 3 in 15 cases (15.6%), and 2 in one case (1.1%); mean qualitative score was 4.25 (± 0.75). Out of 96 patients of group B, the image quality was rated 5 in 44 cases (45.8%), 4 in 36 cases (37.5%), and 3 in 16 cases (16.7%); mean qualitative score was 4.29 (± 0.74).p = 0.672).In summary, image quality scores for coronary arteries did not differ significantly between patients with bolus-tracking ROI in LA and those with bolus-tracking ROI in AA  was 311.47 (± 159.69) HU and for group B (bolus-tracking ROI in AA) 183.19 (± 114.14) HU. In the LPA, the mean value of signal intensity for group A was 310.98 (± 158.80) HU and for group B 186.32 (± 114.06) HU.p < 0.001) and left (p < 0.001) pulmonary artery was significantly higher in group A than in group B  and for group B 5.89 (± 2.98). In the LPA, the mean value of SNR for group A was 9.06 (± 4.03) and for group B 6.25 (± 3.25).p < 0.001) and LPA (p < 0.001) for bolus-tracking ROI positioning in LA than for bolus-tracking ROI positioning in AA , 4 in 18 cases (18.8%), 3 in 19 cases (19.8%), 2 in five cases (5.2%), and 1 in seven cases (7.3%); mean qualitative score was 3.97 (± 1.25). Out of 96 patients of group B, the image quality was rated 5 in eleven cases (11.5%), 4 in four cases (4.2%), 3 in 19 cases (19.8%), 2 in 25 cases (26.0%), and 1 in 37 cases (38.5%); mean qualitative score was 2.24 (± 1.32).p < 0.001).In summary, the image quality scores for bolus-tracking ROI positioning in LA were significantly higher than those for bolus-tracking ROI positioning in AA  and different scores in 27.6% (53/192), but they never differed by more than one grade. The resulting weighted kappa was greement .κ = 0.846, indicating almost perfect interrater agreement [For the qualitative analysis of pulmonary arteries, both radiologists assigned identical scores in 74.0% (42/192) and different scores in 26.0% (50/192) and they differed only in one case by more than one grade. The resulting weighted kappa was greement .p = 0.501).The mean dose-length product was 229.23 (± 177.24) mGycm in patients with bolus-tracking ROI in LA and 229.31 (± 141.63) mGycm in patients with bolus-tracking ROI in AA. The corresponding mean effective doses were 4.13 (± 3.19) mSv and 4.13 (± 2.55) mSv . Thus, rOur study shows that positioning of bolus-tracking ROI in either the LA or the AA does not have a significant impact on coronary artery depiction in CCTA. This result indicates that positioning of the ROI in the AA, which is currently preferred by most radiologists when performing CCTA, is feasible, if coronary artery disease is the main indication for CT.Our study shows that positioning of the ROI in the LA leads to significantly better image quality within pulmonary arteries and does not adversely affect depiction of the coronary arteries, when compared with conventional positioning in the AA. This implies that as well as achieving superior contrast within the pulmonary arteries, coronary arteries can be reviewed at the same time without loss of image quality by using this ROI position, so it is a valid option when performing a TRO examination. Our results are also in keeping with a study by Ayaram et al , which dThe mean signal intensities in the coronary arteries ranged from 455.51 to 531.64 HU, depending on measuring point and position of bolus-tracking ROI. A study by Becker et al  showed aConsidering the aforementioned study , mean siIn this study, we used adaptive tube voltage, leading to automatic dose adjustment depending on patients’ physique. Mean radiation exposure was 4.12 mSv. In a study looking at obese patients in CCTA, also using the step-and-shoot technique, mean radiation exposure was 12.34 mSv in the patient group with BMI values comparable with that of our patient group. A possible reason could be the use of constant tube voltage of 120 kV in that study . In cont2). Our results therefore show that 50 ml of contrast medium leads to good coronary image quality and further reduction of contrast volume or concentration might be feasible.In this study, 50 ml of contrast medium was applied for each examination instead of 80 to 100 ml, which was used for examinations with older device generations . MangoldThe evaluation of interrater reliability shows substantial agreement of both radiologists regarding the analysis of coronary arteries, which is in keeping with the findings of several other studies , 33. ForAnother significant limitation of this study is the lack of correlation with digital subtraction angiography (DSA), which still represents the gold standard for the diagnosis of coronary heart disease. Our study evaluates image quality, but not accuracy of detecting coronary stenoses on CT. Further studies are necessary to compare DSA and CCTA with regard to this. The use of axial slices to measure SNR might also be a limitation. In small vessels like the coronary arteries, the use of orthogonal images could potentially reduce partial volume effects.Further limitations are the retrospective study design and the use of propensity score matching. Only known influencing factors can be eliminated using this method. And even the considered factors can never agree completely in both patient groups, since the study population is limited.In conclusion, ROI positioning in the LA leads to good image quality with regard to coronary and pulmonary artery depiction. Therefore, our protocol is feasible to perform TRO-CTA in patients with chest pain.


