Neonatal death is the major problem in developing world. Burden and predictors of neonatal mortality vary across countries and even among regions of a country, so understanding the problem concerning these factors is essential to overcome the problem. Therefore, this study aimed to determine time to death and its predictors of neonatal mortality among neonates who were admitted to the neonatal intensive care unit of Tertiary Hospital, Addis Ababa, Ethiopia.A hospital-based retrospective cohort study was employed among 434 neonates admitted in Tertiary hospital, Addis Ababa, Ethiopia. A Kaplan Meier curve and a log-rank test were used to estimate the survival time and compare survival curves between variables. The cox proportional hazard model was also fitted to identify predictors.A total of 434 neonates included in the study, 11.1% of which were died, and the incidence rate was 19.2 per 1000 live births. The time to death of neonates was 17 days. Independent predictors of neonatal mortality were incomplete maternal antenatal follow up[AHR: 3.7 ], lowscore[AHR:5.0 (95%CI:1.51–15.04)], perinatal asphyxia [AHR:5.2 (95%CI:1.92–14.30)], preterm 4.2 (95%CI: 1.32–8.83)]. Moreover, small for gestational age [AHR:4.8 (95%CI:2.33–9.72)], respiratory distress[AHR: 2.5 (95%CI: 1.24–5.09)], sepsis [AHR: 3.4 (95%CI: 1.71–4.01)], low birth weight[AHR: 7.3 ], and tracheoesophageal fistula [AHR: 2.2 (95%CI: 1.13–4.32)].th min APGAR score, neonatal sepsis, respiratory distress, perinatal asphyxia, and tracheoesophageal fistula.The overall incidence rate was 19.2 deaths per 1,000 live births. Emphasis should be given to incomplete Antenatal care follow up, small for gestation, preterm, low birth weight, low 5 Globally, it is estimated that ~6,500 neonatal deaths occurred every day. Of those, about a third of all neonatal deaths occurred within the first day after birth, and three-quarters occurring within the first week of life . BesidesThe three major causes of neonatal mortality in developing countries include prematurity, infections, and perinatal asphyxia , 8, 9. NIn Ethiopia, a 2020 report estimated that neonatal mortality rate for Ethiopia was 27 deaths per 1,000 live births. The rate of neonatal mortality decreased from 47.8 deaths per 1,000 live births to 27 deaths per 1,000 live births in 2001 and 2020, respectively . Over twIn particular, under-five mortality rates declined from 166 to 67 deaths per 1,000 live births in 2016. Similarly, infant mortality decreased from 97 to 48 deaths per 1,000 live births in the same period, but the neonatal mortality decreased from 54 to 29 per 1,000 live births –17. ThisDespite different initiatives and implementations that have been implemented to prevent neonatal death, it is still high and not reduced as expected in developing countries including Ethiopia. Although several studies were made in different countries on the survival status and predictors of mortality among neonatal intensive care unit [NICU] admitted neonates, but only a few studies were done in Ethiopia. Moreover, studies regarding neonatal mortality have focused on rate and little has been done on the time to death and predictors.Therefore, this study aimed to determine the time to death and its predictors of neonatal mortality among neonatal intensive care unit admitted neonates at Tertiary Hospital Addis Ababa, Ethiopia.A retrospective cohort study was conducted at tertiary hospital Addis Ababa Ethiopia among live-born neonates who were admitted to NICU from 1 January 2015 to 30 December 2018. Addis Ababa has ten sub-cities at which the City lies at an altitude of 7,546 feet  . There aAll live-born neonates who were admitted to NICU of Tikur Anbessa Specialized Hospital from 1 January 2015 to 30 December 2018, Addis Ababa, Ethiopia were included. Whereas, Neonates of incompletely registered NICU logbooks and lost records at the time of data reviewing were excluded from the study.P1 = 10 % P2 = 20% ; maternal health factors ; health service-related factors .Censored: didn't know survival time exactly due to study ends, loss to follow-up, withdrawal or being survived from study. Low APGAR score: a score < 7. Event: death after NICU admission. Asphyxia: a neonate with an APGAR score of <7. Time to death: it is the time from admission at NICU to the occurrence of the outcome/event. Time scale: days from admission of a neonate to the occurrence of an outcome. Time origin: date of admission or start time of the cohort. Complete ANC follow up: ANC visit≥4 times at current pregnancy period. Multigravida: recorded gravida of ≥2. Multiparity: recorded parity of ≥2. Preterm birth: any infant born before 37 weeks of gestational age. Low birth weight (LBW): birth weight <2500 gm.Data was collected by using a checklist developed from neonatal intensive care unit registration book format, which was prepared nationally as an "Ethiopian NICU form. The checklist consisted of new-born information recorded at admission and records of maternal information which were collected using a uniform extraction format developed by taking in to account all the relevant variables in the standard NICU registration book. Then all medical records that fulfill the inclusion criteria were reviewed retrospectively.The checklist was prepared in English. A pretest was done on 5% of the sample size in Yekatit 12 hospital before the time of the actual data collection. The checklist was also examined by experts to check for content validity.The data reviewers and supervisors were 8 BSc and 3 MSc Nurses. Before starting the actual work, one-day training and orientation were provided to chart reviewers on the objectives of the study, data reviewing techniques, how to keep confidentiality of information, how to fill the data abstraction checklist and data quality management. Close supervision was carried out by supervisors and investigators to ensure data quality. Then, the collected data was checked for its completeness and consistency before analysis.p-value < 0.25 in the bivariable analysis were included in the multivariable cox-proportional hazards regression model. Then, those variables with P-value ≤ 0.05 at 95% confidence interval were considered as statistically significant.Data was coded, cleaned, edited and entered using Epi-data version 4.21 and exported to STATA SE version 14 for analysis. The event of interest was death. The time to death was calculated in days between the date of admission and the date of death. The log-rank test employed to illustrate whether considered covariates in the Kaplan Meier curves are statistically significant and in line with the Kaplan Meier curves. The bivariable cox regression was done and those variables having p-value was 0.7156 > 0.05], which indicates that the PH assumption has been met.Kaplan Meier survival curve together with log-rank test was fitted to test the survival time of neonates, and their survival curves didn‘t cross over each other. A goodness-of-fit  test wasAbout 434 charts were reviewed with a response rate of 100%. Around 54 [12.4%] of mothers were below age twenty, 262 [61%] between 20–34 years old, 114 [26.5] between 35–45, and 4 [0.04%] were above 45.Among 239 males 27 [11.3%] of neonates died, and among 195 females 21[10.8%] of them died. The pattern of neonatal death in the 1st 24 h,1st 7 days, within the first 14 days, and the 1st 28 days was 12.9,7.6,11.1, and18.2%, respectively .Neonates born from mothers who had a complete antenatal follow up during their current.Pregnancy, their death was 48/1,000 neonates, but neonates born from mothers of incomplete ANC was 360/1,000 neonates, and 615/1,000 for neonates born from mothers who did not have antenatal follow up were died.About 24 [11.9%] of neonates born from primigravida mothers, 201 [46.3%] were died, and 24 [10.3%] of neonatal death was from multi gravid mothers 233 [53.7%] .About 15 [10.9%] of neonates born from mothers who had problems of obstetric problems died and 33 [11.1%] of neonates died born from mothers who did not have such problems .Neonates born from hypertensive mothers had 18% neonatal death risk than neonates born from non-hypertensive mothers 13.3%. HIV positive mothers had 29% hazard for neonatal death, but HIV negative mothers had 19% hazard of neonatal death .Regarding the neonatal medical conditions; the common medical problems identified were respiratory distress 121 [28%], perinatal natal asphyxia 143 [33%],low APGAR score , low birth weight 84 [20%], Prematurity