To investigate the serum level of osteocalcin (OC), also known as bone Gla protein, in maintenance hemodialysis (MHD) patients and its correlation with abdominal aortic calcification (AAC).From July 2017 to February 2020, we enrolled 108 adult MHD patients. Routine fasting blood laboratory tests were performed before the start of the second hemodialysis in a week. Abdominal aortic calcification score (AACs) was assessed within 1 month. Pearson correlation and Logistic regression were used to analyze the data.The OC level was 231.56  ng/ml, elevating significantly in this group of MHD patients. It had a positive correlation with serum phosphorus , intact parathyroid hormone(iPTH) , fibroblast growth factor 23(FGF23)  and a negative correlation with age. Based on the AACs, patients were divided into two groups. Serum OC level were higher in patients with AACs≥5 (p=0.032). A multiple logistics regression analysis revealed that age  and OCwere risk factors for high AACs(≥5).The study implicated that OC elevated significantly in this group of MHD patients.OC is positively correlated with phosphorus, iPTH, FGF23, and a negative correlation with age. OC was a risk factor for vascular calcification in this study, but this study did not classify osteocalcin as c-OC and unOC. Whether unOC is associated more directly with vascular calcification requires further study. Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a common complication in end-stage renal disease(ESRD). CKD–MBD is characterized by abnormal mineral markers, abnormal bone metabolism, and soft tissue calcification, such as vascular calcification (VC) . VC is tAbdominal aortic calcification(AAC) is highly prevalent in the hemodialysis population . KauppilThe pathophysiologic mechanisms underlying the process of VC in ESRD have not yet been fully elucidated. VC has been associated with numerous traditional cardiovascular risk factors, including advanced age, hypertension, diabetes, and dyslipidemia, as well as with nontraditional cardiovascular risk factors, such as hyperphosphatemia, hyperparathyroidism, and excessive calcium intake. Today VC in ESRD is considered as an active, complex process, where the first, crucial step toward calcification is the transformation of vascular smooth muscle cells (VSMCs) to osteoblast phenotype, a process similar to bone formation .Osteocalcin (OC), also known as bone Gla protein, a highly specific marker involved in bone formation, is the most abundant non-collagenous peptide found in the mineralized matrix of bone, concomitantly being an intriguing hormone and expanding the endocrine function of the skeleton with far-reaching extra-osseous effects. OC is produced primarily by osteoblasts in bone, it is also produced locally by VSMCs. The detection of OC in circulation raised the question whether it is involved in the process of arterial mineralization. The carboxylation pathway, vitamin K mediated, is pivotal for the transformation of OC from the undercarboxylated form (ucOC) into the fully functional carboxylated form (c-OC). CKD patients often show a subclinical vitamin K deficiency . SchurgeThis study aimed to explore the relationship between the serum OC level and other indices of VC and to determine whether serum OC level is the risk factor affecting VC in MHD patients with CKD–MBD.The study protocol was approved by the ethics committee of 960th Hospital of the PLA Joint Logistics Support Force (protocol number: 20140214). The study conforms to the principles outlined in the Declaration of Helsinki, and written consent was obtained from all patients before the enrollment.We performed an observational cross-sectional study on 108 clinically stable MHD patients, enrolled from July 2017 to February 2020, at the blood purification center of the 960th Hospital of the PLA Joint Logistics Support Force. They were screened continuously from 260 patients in our department. All of the 108 subjects completed the study Figure 1The inclusion criteria were as follows: (1) age not less than 18 years, (2) dialysis vintage for more than 3 months, (3) patient or legally accepted representative willing to sign Data Release Consent Form. The exclusion criteria were as follows: (1) patients’ life expectancy <6 months. (2) patients with acute kidney injury, active inflammatory diseases, parathyroidectomy, evident malignancies, and abnormal liver function, (3) concomitant diseases that affect calcium status and soft tissue calcifications ,(4)patients on anticoagulants such as warfarin.The dialysis regimen for all MHD patients was thrice a week, 4 h per session. The dialysate calcium concentration was 1.5 mmol/L, blood flow was 200–260 mL/min, and dialysate flow was 500 mL/min. The recommended protein intake ranged from 1 to 1.2 g/kg per day. The drugs dose administered for regulating calcium, phosphorus, and intact parathyroid hormone (iPTH) was as per the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder Guideline Update . ClinicaThe complete osteocalcin (amino acid 1-49) is unstable in peripheral blood. The amino acid between 43-44 carboxyl end is easily hydrolyzed by protease, and the N-mid fragment is much more stable. In this study, the stable N-mid and intact osteocalcin in serum were detected by the kit . This result reflects the value of total osteocalcin in serum. It should be noted that this test does not distinguish between c-OC and unOC. A detailed test method can be found in the Abdominal aortic calcification (AAC) is assessed within 1 month of admission  by semiqData management and analysis were performed using SPSS Statistics 17.0 and a P-value of < 0.05 was considered statistically significant. All continuous variables that follow a normal distribution were expressed as mean ( ± standard deviation), and variables without normal distribution were expressed as median (interquartile range). Categorical variables were expressed as number (percentage). Student’s t test or Mann–Whitney U test (2-tailed) were performed to determine the between-group differences. The chi-squared test was used to compare categorical variables. Pearson correlation was used to determine the correlation, bivariate relationship, and strength of association among variables. A multiple logistics regression analysis was performed to investigate the determinants of AAC.The OC level of all 108 patients was 231.56  ng/ml. It was higher than the normal range provided by our laboratoryTable 1.AACs scores higher than 5 were reported to have predictive value for cardiovascular disease in hemodialysis patients , 13. BasPearson correlation analysis revealed that OC was positively correlated with serum phosphorus , iPTH , FGF23 , AACs , and a negative correlation with age . There was no correlation of OC with serum calcium , total alkaline phosphatase , and dialysis vintage .2 remained almost unchanged, we removed DM and PTH from the variables. Finally, the multiple logistics regression analysis revealed that age  and OC  are risk factors for high AACs   and low AACs group(AACs <5). In the process of logistic regression, we grouped some variables. The assignment method of grouping variables was shown in <0.0001) Table 3.MHD patients with CKD-MBD experience severe mixed intimal and medial vascular calcification, which contributes to the increased cardiovascular mortality and morbidity . VC is avia increasing the number of OC-positive endothelial progenitor cells . The patients/participants provided their written informed consent to participate in this study.All authors contributed to the article and approved the submitted version.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.