To the editor:Honore et al.  suggesteEleven patients 34.4%) included in our trial 4.4% incl did not However, we support the warning launched by Honore et al.  about th


Gonadotropin-releasing hormone agonist (GnRHa) treatment improves the potential for gaining height in patients with central precocious puberty (CPP). However, most studies have focused on girls because CPP in boys is relatively rare. Therefore, we aimed to determine the effect of GnRHa treatment on auxological outcomes in boys with CPP.Eighty-five boys with CPP were treated with leuprolide or triptorelin acetate 3.75 mg over 2 years. Anthropometry, bone age, sexual maturity rating, and predicted adult height (PAH) were assessed every 6 months. Furthermore, 20 boys were followed up after treatment discontinuation until achievement of the final adult height (FAH).p = 0.006). In multivariate analysis, the height gain (the difference between the FAH and PAH at treatment initiation) significantly correlated with the target height.The mean chronological age (CA) and bone age (BA) of the patients with CPP at treatment initiation were 9.5 ± 0.5 years and 11.7 ± 0.9 years, respectively. The mean duration of treatment was 2.87 ± 0.63 years. The PAH at treatment initiation was 172.1 cm (-0.23 ± 1.05 PAH standard deviation score). The PAH at treatment discontinuation (176.2 ± 6.6 cm) was significantly higher than the pretreatment PAH. In addition, the mean final adult height in the 20 boys who were followed up after discontinuation of treatment was 173.4 ± 5.8 cm, which was significantly higher than the initial PAH (170.1 ± 4.5 cm; Long-term GnRHa treatment significantly improved the growth potential and FAH in boys with CPP. Precocious puberty (PP) refers to the development of secondary sexual characteristics before the age of 8 and 9 years in girls and boys, respectively . CentralCurrently, gonadotropin-releasing hormone agonists (GnRHa) have been used in the treatment of CPP –5. AlthoClinical records of 85 boys with CPP who were treated with GnRHa for >2 years at Ajou University Hospital, South Korea from 2007 to 2017 were reviewed. CPP was diagnosed based on the following criteria: (1) objective testicular volume ≥4 mL before 9 years of age, (2) advanced bone age (BA) >1 year above the chronological age (CA), and (3) peak values of pubertal luteinizing hormone (LH)  achieved during a GnRH stimulation test. Plasma thyroxine and thyroid-stimulating hormone levels were also measured to exclude hypothyroidism. Boys with brain tumor, congenital adrenal hyperplasia, hypothyroidism, or those who received cranial irradiation were excluded from the study. Patients who were treated with growth hormones were also excluded. Of the 85 boys with CPP, 76 boys underwent magnetic resonance imaging (MRI) of the hypothalamic–pituitary area. The other 9 patients refused to undergo MRI. MRI abnormality was not detected in 68 subjects. Brain lesions not definitively related to CPP were found in 8 boys. These included pituitary hyperplasia (n = 4), Rathke’s cleft cyst (n = 2), pineal cyst (n = 1), and arachnoid cyst (n = 1). However, none of the 8 boys had any neurologic symptoms such as headache or seizure.The standard treatment regimen was subcutaneous administration of leuprolide or triptorelin acetate 3.75 mg every 4 weeks. Twenty-four patients were treated with leuprolide acetate and the other 61 patients were treated with triptorelin acetate. Height, weight, Tanner stage, BA, LH concentration, follicle-stimulating hormone (FSH) concentration, and testosterone concentration were evaluated every 6 months. The LH level was determined 30 min after GnRHa injection every 6 months during the treatment to monitor the suppression of the hypothalamic–pituitary–gonadal axis. LH level <3 IU/L was considered therapeutic suppression , 12. TreHeight was measured to the nearest 0.1 cm using a Harpenden stadiometer . Weight was recorded to the nearest 0.1 kg using an electronic scale . The volume of