or SGA 88 [21%], sepsis 133 [31%], preterm birth 95 [23%], hypothermia 140 [32.3%], meconium aspiration syndrome 79 [18.2%], neonatal jaundice 177 [40.8%], neural tube defects 31 [7.1%], and trachea esophageal fistula 134 [31%]. Concerning causes of death, PNA 43 [30.1%], sepsis 31 [23.3%], LBW 41 [49%], Respiratory distress 35 [28.9%], low Apgar score 42 [21.6%], SGA 38 [43.2%], preterm 32 [33.7%], hypothermia 12 [8.6%], MAS 3 [3.8%], jaundice 25 [14%], neural tube defects 3 [9.7%] trachesophageal fistula 33 [24.6%] were identified medical conditions related to neonatal death in their NICU stay .A total of 434 neonates who were admitted to the NICU of TASH during the study period have been followed from 0 to 28 days. The overall time to death was 17 days [95%CI: 16.71–19.35] with a minimum and the maximum follow up time of 1 and 23 days. In this study, 48 [11.1%] of the neonates died during the follow-up period. Out of 386 censored, 310 [80.3%] were alive and discharged to home, 65 [16.8%] referred and 11 [2.9%] were lost to follow-ups.st, 7th, 14th, and 23rd days was 99.8, 87.5, 66.3, and 61.2%, respectively. The overall probability of survival of neonate was about 0. 612 [95% CI: 0.46–0.73] for the follow-up period of time ].th min were about 5 times more likely to die as compared to those who had an APGAR of >7 [AHR:5.0 (95% CI: 1.51–15.04)]. Pre-term newborns had 4 times increased hazard of death than term newborns [AHR 4.2 (95% CI: 1.32–8.83)]. Neonates who diagnosed and admitted with perinatal asphyxia were 5 times more likely to die as compared to those who were not asphyxiated [AHR: 5.2 (95% CI: 1.92–14.30)]. Neonates born from mothers who did not attend ANC visits during their pregnancy were four times at higher risk of death than neonates born from mothers who had antenatal follow up [AHR: 3.7 ]. Low birth weight neonates were 7.3 times more likely to die than normal birth weight neonates [AHR: 7.3 ]. Neonates who were in respiratory distress had nearly 2.5 times more likely to die than those who were not in distress [AHR: 2.5 (95% CI: 1.24–5.09)]. Those who had neonatal sepsis at the time of admission were three times more likely to die than those who did not have sepsis [AHR: 3.4 (95% CI: 1.71–4.01)]. Neonates diagnosed as having TEF had 2.2 times more Hazardous than those neonates who did not have [AHR: 2.2 (95% CI: 1.13–4.32)] (Those neonates who had an APGAR score of less than 7 at 53–4.32)] .The study showed that the overall incidence rate was 19.2 deaths per 1,000 live births. Neonates were followed for 2,499  days, resulting in an overall incidence rate of 19.2 deaths per 1,000 live births. This finding was lower EDHS 2019 report [33 deaths per 1000 live births], respectively , Tigray The result of this study showed that about 11.1% newborns were died, which was less than studies done in Cameroon 15.7% . The difIn this study, about 70% neonatal deaths were registered in the early neonatal period [0–6 days], and 30 % of were died during the late neonatal period which was inconsistent with study done in Kara Mara, in which 96 % were early neonatal deaths  and a stIn this study, being pre-term newborn had an increased hazard of death than term neonates and was consistent with studies done in Cameroon , and GhaThe finding of this study had a lesser hazard of death than studies done in Ghana , and a pAnother significant predictor of neonatal death was perinatal asphyxia. Asphyxiated neonates were more likely to die than neonates without asphyxia, which makes it similar to a study done in NICU of Komfo Anokye Teaching Hospital [KATH] in Ghana , and NICth min APGAR score which is a useful index of the response to resuscitation efforts, and low APGAR score neonates are risky to be oxygen-deprived than an APGAR of >7. This discrepancy might be explained by the sample size, and obstetrical care, and neonatal resuscitation efforts. Low birth weight neonates were more likely to die than normal birth weight neonates, this was in line with a study done in NICU of Kath in Eastern Ethiopia  was the other predictor of neonatal death. Neonates diagnosed as having TEF were more hazardous than those neonates who did not have. In this study, about 24.6% of neonates were