BackgroundInfusion of crystalloids fluid replacement therapy tends to cause a greater expansion of intravascular volume. However, colloids can affect blood coagulation leading to greater blood loss and transfusion requirements. This study compared the intraoperative and postoperative blood loss with Ringer’s lactate (RL) versus 6% hydroxyethyl starch (HES) 130/0.4 as infusion fluid during cardiac surgery.MethodsEighty adult male and female patients undergoing elective cardiac surgery were randomly assigned to receive either RL or 6% HES 130/0.4 20 ml/kg during off-pump coronary artery bypass graft (OP-CABG) surgery. Intraoperative blood loss and 24 hours postoperative chest tube drainage were the primary outcomes. Simultaneously, blood transfusions, thromboelastometry variables, total fluid requirement, renal function, and intensive care unit (ICU) stay were assessed.ResultsThe intraoperative blood loss was similar (p > 0.05) with HES (716 ml) and RL (658 ml). Postoperative chest tube drainage was higher (p < 0.05) with HES (513 ml) as against RL (449 ml). The total fluid requirement was higher in the RL group. Alteration of thromboelastometry variables, renal function, and ICU stay was comparable between the two groups. Postoperative chest tube drainage was less with the use of RL during cardiac surgery. A lesser total fluid requirement in the HES group did not lead to any improvement in renal function and the length of ICU stay.ConclusionsCrystalloids (RL) provide similar outcomes to HES and can be used as substitutes to colloids during cardiac surgery. However, further large-scale multicenter studies with varied indications can be suggested to substantiate the equivalence of crystalloids to colloids in perioperative management. Patients with coronary artery bypass graft (CABG) surgery may be hemodynamically unstable during the immediate postoperative period and need fluid support . ColloidFive percent human albumin 5% HA) has been in use for a long time during cardiac surgery as a colloid. However, due to its cost and availability, colloids such as hydroxyethyl starches (HES) are being used. However, HES preparations have shown to impair coagulation and renal function ,5. HES h% HA has The aim of this study was to compare the effect of 6% HES solution with RL solution on intraoperative and postoperative blood loss when used as the main infusion during cardiac surgery in patients after CABG surgery.Study participantsPatients posted for coronary artery bypass graft (CABG) surgery at the study sites were screened for eligibility based on the study inclusion/exclusion criteria. The study documents were reviewed and approved by the Institutional Ethics Committee (IEC). Male and female patients between 30 and 70 years of age who were planned to undergo elective off-pump (OP) CABG and those who signed the informed consent were included. Patients with known allergy to HES, presence of anemia, coagulation disorders (INR > 1.2), activated partial thromboplastin time > 40 seconds, platelet count < 0.5 million cells/cubic mm), and left ventricular ejection fraction (LVEF) < 40% were not included. Also, those with serum creatinine > 1.5 mg/dl or those who are receiving any anticoagulants or antiplatelet therapy within seven days before surgery were excluded. A total of 98 patients were screened out of which 80 were enrolled and randomized in this randomized, comparative, double-blind study.Randomization, blinding, and fluid regimenPatients were randomized to receive either RL (n = 40) 20 ml/kg body weight or HES (n = 40) 20 ml/kg body weight. Randomization was performed using the sealed envelope technique. The hospital pharmacy prepared the study solutions that were supplied in identical 500 ml bottles. Bottles and infusion sets were wrapped with opaque covers for blinding. Normal saline (0.9%) was used as fluid for any additional requirement.ProceduresAnesthesia was induced with thiopental (5 mg/kg) and fentanyl (5 mcg/kg), and tracheal intubation was facilitated by rocuronium (0.6 mg/kg) intravenously. Propofol (1 mg/kg/hr) and fentanyl (2 mcg/kg/hr) infusions were used for maintenance. Muscle paralysis was maintained with rocuronium infusion (0.3 mg/kg/hr).Fluid administration was started with 250-500 ml of study solution during induction of anesthesia. The remaining allotment of the study solution was used subsequently. Any additional fluid requirement was fulfilled with 0.9% normal saline (NS) in both groups. Baseline thromboelastometry variables were measured after induction of anesthesia. All patients received the same standard dose of heparin and tranexamic acid. Activated clotting time (ACT) was measured regularly and maintained above 300 seconds till the completion of the anastomosis. After the procedure, the heparin effect was reversed using protamine (1.5 mg for each 100 IU of heparin given). Norepinephrine was used, if necessary, to maintain mean arterial pressure > 60 mm Hg. Transoesophageal echocardiography was used to assess ventricular function. Intraoperative blood loss was measured by measuring blood in the suction bottle and mops (by gravimetric method). PRBCs were transfused when hemoglobin (Hb) was less than 7 gm%. The administration of fresh-frozen plasma (FFP), platelets, and coagulation factors was based predominantly on thromboelastometry variables and the pre-operative and postoperative coagulation profile of each patient.After the procedure, the patient was transferred to the intensive care unit (ICU), and further fluid management and inotrope support were at the discretion of the attending consultant and not controlled by protocol. Postoperatively, the amount of chest drains for 24 hours and blood transfusion requirements were measured. Blood samples were collected to assess complete blood counts, renal function tests, and thromboelastometry 24 hours after surgery.Statistical analysisAll the continuous variables were assessed for normality using Shapiro-Wilk test. Normally distributed data are presented as means with standard deviation (SD), whereas non-normal data are presented as medians with interquartile range (IQR). All the categorical variables were expressed either as percent or proportion. Comparison of normally distributed continuous variables was done by independent sample test or analysis of variance (ANOVA). Comparison of non-normally distributed continuous variables was done by Mann-Whitney U test or Kruskal-Wallis H test.Comparison of categorical variables was done by Chi-square test or Fisher’s exact test based on the number of observations. Data entry was done in Microsoft Excel , and data analysis was carried out using Statistical Package for the Social Sciences (SPSS) version 17.0 . All the p-values < 0.05 were considered statistically significant.All randomized patients completed the study as per the protocol. Figure  The pre-operative data, postoperative data, and the change from pre-operative data are presented in Table Figure Figure There were no differences between the HES and RL groups (adjusted for covariates) for change in laboratory parameters Table . This siOptimization of perioperative fluid therapy helps in reducing the morbidity and mortality associated with CABG. The type of fluid to be used is still controversial. Colloids have the theoretical advantage of greater retention in the intravascular compartment, thereby reducing the fluid requirement. However, a high cost and higher chances of coagulopathy and renal injury limit its use. The various side effects associated with first and second degree HES such as coagulopathy, anaphylactoid reactions, renal impairment, and increase in serum amylase levels led to development of newer starch-based volume expanders like 6% hydroxyethyl starch 130/0.4 . The molWe compared the effect of RL solution versus HES (130/0.4) 6% solution on intraoperative and postoperative blood loss when used as the main infusion during cardiac surgery in patients after CABG surgery. In our study, there was no significant difference in the extent of hemodilution seen in the two groups. The postoperative chest tube drainage was higher in the HES group, but that did not lead to any significant increase in the need for blood transfusion. This can be explained by the lower cut-off hemoglobin of 7% for transfusing blood, which we followed in the study. The reduction in total fluid requirement in the HES group did not translate into any reduction in the ICU and overall hospital length of stay. Alteration of coagulation and renal function assessed by thromboelastography (TEG), serum creatinine, and urine output was also comparable in the two groups.The concentration of intravenous (IV) solution influences the initial volume effect, i.e., 6% HES solutions is iso-oncotic in vivo, with 1 L replacing about 1 L of blood loss, whereas 10% solutions are hyperoncotic, with a volume effect considerably exceeding the infused volume (about 145%). The HES (130/0.4) 6% is a low molecular weight third-generation starch prepared to have minimal effects on the coagulation, kidney, and serum amylase levels apart from being less immunogenic . Also, iThe study had few limitations in terms of a small sample size and a study restricted to one indication and a single tertiary care center. Our study involved less intraoperative blood loss, but the hemodynamic parameters may be altered during moderate to severe blood loss, and the patients may require colloid or vasodilators. Hence, the observations could not be generalized to other surgical conditions and the entire population.Crystalloids may be a safe and cost-effective fluid replacement option during perioperative period in patients undergoing OP-CABG cardiac surgery in economically challenged countries. However, further large-scale multicenter studies with varied indications are recommended to substantiate the equivalence of crystalloids to colloids in perioperative management.