each testis was estimated by comparative palpation using a Prader orchidometer by a single pediatric endocrinologist . PubertaThe protocol was approved by the Institutional Review Board of Ajou University Hospital (AJIRB-MED-OBS-16-372). Written informed consent was obtained from all the subjects or their parents before FAH evaluation.p < 0.05. Results are presented as mean ± standard deviation, unless indicated otherwise.All statistical analyses were performed using SPSS . The values at treatment initiation and at treatment discontinuation were compared using a repeated-measures ANOVA test. Comparisons of the results between the groups were assessed using the independent t-test or Mann–Whitney U test, depending on the data distribution. To determine significant associations with the gain in height (the difference between the FAH and PAH at the initiation of treatment), univariate and multivariate analyses were performed with stepwise variable selection, including age at diagnosis, height SDS, TH, and duration of treatment. Statistical significance was set at The mean age at diagnosis was 9.5 ± 0.5 years (range: 6.6–9.9 years). The mean duration of GnRHa treatment was 2.87 ± 0.63 years. The mean BA at the time of treatment initiation was 11.7 ± 0.9 years . The peaThe changes in auxological outcomes are summarized in p < 0.001). The PAH at treatment discontinuation was significantly higher than the TH in boys with CPP.There was a significant increase in the PAH after GnRHa treatment in boys with CPP. The PAH at treatment initiation was 172.1 ± 5.9 cm, while that at treatment discontinuation was 176.2 ± 6.6 cm  patients achieved a higher FAH than the PAH at treatment initiation. To identify the factors that determined the gain in height, which was defined as the difference between the FAH and PAH at treatment initiation, we divided the 20 boys into two groups—group A, FAH > PAH at treatment initiation (iPAH) (n = 16) and group B, FAH < iPAH (n = 4). We compared clinical variables such as age, height SDS, weight SDS BMI SDS, bone age, and PAH between the two groups. However, the variables were not significantly different between the two groups (data not shown).In the univariate analysis, the height gain (the difference between the FAH and iPAH) positively correlated with the TH. Moreover, multivariate analysis revealed that the gain in height was influenced significantly only by the TH in 20 boys with CPP who were followed up until achievement of the FAH .In our study population, the PAH significantly increased by approximately 4.1 cm after GnRHa treatment in boys with CPP. The FAH was significantly higher than the iPAH and TH. Moreover, the TH was a strong determinant of the height gain.Many studies in girls have reported that GnRHa treatment preserves or improves the growth potential in patients with CPP. However, limited data are available on the long-term outcomes of GnRHa treatment on growth in boys with CPP. Previous studies have demonstrated that untreated boys with CPP showed a FAH of approximately -3 standard deviations below the population average , 20. OerSeveral factors such as age at treatment initiation, duration of treatment, parental height, and height before treatment influence the growth outcomes after GnRHa treatment in patients with CPP. In our study, the TH was an important predictor, with better long-term growth outcome in 20 boys with CPP. Lazar et al.  reportedOur study has several limitations. First, the number of subjects evaluated for the final height was relatively small. Second, we did not have untreated groups with CPP for ethical reasons. Third, PAH might have been overestimated in this study. Drop et al.  reportedIn conclusion, GnRHa treatment can significantly improve the growth potential in boys with CPP. The FAH was significantly higher than the initial height prediction. The target height was the main factor determining the long-term growth outcome.S1 File(SAV)Click here for additional data file.