died due to diagnosed TEF, which is consistent with previous study . NeonateStrength of this study includes:- This is an approach to clearly indicate the temporal sequence of the predictor and outcome variable (death); Data reviewing was conducted by trained nurses, and standardized data abstraction tool was used and It enables to estimate the survival time of neonates, and identify predictors for future trend estimation and other related prevention and intervention programs.Using secondary sources may result in loss of potential predictors, which may not be addressed in this study design like; maternal nutritional status, educational level, and family-related issues. As the incomplete charts were excluded from the study there may be selection bias. This study was done retrospectively which might cause recall bias due to failure of the caregiver to remember what was happened previously.The overall incidence rate during the 2,499 person-time was 19.2 deaths per 1,000 person-day observation with a time to death of 17 days.th min Apgar score, neonatal sepsis, respiratory distress, perinatal asphyxia, and TEF. This recommended that maternal health during pregnancy, including quality of antenatal care utilization should be further strengthened, and risky pregnant mothers should be identified antenatally. Initiating different strategies to work on early identification, quality and continuous care for neonates coming with an assessment of preterm, low birth weight, perinatal asphyxia, respiratory distress, and sepsis and tracheoesophageal fistula and implementing it to ensure quality neonatal care.The independent predictors were incomplete or no maternal antenatal follow up, being small for gestation, preterm, low birth weight, low 5The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by AAU, College of Health Science, School of Nursing and Midwifery Institutional Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MM, GM, WK, FT, and BA was responsible to conception, design, acquisition of data, analysis and interpretation of data, and was responsible in the writing the original research and preparation of the manuscript for publication. BG and KD were responsible for design, supervision, and reviewing it for accuracy and integrity. All authors play roles in this research article, read, and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Reviewers WS and YA, declared a shared affiliation with the authors to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Oncological follow-up after liver transplantation for cholangiocellular carcinoma must consider the risk of recurrence. Immunosuppressive medication with so-called mTOR inhibitors seems to have a tumor-suppressive effect, as improved survival has been shown under this medication for patients with recurrent hepatocellular carcinoma after liver transplantation. The aim of our study was to investigate recurrence and survival in relation to tumor type and type of immunosuppression for cholangiocellular carcinoma after liver transplantation. The time from liver transplantation to recurrence and survival after cancer recurrence were endpoints of the study. Significant improvement in survival for recurrent cholangiocellular carcinoma was seen after surgical resection and reduction in immunosuppression, while N1 status at transplantation and histological Grading >1 were associated with worse outcomes.n = 67) were retrospectively analyzed. Endpoints were the time from LT to recurrence (n = 44) and survival after recurrence. Statistically significant impairment in survival for recurrent CCA (rCCA) was shown in patients not eligible for surgical resection . Histological proven grading >1 and N1 status at initial transplantation were associated with impaired survival (HR 0.13 (CI: 0.03–0.58); p < 0.01 and HR 3.4 (CI: 1.0–11.65); p = 0.05). Reduced IS after tumor recurrence improved survival . MTORI initiation before recurrence or after had no significant impact on survival. Our data thereby indicate, similar to findings in recurrent HCC after LT, that patients with rCCA after LT benefit from a reduction in IS upon recurrence.Liver transplantation (LT) for cholangiocarcinoma (CCA), or biliary tract cancer (BTC), remains controversial regarding