Conclusions. eGFR, as calculated with the Donadio formula, was an independent predictor of mortality in patients with HF as well as the measurements derived from MDRD4 and CKD-EPI formulas, but less accurate than Cockroft-Gault.The estimation of glomerular filtration rate (eGFR) provides prognostic information in patients with heart failure (HF). Bioelectrical impedance analysis may calculate eGFR (Donadio formula). The aim of this study was to evaluate the impact of the Donadio formula in predicting all-cause mortality in patients with HF as compared to Cockroft-Gault, MDRD-4 , and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. Four-hundred thirty-six subjects with HF  were enrolled. Ninety-two patients (21%) died during the follow-up . The area under the receiver operator characteristic curve for eGFR, as estimated by Cockroft-Gault formula (AUC = 0.75), was significantly higher than those derived from Donadio (AUC = 0.72), MDRD-4 (AUC = 0.68), and CKD-EPI (AUC = 0.71) formulas. At multivariate analysis, all eGFR formulas were independent predictors of death; 1 mL/min/1.73 m The assessment of glomerular filtration rate (GFR) is mandatory in the management of patients with heart failure (HF). About 23% of patients with HF show worsening renal function (WRF) as a consequence of the impairment in kidney perfusion, pharmacological treatments, and neuro-hormonal activation ,2,3. TheThe worsening in kidney function in both acute (AHF) and chronic (CHF) patients is related to poor outcomes . It is aNo matter the type of HF ,6, WRF iTherefore, the need for monitoring renal function is one of the mainstays in the general management of patients with both AHF and CHF. Several formulas and equations have been created to assess and monitor the performance of the kidneys during hospital stay for HF: Cockroft-Gault, Modification of Diet in Renal Disease Study (MDRD-4), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are the best representative formulas in this setting ,8,9. TheIndeed, the influence of body weight, muscular mass, and creatinine production may limit the use of creatinine-based formulas. The application of bioimpedance analysis (BIA) to the estimation of glomerular filtration rate (eGFR) may provide further insights to clinicians ,18. DonaThe aims of this study were to evaluate the prognostic value of eGFR as assessed by the Donadio formula, and to compare it to Cockroft-Gault, MDRD-4, and CKD-EPI formulas in HF patients.This was a retrospective study based on a cohort of patients who were consecutively admitted to the Cardiology Unit of “F. Perinei” Hospital in Altamura , due to AHF or CHF, between January 2016 and November 2019.The dataset included the clinical/anthropometric characteristics of the study population, blood biochemical data, BIA measurements, and pharmacological treatments. The left ventricular ejection fraction (LVEF) was calculated with Simpson’s method by means of echocardiography. BNP levels were assessed using a microparticle enzyme immunoassay , while serum creatinine was measured with a Beckman Coulter AU 680 chemistry analyser . All these measurements were routinely performed for all patients at admission to our ward.Exclusion criteria consisted of myocarditis, pericarditis, pulmonary embolism, acute coronary syndrome, and recent cardiac surgery intervention.The primary endpoint was all-cause death as ascertained from available medical records or National Death Records.All patients gave their written informed consent to collect all the data related to their hospital stay. The performance of the study was in agreement with the Declaration of Helsinki. The study was approved by the local Institutional Review Board of the ASL BARI .2:(1)The Donadio formula was obtained by using tetrapolar impedance plethysmography, which emitted a single alternating sinusoidal current at 50 kHz . The values of resistance and reactance were measured, and BCM was calculated according to the manufacturer’s equation. Urinary Creatinine Excretion (Ucr) estimation was obtained as follows: Ucr (mg/24 h) = BCM (Kg) × 30.2 + height (cm) × age (years) × 8.35 − 2222, while eGFR was calculated as: Ucr (mg)/plasma creatinine (mg/mL) × 1440 min ,18;(2)The Cockroft-Gault formula: (140 − age) × (weight)/(72 × serum creatinine) × 0.85  .t-test or Mann-Whitney U-test where appropriate. Receiver-operating characteristic (ROC) curve analysis was performed to calculate the area under the curve (AUC) values, and the optimal cut-off values for mortality were calculated as the point of maximum sensitivity and specificity. The AUCs were compared using Hanley and McNeil tests. Survival was calculated using Kaplan-Meier analysis.Because the distribution of BNP levels had a skewed distribution, a logarithm was used to obtain an optimal residual analysis. The comparisons between survivor and non-survivor groups were performed with a Student’s r > 0.60 for all), blood urea nitrogen dropped from multivariate Cox analysis because it was redundant. p-values below 0.05 were defined as statistically significant. The analyses were performed using STATA software, version 12 .Univariate and multivariate analyses were performed to evaluate hazard ratios (HR) between eGFR formulas and all-cause mortality using Cox for proportional hazards. For multivariate analysis, we adjusted for variables considered to be of potential prognostic impact, such as ischemic heart disease, history of diabetes, atrial fibrillation, NYHA functional class, LVEF, serum sodium, BNP, hemoglobin, and HF status (AHF vs. CHF). After Pearson’s test between blood urea nitrogen and eGFR formulas . ROC curves analysis tried to evaluate the role of eGFR formulas in predicting all-cause mortality risk and the optimal cut-off points to be considered for the best prediction (Ninety-two (21%) patients died during the follow-up . Patients with AHF showed a significantly higher mortality rate (31%) than those with CHF (13%) . The literature provides concerns about this adjustment in clinical practice, as it may alter the correct estimation of eGFR, for example, in obese individuals ,41. Neve2) [2) might effectively impact on eGFR calculations. Although the Donadio equation seemed to perform well in mildly obese individuals [Equations may also underestimate eGFR in obese patients, above all when considering patients with severe forms of obesity (BMI > 35 Kg/m2) ,43. Indeividuals , the rolThe lack of information about proteinuria and albuminuria is a further matter of debate for this research, above all in relation to the percentage of the enrolled diabetic patients (24%). The impact of these parameters on cardio-renal syndrome has been previously established . AlbuminThe recent guidelines of the European Society of Cardiology on the management of HF  outlinedA further limitation derives from the single center experience. Attempts to include further centers are ongoing, in the interest of demonstrating the validity of the results on larger populations.The CG formula was confirmed to be an independent predictor of all-cause mortality in patients with AHF and CHF. The CG formula was superior to MDRD-4, Donadio, and CKD-EPI in the overall assessment of the prognosis of patients with HF. In addition, the application of BIA in a real-life cohort of patients with HF confirmed its prognostic value. Beyond the evaluation of congestion, BIA allows for the calculation of GFR and the prediction of adverse events related to kidney dysfunction in HF patients.


Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.NCT01949129).FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI  versus chemoconditioning . Two-year cumulative incidence of relapse and treatment-related mortality were 0.12  and 0.02  following TBI and 0.33  and 0.09  following chemoconditioning, respectively.Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT. With a view to improving options for patients, the FORUM randomized, controlled, open-label, international, multicenter, phase III trial was designed to investigate whether preparative combination chemotherapy is noninferior to TBI.Knowledge GeneratedP < .0001) following TBI versus 0.75  following chemoconditioning.After random assignment of 417 pediatric patients with high-risk ALL, a futility stopping rule was applied because patients receiving chemoconditioning with fludarabine, thiotepa, and either busulfan or treosulfan had inferior overall survival (OS) to those receiving TBI plus etoposide. Two-year OS was 0.91  with TBI-based versus busulfan-based conditioning.10 However, TBI has lifelong adverse effects. Impairment of growth, gonadal function, and cognitive function, cataracts, and secondary malignancies are more frequent after TBI than irradiation-free conditioning regimens.13A small, randomized, controlled trial found significantly higher event-free survival (EFS) with TBI, etoposide, and cyclophosphamide versus busulfan, etoposide, and cyclophosphamide conditioning in pediatric ALL patients receiving an unrelated donor HSCT, but a nonsignificant difference for those receiving a related donor HSCT.17 Head-to-head prospective comparisons of chemoconditioning versus TBI-containing regimens have not evaluated disease-free survival or acute and long-term adverse events (AEs).New chemotherapeutic agents and combinations have brought promise of fewer acute and late effects compared with TBI that may outweigh the risk of leukemic reappearance; in particular, fludarabine, thiotepa, targeted busulfan, and treosulfan show promise.19 could replace TBI in pediatric patients with high-risk ALL.We conducted this prospective, randomized, controlled trial to investigate whether optimal chemoconditioning regimensNCT01949129). We report on the randomly assigned part, conducted in 88 centers in 21 countries, with the primary aim to test noninferiority of chemoconditioning versus TBI with regard to overall survival (OS).The For Omitting Radiation Under Majority age (FORUM) study is an international, randomized, open-label, phase III study  and statistical analysis plan were approved by the investigational review board or independent ethics committee and national authorities for each center. The trial was performed in accordance with the Declaration of Helsinki principles.An Independent Data Monitoring Committee (IDMC) periodically reviewed safety and efficacy data. Per stopping rules, random assignment would end if chemoconditioning was significantly worse than control . The IDMC recommended random assignment suspension in December 2018. After extensive data analyses, we confirmed the findings and stopped random assignment on March 31, 2019.Patients eligible for random assignment had high-risk ALL, were ≤ 18 years old at initial diagnosis, 4-21 years old at HSCT, had an indication for allogeneic HSCT, were in complete morphological remission pre-HSCT, and had an MSD or MD allelic matched at nine or 10 out of 10 HLA loci. Exclusion criteria included prior HSCT, pre-HSCT cranial radiation > 18 Gy at any time or > 12 Gy in the previous 24 months, pre-existing severe organ toxicities, pregnancy, or secondary malignancy. Written informed consent was provided by patients, parents, or legal guardians.The recommended stem cell source was bone marrow or cord blood from an MSD, or bone marrow, peripheral blood stem cells, or cord blood from an MD.2; upper total dose 3.6 g) once on day 3 before HSCT or to intravenous fludarabine 30 mg/m2 once a day over 5 days, thiotepa 5 mg/kg twice a day for 1 day, and either treosulfan 14 g/m2 once a day for 3 days or busulfan over 4 days. National coordinators chose busulfan or treosulfan. Busulfan was dosed once, twice, or four times a day according to local guidelines, age, and body weight, commonly with therapeutic drug monitoring and pharmacokinetic dose adjustment. TBI was delivered from a linear accelerator at 12 Gy in six fractions over 3 days with lung shielding at 10 Gy.Patients were randomly assigned 1:1 either to TBI plus 60 mg/kg intravenous etoposide (1.8 g/mGraft-versus-host disease (GVHD) prophylaxis was contingent upon donor type and stem cell source. MSD recipients received cyclosporine A only, while MD recipients also received methotrexate and antithymocyte globulin.