VGC) = 0.48 (p = 0.58) or intraobserver; AUCVGC for Observer 1 and 2 respectively, 0.49 (p = 0.85) and 0.53 (p = 0.52) for MRA compared with 0.54 (p = 0.30) and 0.49 (p = 0.81) for DSA. Interobserver differences were seen: AUCVGC of 0.63 (p < 0.01) for DSA and 0.80 (p < 0.01) for MRA. These results were confirmed using Krippendorff’s α for the three observers showing 0.13  −0.07–0.31) for MRA and 0.39 (95% CI 0.23–0.53) for DSA. Poor interobserver agreement was also found in the choice of a target vessel on preoperative MRA: Krippendorff’s α = 0.19 (95% CI 0.01‒0.36). In conclusion, infrapopliteal lesions can be reliably determined on preoperative MRA, but interobserver variability regarding the choice of a target vessel is a major concern that appears to affect the overall TASC II grade.This paper aimed to study the agreement and repeatability, both intra- and interobserver, of infrapopliteal lesion assessment with magnetic resonance angiography (MRA), using the TransAtlantic Inter-Society Consensus (TASC) II criteria, with perioperative digital subtraction angiography (DSA) as a reference. Sixty-eight patients with an MRA preceding an endovascular infrapopliteal revascularization were included. Preoperative MRAs and perioperative DSAs were evaluated in random order by three independent observers using the TASC II classification. The results were analyzed using visual grading characteristics (VGC) analysis and Krippendorff’s α. No systematic difference was found between modalities: area under the VGC curve (AUC The prevalence of lower extremity artery disease (LEAD) is increasing worldwide ,2. LEAD In current practice, the indication for revascularization is based on symptoms and clinical findings, while the revascularization strategy is based on non-invasive preoperative imaging techniques such as magnetic resonance angiography (MRA), computed tomography angiography (CTA) and duplex ultrasonography . In manyLesions can be graded according to the TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) classification, which was introduced in 2007 . The TASThe aim of this study was to assess agreement and repeatability, both intra- and interobserver, of infrapopliteal lesion assessment with MRA, using the infrapopliteal TASC II lesion criteria and with perioperative DSA as a reference.Preoperative MRA and perioperative DSA examinations were independently evaluated in randomized order by three observers. The observers were blinded to all the clinical patient data. The examinations were assessed according to the infrapopliteal TASC II classification .All patients aged 50 years and older who underwent an endovascular isolated infrapopliteal revascularization for CLTI between 2008 and 2016 at our tertiary center were identified using the national quality register for vascular surgery (Swedvasc) ,13. The ®, Guerbet, Roissy CDG, France, or, in some of the earlier examinations, gadobutrol, Gadovist®, Bayer Inc., Toronto, ON, Canada) with volumes of 12, 8 and 10 mL for the lower leg, thigh and pelvis respectively, using a 3D T1 weighted sequence and a contrast flow rate of 1 mL/s. The parameters were TR/TE: 4.7 ms/1.5 ms; feet-head coverage: 450 mm; acquired voxel size: 1.4 × 1.4 × 2 mm and reconstructed voxel size: 0.7 × 0.7 × 1 mm. A minority of the examinations (16 of 68) were performed at local hospitals in our region. Ten examinations were performed on a Siemens Symphony  and the rest on a Philips Intera. Only static 3D maximum-intensity projections (MIP) and/or dynamic MIP series, depending on the clinical protocol, were presented to the observers. All DSA studies comprised imaging documentation captured during endovascular revascularization procedures.Preoperative MRA and DSA images were obtained from the picture archiving and communication system. The contrast-enhanced MRA examinations were performed on 1.5 T magnetic resonance systems using standard clinical protocols. The majority of the examinations (52 of 68) were performed on a whole-body Philips scanner  using a SENSE XL coil between 2008–2014 and a dStream Posterior coil between 2015–2016. The clinical protocol consisted of a three-station subtracted acquisition during the intravenous administration of a gadolinium-based contrast agent  that describes the degree of separation between two datasets. A random-reader analysis was employed for comparisons between modalities and for level of confidence, while a fixed-reader analysis was used for inter- and intraobserver comparisons.Visual grading characteristics (VGC) analysis ,20 was uTo estimate intra- and interobserver agreement, Krippendorff’s α was used . Lower αThe statistical software used was SPSS version 24 .Ethical approval was obtained from the ethics committee at the University of Gothenburg (entry nos. 220-17 (26 April 2017) and T1060-17 (4 December 2017)). For this type of study, individual patient consent was not required.In all, 119 patients with infrapopliteal revascularization were identified. In 68, both preoperative MRA and perioperative DSA images were available and were included in the analysis. A flow chart of the cohort is presented in Descriptive statistics on the number of examinations with sufficient diagnostic quality and