high recurrence rates and poor prognosis. Oncological follow-up may benefit from tumor-inhibiting properties of mTOR inhibitors (mTORI), shown with improved survival for recurrent hepatocellular carcinoma (HCC) patients after LT. The aim of this study was to investigate the recurrence and survival in relation to tumor type and type of immunosuppression (IS). LT patients with CCA or mixed HCC/CCA (mHCC/CCA) ( Cholangiocarcinoma (CCA) is the second most common primary liver malignancy after hepatocellular carcinoma (HCC) . There iBoth primary hepatic malignancies, CCA, as well as hepatocellular carcinoma (HCC), are potential indications for liver transplantation (LT) under certain conditions. LT for early-stage HCC, particularly within the so-called Milan criteria, shows excellent treatment results . LT may The recurrence rate of the aforementioned tumors after LT is considerable, which confronts the clinician with the question of how far the extent of IS is related to the occurrence of tumor recurrence and the course after tumor recurrence, and whether improved management of immunosuppression may prolong the already limited survival in case of recurrence. Little is known about this option, so the aim of the present study was to fill this gap and derive a practical recommendation using a representative cohort of transplant patients from the context of CCA based on the experience of three decades of LT.t-test were used in nominal variables for normally distributed or continuous variables. For testing of non-normally distributed values, Mann–Whitney U test or Kruskal–Wallis test were chosen. For survival analysis, univariate analysis and Kaplan–Meier analysis were conducted and Breslow and log-rank tests were calculated. Correlation was tested using Pearson or Spearman test depending on variables. Multivariate and univariate Cox-regression models were used, and hazard ratio (HR) and confidence interval (CI) were calculated. Relevant variables or confounders for integration in multivariate analysis were identified by clinical experience. A p-value of ≤0.05 was considered significant. The statistical analysis was not designed for multiple testing, and the p-values were considered exploratory. All statistical analyses were performed using SPSS Statistics Version 26.0 .All patients that underwent LT for histological proven CCA or mHCC/CCA at our institution between 1988 and 2022 were included in this retrospective study. The follow-up regimen of all patients was performed in a life-long manner at our outpatient center and in correspondence with other treating physicians. Intervals of clinical examinations and laboratory assessment, as well as ultrasounds of transplant and radiological imaging  and magnetic resonance imaging (MRI) were dependent on time after LT and recent guidelines of surveillance after malignancies; internal standard protocol required visitation twice a week to every twelve weeks. Ultrasound-guided, transcostal needle biopsies of the graft were performed at 1, 3, 5, 7, 10, and 13 years and are ongoing, as well as on individual patients’ clinical course. Diagnosis of recurrence of initial tumor disease was established by experienced radiologists and confirmed by histopathology if needed, and staging was conducted according to guidelines. TNM classification and classification of the Union for International Cancer Control (UICC) were used for staging. The grading of mHCC/CCA was determined by the histopathological report of the explanted liver. Early-onset recurrence was defined as an occurrence within two years after LT ). Managen = 44/65.7%), and the median age was 54.4 (30.0–70.0) years. Overall, three patients (4.5%) underwent re-LT, two because of thrombotic events and one due to recurrence of underlying primary sclerosing cholangitis (PSC). Five patients (7.5%) received combined LT with pancreaticoduodenectomy for eCCA. There was no significant difference in the rate of recurrence in the group of patients with eCCA in dependence on transplantation modus (p = 0.290). Overall median survival was 37.9 (3.1–333.3) months, and at the end of follow-up, 53 (79.1%) were deceased. Subgroup analysis for different entities did not show significant differences in survival for