−3 for flow cytometry or > 10−4 for PCR. Relapse was defined as ≥ 5% leukemic blasts in bone marrow and/or detection in extramedullary sites .Complete remission (CR) was defined as ≤ 5% bone marrow blasts and no evidence of extramedullary disease. Minimal residual disease (MRD) in bone marrow was assessed by flow cytometry or polymerase chain reaction (PCR) in the 2 weeks before conditioning therapy. MRD positivity was defined as > 1020Clinicians assessed patients for AEs, adverse reactions, serious AEs, and suspected expected or unexpected serious adverse reactions per good clinical practice guidelines. AEs were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Serious AEs were fatal, life-threatening, or other medically important serious events, leading to intensive care unit admission . Acute and chronic GVHD  were assessed at each visit and graded as previously described.The primary end point was OS from random assignment date. Death from any cause was considered an event. Patients lost to follow-up without an event were censored at last follow-up. Secondary end points included EFS, cumulative incidence of relapse (CIR), TRM, aGVHD, cGVHD, toxicity at day 100, and GVHD-free, relapse-free survival.The design was a noninferiority study with an 8% margin. With a sample size of 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and a one-sided alpha of 5%, 80% power was calculated. Early stopping made follow-up too short for the intended primary analysis to be feasible.In FORUM, patients randomly assigned to TBI yet who received chemoconditioning could be anticipated to be at lower risk than patients randomly assigned to chemoconditioning yet who received TBI, meaning that a per-protocol analysis might favor chemoconditioning. Accordingly, the ITT population was protocol-specified for the primary analysis . The results reported are from ITT analyses unless otherwise indicated . For the modified as-treated and univariate analyses, pairwise comparisons were performed if the global Between April 18, 2013, and March 31, 2019, a total of 543 patients were screened and 413 were randomly assigned , OS was significantly higher following TBI versus chemoconditioning, with a 2-year probability of OS of 0.91  versus 0.75 , respectively , 2-year EFS (but not OS) was significantly higher with TBI versus chemoconditioning .For 224 patients transplanted in CR1, 2-year OS and EFS were 0.85  and 0.80 , respectively, with both being significantly higher in the TBI versus chemoconditioning arm (Data Supplement). For 87 patients transplanted in second complete remission (CR2) who relapsed > 30 months after diagnosis, 2-year OS and EFS were 0.89  and 0.69 , respectively; both end points were significantly higher in the TBI versus chemoconditioning arm (Data Supplement). In 69 patients with a P = .0269). Of the TBI, busulfan-containing chemoconditioning, and treosulfan-containing chemoconditioning groups, 7/194 (3.6%), 7/96 (7.3%), and 9/90 (10.0%) patients, respectively, died without relapse  following TBI and 0.09  following chemoconditioning . Two-year CIR was 0.12  following TBI and 0.33  following chemoconditioning ; 39 received salvage therapy with curative intent. In patients who relapsed post-transplant, there was no significant difference in OS between conditioning regimens .There were no suspected unexpected serious adverse reactions. Regimens were associated with substantial degrees of reported toxicity, as expected. The most common grade 3-4 AEs at day 100 in all arms were cytopenia, mucositis, nausea, and infection (Data Supplement).In the modified as-treated analysis, TRM occurred in 7/194 patients following TBI, 7/96 patients after busulfan-based chemoconditioning, and 9/90 patients after treosulfan-based chemoconditioning. The most common causes were infection, organ toxicity, or GVHD, with no significant difference between conditioning regimens (Data Supplement).There was no significant difference in the proportion of patients experiencing aGVHD or cGVHD between arms Table . Of 396 P = .0041). Two-year TRM was significantly higher for patients with grade 3-4 aGVHD versus those with grade 0-1 or 2 .Two-year EFS across the whole study population stratified by aGVHD grade 0-1, 2, and 3-4 was 0.72 , 0.85 , and 0.54 , respectively (No significant difference in the incidence and severity of aGVHD was observed when patients were stratified by donor type or conditioning regimen (Data Supplement). Two-year cumulative incidence of cGVHD did not significantly differ between arms Table .P < .0003; Table The probability of GVHD-free, relapse-free survival at 2 years was 0.72  following TBI and 0.51  following chemoconditioning (P = .016) (Data Supplement). Analysis of OS by risk factor and conditioning regimen is shown in Figure In univariate analyses, MSD and CR1 significantly predicted better OS and EFS. Female patients had a lower probability of EFS  versus male patients , EFS , and relapse rate  (Table P = .0371). Surprisingly, the presence or absence of MRD positivity pretransplant assessed by flow cytometry or PCR did not significantly influence OS or EFS in subgroup or multivariable analyses.In multivariable analyses, conditioning regimen reached statistical significance for OS  in pediatric patients with high-risk ALL. Despite several hurdles in initiating the trial in over 20 countries and 5 continents, FORUM was made possible by collaboration between international study groups. Patients underwent allogeneic HSCT according to standardized transplant indications, donor selection criteria, stem cell source, GVHD prophylaxis, and conditioning regimen. Investigators were given recommendations for monitoring MRD and intervention strategies to reduce MRD pretreatment and post-transplant. Strong random assignment compliance, rigorous data collection, and careful, prompt interim analysis allowed detection of the inferiority of chemoconditioning to TBI plus etoposide.21 In a recent retrospective analysis of over 3,000 pediatric patients with ALL, no significant difference in OS was observed between patients in CR1 transplanted after TBI versus chemoconditioning; however, in patients transplanted in CR2, the TBI arm had significantly better OS, EFS, relapse incidence, and TRM.22 A similar trend was observed in our subgroup analyses; however, our study was not powered to assess statistical significance in a sample size of 413 patients. Highly encouraging 2-year OS and EFS of 0.91 and 0.91, respectively, were observed for patients transplanted in CR1 after TBI, which we believe is the highest survival rate reported in HSCT trials in childhood ALL.In a retrospective trial, it was shown that chemoconditioning can supplant TBI at least in some young patients with ALL and favorable prognosis pre-HSCT (CR1 or age < 12 years).Patients receiving TBI had a significantly lower risk of relapse and TRM than those given chemoconditioning. This resulted in early termination of random assignment.23 could jeopardize the survival advantage of TBI plus etoposide.The majority of post-HSCT leukemic relapses in children occur within 24 months; thus, a dramatic change in Kaplan-Meier estimates of relapse with further follow-up is unlikely. In part, the difference in relapse risk between arms could be detected early due to the low rate of TRM . There was a plateau in the rate of relapse with TBI plus etoposide after 2.5 years, whereas an extended relapse cascade was apparent with chemoconditioning. The lack of an asymptote in relapse rate after chemoconditioning suggests that between-group differences may continue to widen over time. It is unlikely that secondary malignancies after TBI 24 Moreover, TRM with chemoconditioning in FORUM was low versus that previously reported.26 However, relapse incidence was still high, and the best chemotherapy-based preparative regimen for patients ineligible for TBI is unknown.28Randomized, international studies are a crucial, up-to-date evidence base supporting clinicians and patients in balancing treatment risks and benefits. We recommend TBI plus etoposide conditioning for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT. However, TBI is not always an option because of lack of facilities, young age, or comorbidities. Fludarabine, thiotepa, and either busulfan or treosulfan have shown high efficacy compared with other preparative regimens in previous studies of pediatric HSCT.30 Furthermore, established risk factors for post-transplant relapse 33 did not significantly impact outcomes. In multivariable analyses, only remission status  and conditioning type influenced OS and EFS. Add-on studies will explore the impact of busulfan, treosulfan, and antithymocyte globulin pharmacokinetics and pharmacogenomics on relapse rate.Despite variations including center size and heterogeneity of supportive care among the participating sites, TRM incidence was lower in FORUM than in other reports.35 Surprisingly, MRD level did not affect EFS in FORUM, probably because of patients' favorable MRD profile. It was a strong mission in our study to reduce MRD to below 10−3 with several treatment modalities including bispecific antibodies, inotuzumab, nelarabine, and other individualized methods, always bearing in mind that additional chemotherapy might increase the risk of TRM . Indeed, most patients had undetectable or very low levels of MRD in pretransplant marrow aspirates. Further analyses by pretransplant MRD will be conducted.We and others have previously demonstrated that high MRD levels pretransplant increased post-transplant relapse risk.In FORUM, relapse after transplant was associated with a low possibility of cure, which negated our premise that such patients would be salvageable by a second HSCT using TBI. This approach was associated with high TRM. The low number of patients who received chimeric antigen receptor T-cell therapy for post-transplant relapse (n = 10) does not allow conclusions to be drawn. However, emerging cell and immune therapies may offer the opportunity for rescue going forward, with potential for deep remissions and higher survival.36The higher probability of EFS observed in patients experiencing grade 2 aGVHD suggests that—at moderate severity—aGVHD is associated with a graft-versus-leukemia effect and protects from leukemia recurrence.Our findings cannot be generalized to centers with limited or no access to TBI. Another limitation is the relatively short median follow-up (2.1 years). Early random assignment closure limited sample size, making the prespecified primary analysis infeasible. The conditional power of the study was assessed to explore the likelihood that noninferiority could be concluded with a sample size of 1,000; which was found to be extremely low.39Recruitment without random assignment is ongoing as several questions of special interest require longer follow-up, that is, effect of conditioning on gonadal function, final height, organ functions, individual genetic variabilities, and secondary malignancies.P = .0003) following chemoconditioning might be a benchmark for future investigations, accounting for second malignancy risk.The composite end point of 2-year GVHD-free, relapse-free survival of 72%  following TBI plus etoposide and 51% (95% CI, 43% to 58%; In conclusion, pediatric patients with high-risk ALL who received myeloablative TBI plus etoposide prior to HSCT had a significantly better survival and lower relapse risk and TRM versus patients who received myeloablative chemotherapy.