the distribution of assessed TASC II classes are presented in n = 46). This resulted in a paired data analysis which revealed no statistically significant difference between MRA and DSA in TASC II classifications .In the VGC analysis for modality comparison, only patients in whom all three observers had deemed the diagnostic image quality to be sufficient for TASC II classification of the lower leg were included  for MRA (n = 61) and 0.54 (p = 0.30) for DSA (n = 62). The corresponding AUCVGC values for Observer 2 were similar: 0.53 (p = 0.52) for MRA (n = 49) and 0.49 (p = 0.81) for DSA (n = 60).In VGC analysis for repeated classification (intraobserver comparison), no statistically significant differences were found for either of the observers. The AUCn = 61) for MRA and 0.49  for DSA for Observer 1. For Observer 2, the corresponding values were 0.58  for MRA and 0.69  for DSA.The intraobserver agreement on the TASC grade assignment resulted in Krippendorff’s α values of 0.15  for DSA (n = 61) and 0.80 (p < 0.01) for MRA (n = 51). Similar results were revealed when analyzing interobserver agreement within modalities using Krippendorff’s α. Interobserver α values for the three observers gave 0.13 (95% CI −0.07–0.31) for MRA and 0.39 (95% CI 0.23–0.53) for DSA  for MRA and 0.57  for DSA for Observer 1. For Observer 2, the corresponding values were 0.53  for MRA and 0.60  for DSA.The intraobserver agreement on choosing the target vessel was fair with Krippendorff’s α values of 0.57  and DSA (n = 61) agreement between the three observers gave a Krippendorff’s α value of 0.19 (95% CI 0.01–0.36) for MRA and 0.41 (95% CI 0.24–0.56) for DSA. The target vessel, being revascularized peri-operative according to medical charts, was distributed as: tibiofibular trunk n = 17 (25%), anterior tibial artery n = 19 (27.9%), posterior tibial artery n = 11 (16.2%) and fibular artery n = 16 (23.5%). In five cases (7.4%) the operators were not able to perform a revascularization procedure. The agreement between the choice of target vessel on preoperative MRA and the target vessel that was eventually revascularized was also poor, with Krippendorff’s α values of −0.02, 0.14 and 0.39 for the individual observers. In 20 of the 68 cases (29.4%), more than one infrapopliteal vessel was eventually revascularized.In contrast, the interobserver agreement regarding the selection of a target vessel was poor . For MRAThere are two main findings in this study. First, no difference in infrapopliteal TASC II classification was found between modalities when the assessment was based on MRA rather than DSA; Second, the interobserver agreement on infrapopliteal TASC II assessment was poor, which might be explained by the poor consensus on choosing the target vessel.Previous research has shown that MRA gives a correct assessment of arterial infrapopliteal lesions compared with the reference method, DSA ,7. The dHowever, agreement on TASC II grade was poor between observers, with a numerical level of agreement between observers approaching the likelihood of pure chance. The same poor agreement was found in the selection of a target vessel for an intended revascularization procedure, which the infrapopliteal TASC II classification requires. The low agreement that was observed applied to both modalities. One probable explanation for the poor TASC II agreement might be the requirement to choose a target vessel. This possibly introduces several limitations to clinical and scientific use. Firstly, different observers and operators may choose different target vessels. Secondly, particularly in endovascular procedures, more than one target vessel may be revascularized. In some patients, there is a potential benefit to be gained from revascularizing more than one vessel to achieve wound healing . This waIn this study, we used the TASC II classification, as this was the main classification available when the study was performed. In 2019, the new Global Anatomic Staging System (GLASS) score was introduced after the image evaluation of this study was completed, and it was therefore not included . HoweverThe limitations of this study include the retrospective design and the fact that only patients with sufficient image quality for both modalities were included. The strengths include the use of consecutive patients with CLTI from clinical routine healthcare, a structured reviewing process with the ViewDEX software and the random-order image evaluation by blinded observers. Furthermore, we also analyzed the variability of the reference method (DSA) and not only for the investigated index method (MRA).Since MRA is one of the leading modalities in the preoperative assessment of peripheral vascular lesions, these findings add new knowledge on how to accurately diagnose and predict outcomes in these patients. Further studies need to be conducted to elucidate whether the poor agreement is due to the choice of the target vessel or whether there are other explanations and ways of overcoming these issues.Infrapopliteal lesions can be reliably determined with preoperative MRA, but interobserver variability regarding the choice of a target vessel is a major concern which appears to affect the overall TASC II grade.


Halichondria okadai   was determined for the first time in this study. The circular genome is 20,722 bp in length, containing 14 protein coding genes (PCGs), two ribosomal RNAs (rRNAs), and 25 transfer RNAs (tRNAs). The nucleotide composition of mitogenome consists of 29.5% A, 14.2% C, 21.5% G, 34.7% T, showing a high content of A + T similar to the other Suberitid sponges. These results will be useful for inferring the phylogenetic relationships among the members of family Halichondriidae within the Suberitids.The mitogenome sequence of Sponge  Halichondria okadai is a thin encrusting species belonging to family Halichondriidae and inhabits in the intertidal zone. Sponges of the genus Halichondria Fleming, 1828 are presently recognized as 93 valid species in the world ocean  of Halichondriid have been reported for their complete mitochondrial genomes . The genomic DNA was isolated from the tissue and the mitogenome sequences were analysed by application of Illumina Hiseq2000 sequencing platform . The sequences were assembled and annotated in comparison with the previously reported mitogenome sequences of Halichondriid species  is 20,722 bp in length, containing 14 protein coding genes (PCGs), two ribosomal RNAs (rRNAs), and 25 transfer RNAs (tRNAs). The overall nucleotide base composition of H. okadai is 29.5% A, 14.2% C, 21.5% G, 34.7% T, showing a high A + T bias (64.2%) similar to the other Halichondriid sponges. All PCGs use the typical ATG as the start codon. Ten PCGs  use TAA as the stop codon while four  genes have TAG. The lengths of tRNA genes range from 71 to 80 bp and all tRNAs have the typical clover leaf structure. The sizes of 12S and 16S rRNAs are 1364 bp and 2834 bp, respectively.The complete mitogenome of H. okadai analysed by molecular phylogenetic tree of combined 14 PCGs sequences using the neighbour-joining (NJ) method with the K2P model in MEGA 6. H. okadai were clustered together as Halichondria sp. (KX244759), previously announced from GenBank. Their cluster is strongly supported by bootstrap values of 100% (H. okadai and Halichondria sp. is 99.6%, they were same species. To conclude, we confirmed that Halichondria sp. reported by Wang et al. (H. okadai. In this study, we determined the complete mitogenome of sponge H. okadai, and it will provide useful information for understanding of evolutionary history and phylogeny of the genus Halichondria in relation to the other genera within family Halichondriidae.The taxonomic position of  of 100% . The simg et al.  was H. o


The aim of this observational study was to follow-up patients with bedtime basal insulin (NPH insulin) added to metformin. In 285 patients with type 2 diabetes, a therapy with bedtime basal insulin added to metformin was started due to failure to achieve a glycaemic goal. Up until July 2019, 272 patients (95.4%) were followed-up . HbA1c decreased by −1.2% and bodyweight by −1.7 kg after a duration of 31.7 ± 29.1 (range 2–133) months. Severe hypoglycaemia did not occur. In 144/272 patients (52.9%), the therapeutic goal for HbA1c was achieved over 32.7 months. In 69/272 patients (25.4%), the HbA1c target was achieved over 25.0 months . In 36/272 patients (13.2%), the HbA1c goal was achieved until the submission of this manuscript (mean duration of treatment 57.4 ± 28.2 (range 13–121) months). Over 90% of patients with type 2 diabetes and failure of metformin reached their HbA1c goal with additional basal insulin at bedtime over several years in association with a reduction of bodyweight and without any event of severe hypoglycaemia. After the failure of comprehensive lifestyle management and patient education, metformin is the first-line drug therapy in patients with diabetes mellitus type 2 ,2. But dIf the metabolic control deteriorates and a refresher course in patient education fails, adding a second oral hypoglycaemic agent is a common strategy to improve metabolic control . HoweverThe German Federal Joint Committee (GBA) recommends human insulin as the first choice. However, long-acting insulin analogues  are widely used in Germany . To starTherefore, the aim of this longitudinal, observational study was to follow-up patients with bedtime intermediate-acting  insulin (NPH-insulin) added to metformin with special focus on glycaemic control, bodyweight, frequency of severe hypoglycaemia, insulin dose and time within individual treatment goals.Compliance with ethical standards. Ethical standard: The study was conducted in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki. Human and animal rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2008 (5). The study was approved by the Ethics Committee of the “State Chamber of Physicians of Hesse” .Between 2005 