GSTT1 and GSTM1 genes polymorphisms. This cross-sectional study in Burkina Faso consisted of 200 patients with essential hypertension and under treatment.Glutathione S-transferases have been associated with experimental resistance to some drugs. The present study investigated the factors associated with blood pressure control in patients with essential hypertension, especially the role of GSTT1 or GSTM1 gene polymorphisms . Current alcohol consumption , Physical inactivity , severe hypertension before any treatment  and heart damage  were statistically more frequent in uncontrolled essential hypertensive patients than controlled hypertensive patients.In the present study, 57.5% (115/200) of patients had their hypertension under control. No statistically significant difference was found between controlled and uncontrolled groups for anthropometric and biochemical parameters as well as for The online version contains supplementary material available at 10.1186/s13104-021-05658-w. Normalization of blood pressure (BP) in hypertensive patients significantly decreases the risk of stroke, heart diseases and improves patients' quality of life .GSTM1) and theta 1 (GSTT1) variants and the risk of developing essential hypertension and found that GSTT1-null genotype was associated with the risk of developing hypertension in Burkina Faso  < 140 mmHg and Diastolic Blood Pressure [DBP] < 90 mmHg) remain low in treated patients, estimated at 37.1% worldwide in 2010 and less than 10% in Sub-Saharan Africa in 2013 . It therina Faso . In the We conducted a cross-sectional study from July 15, 2017 to March 27, 2018, including 200 essential hypertensive patients followed in the cardiology department of Saint Camille Hospital of Ouagadougou (HOSCO), University Hospital Center Yalgado Ouédraogo (CHUYO) and the Medical Center of General Aboubacar Sangoulé Lamizana military Camp).The study population consisted of subjects under antihypertensive treatments regardless of gender or social characteristics, aged from 18 to 70 years old.Patients with secondary hypertension or no antihypertensive treatment, pregnant women and subjects not descendants from Burkina Faso were not included in this study.Controlled blood pressure was defined as an average of SBP < 140 mmHg and DBP < 90 mmHg for all patients  during tA standardized questionnaire was used to collect socio-demographic, lifestyle, clinical and biological data , overweight (25–30 kg/m2), normal weight (20–25 kg/m2) and underweight (≤ 20 kg/m2). We determined waist circumference (WC) and abdominal obesity in men was determined when WC ˃ 102 cm and in women when WC > 88 cm [Body mass index (BMI) was used to classify patients as obese . After amplification, PCR products were migrated on ethidium bromide-stained 3% agarose gel during 45 mn, bands were visualized under UV light at 312 nm using the Geneflash revelation device  and Epi Info (6.0) for data analyses. To determine sample size, we have taken into account following values: 95% of two-sided confidence level, 80% of power, odds ratio more than 2.2, ratio of controlled BP to uncontrolled BP 1.1, the proportion of controlled BP patients group having The Table p > 0.05).Regarding the socio-demographic and biochemical data, there was no significant difference between the controlled and the uncontrolled group . Additional file GSTM1 and GSTT1 variants between the controlled and uncontrolled SBP groups, between the controlled and uncontrolled DBP groups and between the controlled and uncontrolled hypertension group. We did not find any significant difference between those groups (p > 0.05). Stratified Analysis by age and sex also showed no association , physical inactivity , severe hypertension before any treatment  and heart damages, including left ventricular hypertrophy, left ventricular relaxation anomalies, left atrial hypertrophy and mitral insufficiency  were more frequent in uncontrolled group than controlled group and differences were significant. Age and sex-stratified analysis showed that this association is specific to women and elderly subjects for current alcohol use, specific to men and elderly subjects for cardiac damages and specific to women for diabetes mellitus , showed that the reduction of alcohol consumption increase the antihypertensive drugs response and that the management of alcohol consumption must be considered as a major component of antihypertensive therapy in alcoholics [However, we found that alcohol consumption, physical inactivity, the high grade of initial hypertension before any medication and cardiac affections were associated with uncontrolled BP. The influence of alcohol consumption on antihypertensive therapy has long been studied. Stewart et alcoholics . Concerncoholics  and Pesccoholics . It is bcoholics . Other mcoholics .Cardiac damages were found more in the uncontrolled group compared to the controlled group and this may be the cause or the effect of uncontrolled BP in essential hypertensive patients.., who showed that age, gender, educational level, marital status, professional status and residency did not affect the control of hypertension [., showed that it was associated with a poor control rate in Tanzania.Our results also showed that there was no association between socio-demographic characteristics, residence areas and gender with BP control, unlike other studies which have shown that women had a higher control rate than men in African countries . Our resrtension . HoweverGSTM1 and GSTT1 genes on the control of essential hypertension. Genetic factors may influence the pharmacokinetics and pharmacodynamics (tissue or organ responsiveness) of drugs [Considering the genetic aspects, we investigated the influence of variants of the of drugs .GST genes; however, associations have been demonstrated with the efficacy of other drugs in other pathologies and conditions. So in cancer cells, Gate et al., demonstrated that GST often show high levels of expression when compared to normal cells [GST Through their detoxification activity, might play an important role in the protection against the toxic effect of the antimicrobial agents which leads bacteria to become resistant to antibiotics [GSTM1 and GSTT1 have been associated with CD4 + count rising above 350 cells/mm3 suggesting that patients with homozygous deletion have slower disease progression and better drug response [GST genes, GSTM1 and GSTT1 are the most investigated in studies exploring genetic and drug response and they have been described as polymorphic in humans [GSTM1 and GSTT1 genes consist in the complete deletion of these genes (GSTM1-null and GSTT1-null) [GSTT1 leads to lack of enzyme activity. The human GSTT1 locus has been mapped on chromosome 22q11.23 (GRCh38/hg38). Regarding GSTT1, the null allele results from the homologous recombination of the left and right repeats of 403 bp, which results in a deletion of 54, 251 bps containing the entire GSTT1 gene. Whether it is GSTM1 or GSTT1, three distinct phenotypes can thus be observed in the population namely the “nonconjugators: 0/0”, the “low conjugators: 1/0” and “high conjugators: 1/1” [GSTM1 and GSTT1 respectively [GSTM1 and GSTT1 play a key role in the metabolism of certain drugs and xenobiotic through their participation in the second phase of xenobiotic metabolism. They facilitate the excretion of electrophilic compounds from cells by conjugating them to hydrophilic compounds with reduced glutathione [GSTM1 or GSTT1, therefore a decrease in the response to these drugs, hence the absence or decrease in BP control in those subjects. However our results showed that neither GSTM1 nor GSTT1 was associated with BP control. This at first sight indicates an absence of association between the active variants of these two genes and the low availability and efficacy of antihypertensive drugs. Some studies estimate that other members of the GST enzyme family must have compensated for the absence of a functional enzyme in the null genotype subjects [In our study, out of 99 patients, 96 used vasodilator drugs  which reduced blood pressure by dilating or preventing constriction of the blood vessels . The remal cells  and thisal cells . It haveibiotics . In Ghanresponse . Among Gn humans . The mosT1-null) . Similarrs: 1/1” . The “noectively , 38, whiectively  and othetathione , 42. Thusubjects , 44, whiGSTM1 and GSTT1 deletion polymorphisms and systolic or diastolic BP control. The patient’s lifestyle seems to be more determining in BP control under treatment than studied genetic factors. Especially alcohol consumption and physical inactivity are associated with a poor control or uncontrolled BP. In addition, given the fact that advanced disease stage, with or without cardiac complications, is also linked to an uncontrolled BP, early diagnosis should be therefore encouraged for effective management and for better therapeutic responses.In this study, we have not detected any apparent link between Our study could have certain limitations, in particular the size of the study population and the lack of information on adherence to antihypertensive therapy. These observations could be taken into account in future studies.Additional file 1: Figure S1.GSTM1, GSTT1 and β-globin genes and corresponding bands in electrophoresis gel. This file shows corresponding bands of GSTM1, GSTT1 and β-globin genes in electrophoresis gel. The number 1 through 14 represents individual sample and M represents Molecular weight marker. The strategy to identify presence or absence of GSTM1or GSTT1was as followed: to validate a PCR product (corresponding to a sample), we must have a band corresponding to β-globin and presence or absence of GSTM1 or GSTT1 was indicated respectively by the presence or absence of bands corresponding for each gene.Additional file 2: Table S1. Level of treatment and antihypertensive drugs used by patients. This file shows the proportion of antihypertensive drugs used by study participants.Additional file 3: Table S2. Sex and age stratified analysis of association between GSTM1 and GSTT1 variants with essential hypertension control. This file shows a stratified analysis of the association between GSTM1 and GSTT1 gene variants with essential hypertension control in order to highlight the probable interactions.Additional file 4: Table S3. Age and sex-stratified analysis of non-genetic factors affecting blood pressure control in patients with essential hypertensive. This file shows a stratified analysis by sex and age of non-genetic factors affecting blood pressure control in patients with essential hypertensive to highlight the probable interactions.Additional file 5: Data collection sheet. Information sheet and questionnaire. This file shows the fact sheets used to explain the study during the recruitment of the participants and the questionnaire which served for the data collection.