and 2016, 1240 patients with type 2 diabetes and metformin single-agent therapy presented in an outpatient centre for diabetology at secondary care level . All patn = 272) and drop-out (n = 13).In order to create a homogeneous cohort, we included only patients with the following criteria: clinically confirmed diabetes mellitus type 2 treated with metformin single-agent therapy for at least one year, non-achievement of the therapeutic goal for HbA1c and cognitive ability to carry out the insulin therapy independently. Furthermore, we declared the following exclusion criteria: pre-treatment with hypoglycaemic drugs other than metformin, contraindications for the continuation of treatment with metformin , consuming diseases and life expectancy less than four years, corticosteroid therapy, severe cognitive or psychiatric disorders, alcoholism, homelessness and pregnancy. Until 31 July 2019, 272 of 285 patients (95.4%) were re-examined and analysed retrospectively. Two patients died due to non-diabetic reasons, one patient has stopped therapy  and 10 individuals were not available. For patient characteristics at baseline see All patients were recommended to take part in a target group-specific, structured treatment and teaching programme (STTP) adapted from the education programme of Grüßer and Jörgens . The conTherapy with basal insulin at night was started with 8 IU. Basal insulin should be injected subcutaneously into the thigh immediately before bedtime. The dose determined by the physician should not be changed. Under no circumstances should the basal insulin be injected during the day.At the beginning of insulin therapy, all patients were instructed to measure blood glucose at 10 p.m., 2 a.m., 5 a.m. and 7 a.m. for two consecutive nights and to document the results in a specially developed protocol sheet. The protocol sheet was then examined by a physician and the insulin dose adjusted to suit the patient’s needs. This was done to prevent night-time hypoglycaemia. For reasons of economy and to reduce the risk of changes in insulin dose by the patient, daily self-monitoring of blood glucose was expressly discouraged. Patients should continue their dietary habits and metformin therapy unchanged.The patients visited the medical practice for follow-up every 3 to 6 months. At each visit, HbA1c was measured. If the individual target value for HbA1c was missed, the insulin dose was adjusted. If the HbA1c was below the individual target, the dose was reduced by 2 IU. At a dose of 4 IU, therapy with basal insulin was terminated. If the value was above the target, the insulin dose was increased by 2 to 4 IU. After each change in insulin dose, the patient was asked to measure and document blood glucose at 10 p.m., 2 a.m., 5 a.m. and 7 a.m. for two consecutive nights and to submit the protocol sheet to the physician. The insulin dose was left if blood glucose values had remained stable over the night. Therapy with basal insulin was terminated when a nightly drop in blood glucose was recorded while the target value for HbA1c was missed. Duration of successful treatment was defined when the last targeted HbA1c was measured.Clinical and routine laboratory data were recorded at baseline and at each visit, respectively, and documented in the electronic patient record. Baseline characteristics were collected at the time of the first injection of basal insulin.HbA1c was measured using “Adams A1c HA-8180V” with a normal range of 4.5 to 6.1%.Severe hypoglycaemia was defined as a condition with the necessity of glucagon injection  or intravenous glucose injection  with or without hospitalisation according to the guidelines of the German Diabetes Association . Frequent-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. To compare more than two groups, univariate ANOVA was used. Multiple linear regression was used to determine which factors lead to the longest possible therapeutic success with the combination of metformin and bedtime basal insulin. Duration of treatment (months) was determined as a dependent variable. Assumed variables were age, duration of diabetes, duration of metformin therapy, change of weight, baseline BMI, baseline HbA1c and change of HbA1c. Additionally, the successful therapy with bedtime basal insulin and metformin is shown in a Kaplan-Meier curve (Kaplan-Meier curves are defined as the probability of being free from an event in a given length of time).All continuous data are presented as mean ± standard deviation (SD). Categorical data are described by absolute and relative frequencies. To compare two groups, unpaired Significance was defined at the 0.05 level. An HbA1c change was considered as clinically relevant if the value changed by at least 