IgA nephropathy (IgAN) is the most frequent primary glomerulonephritis worldwide. Due to its heterogenicity, there is a need to establish robust biomarkers for IgAN, to support treatment decisions and evaluate the risk of progression to end-stage renal disease. Using both clinical and histopathological data, derived from renal biopsies, we aimed to find predictors of renal function deterioration and proteinuria reduction. Clinical and histopathological data of 80 patients with biopsy proven IgAN were analyzed. In a multivariate logarithmic regression model, the presence of endocapillary hypercellularity (E1) predicted a decline in estimated glomerular filtration rate (eGFR)of at least 50% with an odds ratio (OR) of 15.2, whereas serum albumin concentration had a negative influence on eGFR deterioration (OR 0.2). In the second multivariate model, the extent of interstitial fibrosis predicted the worsening of eGFR by 50% (OR 1.1) and serum albumin concentration had a protective impact (OR 0.1). In the univariate logarithmic regression, both the extent of interstitial fibrosis and the presence of endocapillary hypercellularity negatively correlated with the reduction in proteinuria below 1.0 g/24 h with an OR of 0.2 and 0.9, respectively. In our paper, we confirmed the utility of histopathological variables, especially endocapillary hypercellularity and interstitial fibrosis, and clinical parameters, particularly serum albumin concentration, in the prediction of both a decline in eGFR and a reduction in proteinuria in IgA nephropathy. IgA nephropathy (IgAN) is the most frequent primary glomerulonephritis worldwide , first dThere is a need for establishing robust biomarkers for IgA nephropathy to aid with diagnosis, treatment decisions, and risk prediction for progressive disease .The Oxford Classification of IgA Nephropathy (MEST score) offers an opportunity to use histology for the prediction of renal outcome, independently of proteinuria, blood pressure, and estimated glomerular filtration rate (eGFR) . The scaRecently, a new risk-prediction tool, including eGFR, blood pressure, use of immunosuppression, angiotensin system blockers (RAS), and proteinuria at the time of biopsy, while also incorporating MEST score, was proposed. It accurately predicted the risk of a 50% decline in eGFR or development of ESKD up to 7 years after biopsy .In this single-center, retrospective study, the clinical and pathological data of IgAN were analyzed to assess the predictability of both a decline in eGFR and a reduction in proteinuria.Eighty adult patients from a single center, with biopsy-proven IgA nephropathy, were enrolled in this retrospective study, from 1 January 2012 to 31 December 2019. The exclusion criteria were secondary causes of IgAN; in our center, this included hepatic cirrhosis and Crohn’s disease.The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Wroclaw Medical University . Specimens obtained by renal biopsy were assessed by experienced pathologists (PD and AH), according to the Oxford classification of IgAN . AdditioThe following clinical parameters were assessed: age, gender, blood pressure (systolic (SBP), diastolic (DBP), and mean (MAP) calculated as ((2 × DBP) + SBP)/3), erythrocyturia in urinary sediment, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and serum concentrations of total cholesterol, triglycerides, uric acid, fasting glucose, serum creatinine, serum albumin, and total protein. The number of red blood cells (RBCs) in urinary sediment was calculated per high-power field (HPF). In the case of RBC/HPF ≤5, RBC/HPF of 6–20, and RBC/HPF >20, the extent of erythrocyturia was assessed as absent, moderate, and severe, respectively. The enzymatic method was used for urea, and Jaffe’s method was used for creatinine evaluation. Kidney function was expressed as eGFR using the MDRD equation . Renal fAll patients, with proteinuria greater than 1.0 g per day, were treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers ARB (in the case of ACEI intolerance) at maximum tolerated doses, to obtain blood pressure below 125/75 mmHg. We did not include the ACEI or ARB doses in our analysis due to their variability. Patients who did not achieve a reduction in proteinuria below 1.0 g per day, after 6 months of treatment with ACEI or ARB, received corticosteroids according to the scheme proposed by Pozzi et al.   and percentage (%) values and compared using the χ2 test. To predict the values of decline in eGFR and reduction in proteinuria, logistic regression models were built. Firstly, univariate models were made to determine the best predictors. Then, multivariate regression was performed, including statistically significant parameters from univariate models. A p-value <0.05 was considered statistically significant.Statistical analysis was performed using Statistica ver. 13 software . Quantitative continuous data were expressed as the mean and standard deviation (SD). The distribution was tested with the use of the Kolmogorov–Smirnov test. Differences between the two groups were assessed with the use of a Eighty patients with primary IgA nephropathy were enrolled in the study, among them 35 women (44%) and 45 men (56%), aged 39 ± 14 years. Detailed patients’ characteristics at baseline are presented in MEST-C classification, the extent of interstitial fibrosis, and the degree of interstitial inflammation are presented in p = 0.34. Urinary protein excretion was assessed as urine protein-to-creatinine ratio (UPCR). Patients suffering from a decline in eGFR by at least 50% had statistically significantly higher PLR and lower concentrations of both serum albumin and total protein. They also had higher levels of proteinuria as assessed using UPCR. Furthermore, they used prednisone more frequently before biopsy.Seven patients (8.8%) suffered from a decline in eGFR of at least 50% during the observation period. Renal biopsies in the group with eGFR deterioration showed a higher degree of endocapillary hypercellularity (E1) and extent of interstitial fibrosis. Differences between both groups in terms of histopathological parameters are presented in Using nonlinear estimation, six parameters among those presented in Using the parameters selected by the univariate logistic regression model, we attempted to build a multivariate model, predicting 50% eGFR reduction. Only those consisting of two variables reached statistical significance. The best-fitting multivariate logistic regression models are presented in In the analyzed group, 38 (47.5%) patients presented urinary protein excretion higher than 1.0 g (as estimated by UPCR) at the time of biopsy. In 23 (61%) of them, daily protein loss was reduced below 1.0 g. The mean time to proteinuria reduction was 8 ± 12 months. In Patients in whom reduction in proteinuria was achieved presented a lower extent  of interstitial fibrosis and lack of endocapillary hypercellularity, compared to those in whom no reduction in proteinuria was achieved.A univariate logistic regression model was built  on the bOnly a univariate logistic regression model, including parameters influencing a decrease in proteinuria <1.0 g/24 h, was built. In contrary to 50% eGFR decline, the multivariate model did not reach statistical significance.A comparison of clinical parameters between patients based on endocapillary hypercellularity is presented in None of the clinical parameters differed between the groups on the basis of endocapillary hypercellularity.Patients with E1 presented higher mesangial hypercellularity, interstitial inflammation, and extent of interstitial fibrosis  and total protein  at baseline. It was accompanied by more severe protein loss, as expressed by UPCR . This finding is consistent with previous papers, pointing out the level of proteinuria as a crucial factor in the progression of renal insufficiency among IgAN patients [In our study, a significant correlation was found between the deterioration of renal function, as expressed by a decline in eGFR by 50%, compared to the baseline values, and the level of proteinuria. The group with a 50% decrease in eGFR had significantly lower concentrations of both serum albumin  and the risk of eGFR deterioration. In both univariate and multivariate logistic regression models, the presence of E1 increased the odds ratio of eGFR decline. On the one hand, this finding is in accordance with a study published by Edstrom et al., showing that the presence of endocapillary hypercellularity was associated with poor renal outcome, expressed by end-stage renal disease or eGFR reduction >50% . SimilarPlatelet-to-lymphocyte ratio (PLR) calculated as platelet count divided by lymphocyte count has been established as a novel marker of malignancies, cardiovascular diseases, and chronic obstructive pulmonary disease ,22,23. IIn our work, PLR was shown, in univariate analysis, to have a predictive influence on eGFR deterioration.2 per year in those with endocapillary lesions, compared with 2.6 ± 5.1 mL/min/1.73 m2 per year in those without endocapillary proliferation (p = 0.02) [It is also worth mentioning that patients with endocapillary lesions were more likely to receive immunosuppressive treatment. In our study, 18 patients were treated with prednisone already at the time of biopsy, and the number of these patients increased after the diagnosis. There are two studies in which no patient received immunosuppression, and both reported that E1 was independently associated with loss of renal function ,26. Amon = 0.02) . These s = 0.02) . In our Using multivariate analysis, we found an influence of E1 on eGFR decline, whereas serum albumin concentration had a protective impact. The second multivariate model involving serum albumin concentration and interstitial fibrosis had an impact on eGFR worsening.In our study, we also found that the presence of E1 influences blood pressure control. Although the number of patients with diagnosed hypertension did not differ between group E1 and E0, we observed a statistically significant difference in systolic blood pressure. Patients with the presence of E1 demonstrated a mean SBP of 137 ± 18 mmHg, in contrast to those with E0 who presented a mean SBP of 129 ± 15 mmHg. The higher values of blood pressure might be related to more active kidney disease, stimulating hormonal disorders responsible for blood pressure control, including activation of the renin–angiotensin–aldosterone system.It is worth mentioning that, although the presence of T lesions in our group did not reach statistical significance, both in the univariate and in the multivariate logistic regression models, we were able to prove that the extent of interstitial fibrosis, at the time of biopsy, influenced the deterioration of renal function. It is now a widely accepted paradigm that the degree of renal fibrosis correlates well with kidney function, both in native kidneys and in kidney grafts . The expSince the level of proteinuria, especially exceeding 1.0 g per day, is a key factor of renal insufficiency progression , we focuThe main limitation of this study was its small sample size. Although IgA nephropathy is the most common type of primary glomerulonephritis, it is generally a rare disease in the entire population. All available patients with biopsy-proven IgA nephropathy and at least 6 months of follow-up were included in the study, after excluding patients with secondary causes. The strength of the study is that we presented the results from one center that provides care for the large region of southwestern Poland and concerns an ethnically homogeneous group. Additionally, the same approach was used to treat all participants.In our paper, we confirmed the utility of the MEST-C score, especially endocapillary hypercellularity, in the prediction of renal function decline, expressed as a 50% decrease in eGFR. A similar conclusion was made for a reduction in proteinuria below 1.0 g/24 h. In addition to histopathological findings, the level of proteinuria expressed by initial serum albumin concentration was found to have an impact on final kidney function.


The in-depth epidemiology of hypertension has not been studied in Kazakhstan (KZ) yet. We aimed to investigate the crude; age and sex standardized prevalence, incidence, and all-cause mortality rate among hypertensive patients in Kazakhstan using a large-scale Unified National Electronic Health System (UNEHS) for the period 2014–2019. Hypertension was defined based on the ICD-10 codes . Of 1,908,419 patients, 1,186,706 (62.18%) were females and 721,713 (37.82%) were males. The majority of the patients (56.3%) were ethnic Kazakhs, 26.6% were Russians, and 16.2% were of other ethnicities. In 2014, the crude rates of prevalence, incidence, and mortality were 3661, 1396.1, and 33.1 per 100,000 population, respectively. The overall prevalence, incidence, and mortality rates among hypertension patients had a gradual increase over the period 2014–2019. The sex and age adjusted rates demonstrate the same trend throughout the entire period. We observed 71% higher risk of crude death in males comparing to females (Hazard ratio (HR): 1.71 [95%CI: 1.69–1.72]); Russian and other ethnicities had 1.56-fold (95%CI: 1.54–1.58 and 1.43-fold (95%CI: 1.41–1.45) higher risk of all-cause death compared to Kazakhs, and the elderly group had the highest risk of death (Hazard ratio (HR): 35.68 [95%CI: 28.11–45.31]) comparing to the younger generation, which remained significant after adjustment to age and sex. Overall, these findings show statistically significant lower survival probability in male patients compared to female, in older patients compared to younger ones, and in patients of Russian and other ethnicities compared to Kazakh. Approximately 1.13 billion people of the worldwide population have hypertension, the majority (approximately 66%) live in low and middle-income countries , while sIt is estimated that hypertension kills 7.5 million individuals each year . Based oData from epidemiological studies by Alikhanova et al. shows that the leading morbidities of the adult population are attributed to diseases of the circulatory system, which are manifested by an increase in blood pressure (7801.4 cases per 100 thousand adults)  of the follow-up period, there were 142,956 deaths (7.49% of the cohort). There is a rise in the crude mortality rate between 2014 and 2019 , which sp < 0.001), from arterial hypertension compared to females, however, patients living in rural areas show the opposite result, with 12% lower risk of death , compared to patients residing in urban areas. The risk of death increases with age—people in the age group 18–24 is the reference group. Finally, by ethnicity groups, Russians and others , respectively) have a higher risk comparing to the Kazakhs , while increased in patients from rural area . As for comorbidities, the risk of death decreased  in patients who have stroke compared with those who did not, while diabetes and chronic kidney disease showed an opposite trend   . The detThis is the first research in Central Asia on the epidemiology of AH using a large-scale healthcare database from Unified National Electronic Health System. The results showed an overall increase in prevalence, incidence, and mortality rates of hypertension from 2014 to 2019. Interestingly, after adjustment for age and gender, there is a statistically significant higher survival probability of ethnic Russians or other compared to previous unadjusted results, and a decrease in survival probability of rural compared to urban places.Bermagambetova et al. results showed that both in the city and in the rural areas there is almost the same degree of hypertension incidence, which can be compared with international data. However, our analysis indicates that the numbers of hypertensive patients located in the city was higher compared to rural places, which suggests that living in urban areas is a risk factor for arterial hypertension ,20,21. LThe relationship between increased blood pressure, age, and gender has been known since a long time. Our findings demonstrate an increase in the incidence of hypertension as patients gets older, especially in women. Similar findings were reached in studies that looked at the link between a patient’s gender, age, and incidence rate. As an example, in the Framingham Heart Study, it was observed that after the age of 60, the incidence in women becomes higher than in men. This may be due to the selective removal of men from the risk group since at the initial level they have higher rates of hypertension and a lower survival rate because of cardiovascular deaths . AdditioAt the same time, mortality rates related to hypertension rose as well and currently rank first among the causes of death. Approximately 40% of the deaths are observed during active working age (20–64 years), of which 64% in the male population, which is in line with previous studies showing higher risk of death (approximately 39%) in the active working age group. . AccordiAH is a common problem to the Kazakhstan public health sector as in the majority of the world’s countries and poses a significant threat to it, as according to the official statistics, the prevalence of AH affects 24.3% of the adult people in Kazakhstan ,28. BetwThere are several limitations in this study that deserve mentioning. The real prevalence of hypertension could be underestimated due to lack of access to healthcare, misclassification of the cases of hypertension, and miscoding of hypertension. We were not able to define a cause-specific mortality data and associations were accounted only for all-cause mortality. Although the impact of few comorbidities such as diabetes, stroke, and chronic kidney disease was assessed, other important confounders were missing, which could have a potential impact on the mortality.As there were an update in the definition of hypertension in adults by the American Heart Association (AHA) and the International Society of Hypertension (ISH) according to the indicators of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in 2017, the coding of hypertension might be misclassified during the study period ,31,32.This is the first retrospective study in Kazakhstan to address the prevalence, incidence, and all-cause mortality rate of AH patients utilizing the large-scale nationwide healthcare records over a six-year period between 2014 and 2019. The results showed an increase in the prevalence, incidence, and mortality rate of AH patients. We observed a lower survival probability in male patients compared to females, in older patients compared to younger ones, and in patients of Russian and other ethnicities compared to Kazakh. Future studies should concentrate on the development of actions to improve measures of primary and secondary prevention of AH, taking into account the main risk factors for their development.


At the individual level, it is well known that pregnancies have a short-term effect on a woman’s cardiovascular system and blood pressure. The long-term effect of having children on maternal blood pressure, however, is unknown. We thus estimated the causal effect of having children on blood pressure among mothers in India, a country with a history of high fertility rates.We used nationally representative cross-sectional data from the 2015–16 India National Family and Health Survey (NFHS-4). The study population comprised 444 611 mothers aged 15–49 years. We used the sex of the first-born child as an instrumental variable (IV) for the total number of a woman’s children. We estimated the effect of an additional child on systolic and diastolic blood pressure in IV (two-stage least squares) regressions. In additional analyses, we stratified the IV regressions by time since a mother last gave birth. Furthermore, we repeated our analyses using mothers' husbands and partners as the regression sample.P < 0.001] and 0.13 mmHg lower diastolic  blood pressure. In the IV regressions, each child decreased a mother’s systolic blood pressure by an average of 1.00 mmHg  and diastolic blood pressure by an average of 0.35 mmHg . These decreases were sustained over more than a decade after childbirth, with effect sizes slightly declining as the time since last birth increased. Having children did not influence blood pressure in men.On average, mothers had 2.7 children [standard deviation (SD): 1.5], a systolic blood pressure of 116.4 mmHg (SD: 14.4) and diastolic blood pressure of 78.5 mmHg (SD: 9.4). One in seven mothers was hypertensive. In conventional ordinary least squares regression, each child was associated with 0.42 mmHg lower systolic [95% confidence interval (CI): –0.46 to –0.39, Bearing and rearing a child decreases blood pressure among mothers in India.  Bearing and rearing a child decreases blood pressure among mothers in India.As fertility continues to decline in India and similar countries, policy makers should design and implement hypertension screening and prevention programmes that specifically target women.Novel health programmes beyond antenatal care are needed to ensure that women without children receive blood pressure screening.,,Pregnancy induces substantial changes in a woman’s cardiovascular system.,,,,,Past cross-sectional,,,Instrumental variable (IV) analyses are a powerful approach for causal inference, which can be used when randomized controlled trials are not possible.We used the National Family and Health Survey (NFHS-4) conducted in India between 2015 and 2016 as the data source for our study. The NFHS-4 provides cross-sectional nationally representative data on women aged 15–49 years for all 29 Indian states, 7 union territories and 640 districts. It employs a stratified two-stage sample design utilizing the 2011 census as a sampling frame. Primary sampling units were census enumeration blocks (in urban strata) and villages . From each of the 28 586 selected primary sampling units, 22 households were randomly selected via systematic random sampling. The NFHS-4 had response rates of 96% for households and 95% for mothers.n = 19 693), as our objective was to measure the long-term effects of bearing and rearing a child rather than the well-known short-term hemodynamic effects of pregnancy.n = 2672) needed to be excluded because they did not experience a latency period between the birth of the first and the planning of the second child. Lastly, we excluded a total of 9643 mothers (2.1% of the remaining sample) who were missing blood pressure measurements. IJE online, shows a study-participant flow diagram. The response rate among selected women was near universal (95%) and we only excluded a very small share of these women due to missing data (2.1%). The final sample for our main analyis comprised 444 611 mothers aged 15–49 years.Our study population comprised all mothers aged 15–49 years who (i) did not report a current pregnancy, (ii) did not give birth to twins at first pregnancy, and (iii) completed the blood pressure measurement in the NFHS-4. We excluded currently pregnant women . This instrument has previously been used to analyse the effect of having children on economic or demographic outcomes among study populations in India and other countries.,,,,An instrumental variable (IV) is a variable that is associated with the exposure of interest, but is independent of observed and unobserved confounders and does not relate to the outcome other than through the exposure.In addition to presenting descriptive sample characteristics, we show the geographic distribution of our exposure and outcomes. We calculated the mean number of children and systolic and diastolic blood pressure levels of mothers in our sample across all 640 districts from the 2011 census in India.,,IJE online. Next, in the first stage of the 2SLS regression, we regressed the number of children on the instrument. The first-stage estimate reveals how the sex of the first-born child influences, on average, the overall number of children. Lastly, in the second stage of the 2SLS regression, we included the predicted number of children from the first stage as an independent variable in a linear regression with maternal systolic and distastolic blood pressure as the outcomes. The resulting effect size represents the causal effect of each child on maternal blood pressure, estimated in the population of women who pursue a further child if their first-born child was a girl, i.e. the so-called complier average causal effect.,IJE online. 