0.5%. Statistical analysis was performed using the Statistical Package IBM SPSS Statistics 25 .p < 0.001, p < 0.001). Severe hypoglycaemic events did not occur in any patient.Successful treatment with NPH insulin and metformin was reached over a mean duration of 31.7 ± 29.1 months: Range 2 to 133 months (median duration: 22.0 months). In all participants, HbA1c decreased from 8.4 ± 0.9% (68.6 ± 9.6 mmol/mol) to 7.2 ± 0.8% : In 23 of 272 patients (8.5%), the therapeutic goal for HbA1c was not achieved after a mean duration of 4.5 ± 1.6 months (range 2–9 months)  despite Group B “treatment failure after long duration” (>9 months): In 144 of 272 patients (52.9%), the therapeutic goal for HbA1c was achieved over 32.7 ± 28.5 months. Mean insulin dose was 14.8 ± 4.9 IU. After 32.7 months a third antidiabetic agent was added or switch to conventional/intensified insulin therapy was necessary to reach HbA1c target.Group C “treatment failure because of overtreatment”: In 69 of 272 patients (25.4%), the therapeutic goal for HbA1c was achieved over 25.0 ± 24.4 months. After 25.0 months, basal insulin at night was discontinued because HbA1c was <6.5%. Subsequently, metformin was again prescribed as monotherapy. Additionally, weight was reduced from baseline to follow-up by −4 kg (over a 25 month period).Group D “ongoing treatment”: In 36 of 272 patients (13.2%), the therapeutic goal for HbA1c was achieved up to the 31 July 2019. After a mean duration of 57.4 ± 28.2 months (range 13–121 months), the combination of metformin and bedtime basal insulin is successfully performed. HbA1c decreased from 8.5 to 7.2%, weight from 91.0 to 88.4 kg . Mean inp < 0.001).In summary, 91.5% of the participants benefited from the combination of metformin and basal insulin . 8.5% had no advantage (Group A). Patients of Group A had a significantly higher baseline BMI than individuals in Group B, C and D . After aAfter the failure of metformin monotherapy, over 90% of patients with type 2 diabetes reached their individual HbA1c goal with additional application of NPH insulin without any event of severe hypoglycaemia over several years. About half of the patients maintained this diabetes therapy over 2.6 years before their diabetes therapy had to be intensified (Group B) and an additional 13% reach their individual HbA1c target by the manuscript submission (Group D).Furthermore, 25% could stop their insulin therapy after two years (Group C). We can only speculate as to the reasons, which may include eating habits. Maybe, these patients have changed their living habits and reduced their bodyweight. These patients lost 4 kg over two years. Moreover, weight reduction was associated with the longest duration of treatment with basal insulin. This may be due to the absence of insulin administered during the day.Only 8.5% of the participants had no benefit from adding basal insulin to metformin (Group A). After only 4.5 months, intensification of diabetes therapy with a third antidiabetic agent or switch to twice daily mixed insulin or prandial insulin was necessary. The reason could be due to the baseline weight. Patients of Group A had a higher BMI at baseline than people who benefit from a combination of metformin and basal insulin.After the failure of metformin, a possible option is adding basal insulin at bedtime recommended in the guidelines ,4 becausFurthermore, intermediate basal insulin injected in the evening only works until the next morning . In conclusion, the risk of hypoglycaemia is lower with once-daily basal insulin than conventional or intensified insulin therapy . There iIn contrast to our study with an HbA1c reduction of 1.2% and a weight reduction of 1.7 kg with basal supported oral therapy (insulin dose of 13 IU), after a mean follow-up of 2.6 years, Holman et al. showed in the 4T-Study [The APOLLO-Study with bedtime insulin glargine showed no severe hypoglycaemic event and an HbA1c reduction of 1.7%, but a weight gain of 3 kg in 44 weeks . Philis-Furthermore, there are some other studies showing that the combination of bedtime insulin plus metformin is superior against other therapy options ,11,12. TThe trial by Raskin et al. showed an HbA1c reduction of 2.4% and weight gain of 3.5 kg with bedtime long-acting insulin (glargine) plus metformin and other drugs, respectively, after 28 weeks . HoweverOverall, previous studies  found siA further reason might be patient education . HoweverIn an outpatient cohort, over 90% of patients with type 2 diabetes and failure of metformin monotherapy reached their individual HbA1c goal with additional basal insulin at bedtime over several years in association with a reduction of bodyweight as well and without any event of severe hypoglycaemia.