2SLS regressions were calculated using the Stata command ‘ivregress’. When we used the limited-information maximum-likelihood estimator instead of the 2SLS estimator for the IV estimation, our results remained essentially the same.To measure the causal effect of bearing and rearing an additional child beyond the first on maternal blood pressure, our analysis followed the common structure of IV analyses and included four estimations: (i) conventional ordinary least squares (OLS) regression; (ii) reduced-form regression; (iii) first stage of a two-stage least squares (2SLS) regression; and (iv) second stage of the same 2SLS regression.The inclusion of covariates is not necessary for unbiased causal inference in IV analyses.To measure the change in the effect of bearing and rearing a child on maternal blood pressure over time following the birth of a child, in an additional analysis, we stratified our estimation by the time that had passed since the last time a woman had given birth. We divided our sample into three groups of equal size according to the number of months passed since the last birth. We rounded group cut-offs to the closest year.In a subsample of 15% of households in the NFHS-4, blood pressure was measured among men aged 15–54 years.,,exclusion restriction that there must be no relationship between the IV and the outcome other than through the exposure. IJE online, discusses the IV assumptions in detail and explains why they are likely met in our analysis. We empirically assessed the IV assumptions using the following tests. First, we assessed whether relevant observed variables varied across the two values of the instrument. This test is akin to the balance test in a randomized controlled trial.,,The key advantage of the IV approach is that, as long as the assumptions for a valid instrument are met, it generates unbiased effect estimates, just like a randomized controlled trial.N = 352 779). As some mothers with one child might have pursued second pregnancies after data collection, they would have been falsely attributed to the compliers or non-compliers. Sixth, given the large effect of age on blood pressure, we allowed for non-linearities in the relationship of age and blood pressure. To achieve this, we used restricted cubic splines, placing knots at ages 22, 28, 34, 40 and 48 years, which are, respectively, the 0.05, 0.275, 0.5, 0.725 and 0.095 quantiles of the data distribution. This approach allows the relationship between age and blood pressure to take a unique cubic form between each pair of knots with linear relationships below age 22 years and above age 48 years. Seventh, we controlled for previous or current use of oral contraceptives, because the use of oral contraceptives might relate to both the sex of the first-born child and maternal blood pressure. Eighth, we repeated our main analyses without covariates. Ninth, previous longitudinal evidence hints at a potential concave shape in the association of the number of children and maternal blood pressure.We conducted several sensitivity analyses to further increase confidence in the robustness of our findings. First, we used an alternative definition of our exposure. Specifically, we only included children in a woman’s birth history who were alive at the time of the interview to rule out incomplete exposure to child rearing. Second, we added further socio-demographic covariates to our model. In addition to our main covariates of age, wealth and educational attainment, we included area of residency , religion  and literacy . Third, we added a constant of 10 mmHg to systolic and 5 mmHg to diastolic blood pressure in the 4.0% of mothers in our sample reporting the use of antihypertensive medication, in order to account for the effect of those drugs on blood pressure. This approach is in line with recommendations on adjusting for hypertensive treatment in quantitative data.All analyses were performed in Stata 15.0.On average, the mothers in our study population were 34.4 years old [standard deviation (SD): 8.1] and had 2.7 children (SD: 1.5) and blood pressures of 116.4 mmHg systolic (SD: 14.4) and 78.5 mmHg diastolic (SD: 9.4). About one in seven mothers (14.7%) was hypertensive, i.e. her systolic blood pressure was ≥140 mmHg, her diastolic blood pressure ≥90 mmHgP < 0.001), but systolic blood pressure (P = 0.287) and diastolic blood pressure (P = 0.509) are not.Illustrating the geographic distribution of our exposure and outcomes , we founP < 0.001) compared with mothers with first-born sons (P < 0.001)] and diastolic blood pressure [–0.35 mmHg ]. The OLS and reduced-form regressions support this finding, revealing effect size estimates in the same direction. These results remained essentially the same across all sensitivity analyses (IJE online).The first stage of the 2SLS regression shows that mothers with first-born daughters on average had 0.31 more children , –0.91 mmHg  and –0.52 mmHg , respectively, in the periods 0–3, 4–11 and ≥12 years since the last birth. The diastolic blood pressure estimates mostly did not differ from zero.P < 0.001) compared with couples with first-born sons. As the second stage of the 2SLS regression reveals, the average effect of each additional child beyond the first one was 0.05  for systolic and 0.14  for diastolic blood pressure.A total of 53 605 men were included in a separate IV analysis . The firIJE online, shows that the observed characteristics were nearly perfectly balanced across the two values of our IV, supporting the exclusion-restriction assumption of our analysis. Next, we stratified our analysis by state-level sex ratio at birth. In our sample, at the time of their first birth, 124 322 mothers resided in states with a sex ratio at birth of <900 girls per 1000 boys, 176 413 in states with a ratio of 900–949 girls per 1000 boys, and 143 876 in states with a ratio of ≥950 girls per 1000 boys. The 2SLS regression results in all three strata were similar to our unstratified main results (IJE online). The main results were also robust to adding state-level sex ratio at birth as a continuous covariate to the model (IJE online) and to including fixed effects for the 28 508 primary sampling units of our sample (IJE online). Considering these findings, we concluded that sex-selective abortions are unlikely to substantially affect our results. Taken together, these tests further confirm that the IV assumptions are likely met in our study (IJE online).Our results suggest that bearing and rearing a child causes a decrease in blood pressure in Indian mothers. Each child beyond the first lowered systolic blood pressure by ∼1 mmHg and diastolic blood pressure by ∼1/3 mmHg. The effect on systolic blood pressure waned over time, yet remained lower than zero even more than a decade after childbirth. Although the effect sizes might be considered small in a clinical context, at the population level, they are substantial,Our findings are important for population health and policy. First, they mitigate common concerns that bearing and rearing a child could increase hypertension and CVD risk among mothers in the long term.,,Second, at the population level, women have lower blood pressure than men, in India as well as globally.,,Third, pregnant women worldwide nearly universally attend antenatal care at least once, where they are nearly universally screened for hypertension.,,,,,Whereas some longitudinal studies suggest an inverse association between having children and maternal blood pressure,,Replication of our quasi-experimental study in other populations with son preference would be desirable to evaluate whether the observed effects are specific to India or also apply to other countries. Pregnancy and motherhood are major events in a woman’s life. Hence, they can affect blood pressure through various pathways that might explain our findings in this study and also apply in other contexts. Whereas blood pressure increases towards delivery,Behaviourally, children can act as a strong motivation for mothers to improve certain health behaviours, such as ceasing smoking.The absence of an effect of additional children on blood pressure in men underscores that our findings for women are likely not due to behavior changes affecting all household members and that underlying pathways are sex-specific. In the Indian context, men tend to take on different roles in raising children compared with women.,,,Our study has several strengths. We estimated the effect of children on maternal blood pressure for the first time in a nationally representative data set. We do so for India, which is projected to overtake China as the world’s most populous country by 2027.,,,Our study also has several limitations. First, the birth history variables in our data set might underreport pregnancies, because the NFHS-4 questionnaire did not explicitly ask for stillbirths and miscarriages. For the same reason, it was also not possible to differentiate between stillbirths and neonatal deaths occurring on the day of delivery.In conclusion, bearing and rearing a child decreases blood pressure among mothers in India. As fertility continues to decline in India and similar countries, policy makers should design and implement hypertension screening and prevention programmes that specifically target women.IJE online.This study used an anonymized publicly available data set with no identifiable information on the survey participants, and thus did not require ethics approval.T.B. was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. T.B. also received funding from the Wellcome Trust under Award Number 208766/Z/17/Z. J.W.D.N. was supported by the Alexander von Humboldt Foundation. P.G. was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR003143. F.T. was supported by the Else Kröner-Fresenius-Foundation within the Heidelberg Graduate School of Global Health at the Heidelberg Institute of Global Health, Heidelberg University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.The NFHS-4 survey data are publicly available and distributed through the website of the Demographic and Health Surveys (DHS).dyab058_Supplementary_DataClick here for additional data file.