eCCA with 36.2 (3.1–333.3) months, compared with iCCA with a median survival of 57.3 (5.2–225.4) months or mHCC/CCA, with 35.2 (4.0–290.3) months, respectively (p = 0.96). Similar, recurrence rate did not differ with statistical significance between entities . An overview of patient characteristics is given in Between 1988 and 2022, 67 patients underwent successful LT for CCA or mHCC/CCA at our surgical department. In total, 37 (55.2%) patients were diagnosed with extrahepatic CCA (Klatskin tumor), 17 (25.4%) with intrahepatic CCA, and 13 (19.4%) with intrahepatic mHCC/CCA. The majority of patients were male  patients suffered from a recurrence of the initial tumor entity, with significantly reduced overall median survival after LT of 29.5 (0.13–72.8) months vs. 144.4 (4.0–333.3) months for patients without  .p = 0.04 and p = 0.03, respectively). Grading did not show an impact on overall survival after LT , whereas the UICC stage showed this effect . However, survival after recurrence was not influenced with statistical significance by either parameter . Correlation analysis showed significance for histopathologically proven tumor manifestation in lymph nodes (N1 status) at LT and recurrence (p = 0.04). Multinominal regression analysis for predictors of recurrence did not show statistical impact of tumor entity (p = 0.32), N status (p = 0.14), underlying disease (p = 0.29), dichotomized UICC stage (p = 0.68), or grading (0.6). However, N1 status was associated with significantly shorter survival of 18.4 (3.9–20.7) months vs. 40.3 (3.1–333.3) months . In multivariable regression analysis, N0 status revealed a statistically significant positive impact on the overall survival of CCA after LT (HR 3.8 (CI: 1.2–12.0); p = 0.02). Additionally, early recurrence (<2 years after LT) was associated with the worst overall impact on survival with HR 75.5 , but tumor entity (p = 0.84), underlying liver disease (p = 0.33), UICC stage (p = 0.73), or grading (p = 0.39) were not (The median age at diagnosis was 56.0 (32.0–74.0) years. The initial classification of carcinoma according to the UICC was stage I in five (11.4%) patients. In total, 18 (40.9%) patients were in stages II and III, and 3 (6.8%) patients were in stage IV. The majority of 27 (61.4%) tumors were graded G2, but 12 (27.3%) patients were diagnosed with G3 malignancies. One histopathological analysis of explanted liver concerning tumor grading was missing. Correlation analysis did reveal a significant impact of the initial UICC stage (I/II vs. III/IV) and grading (G1 vs. G2/G3) on recurrence (were not .p = 0.035) but did not reach statistical significance in Kaplan–Meier analysis  when compared to patients with recurrence after 2 years. Frequent localizations of recurrence were within the peritoneum (n = 17/38.6%) and lungs (n = 13/29.5). Multiorgan manifestation was observed in 32 (72.7%) patients, and in 7(15.9%), singular recurrence occurred within the transplant, but neither affected survival outcomes in Kaplan–Meier analysis .The median time from LT to tumor recurrence was 15.8 (0.8–128.2) months. In the majority of 29 (65.9%) cases, recurrence was within 2 years after LT and was similarly associated with shorter survival after diagnosis of 6.2 (0.53–51.5) months vs. 15.8 (0.13–72.8) months  patients were eligible for surgery, with 7 (15.9%) receiving only surgery only and 5 (11.4%) needing additional chemo- or radiotherapy. In 15 (34.1%) patients, palliative chemotherapy or radiotherapy was initiated, but 17 (38.6%) patients received the best supportive care only. The outcome of survival after diagnosis was significantly affected by therapy strategies, with a median survival of 18.1 (3.6–72.8) months for patients undergoing surgery with or without chemo-/radiotherapy, 12.2 (1.0–42.5) months under chemo-/radiotherapy only and just 1.2 (0.13–25.9) months when only symptomatic therapy was possible  .n = 13/29.5%), glucocorticoids (n = 15/34.1%) or mTORI (n = 10/22.7%). Four (9.1%) patients received monotherapy with mTORI. The mean IS score was 3.4 (±2.4) units. The analysis presented a significant correlation of IS score with recurrence, both when analyzing absolute scores and after grouping into low (IS score 0–1.5), medium (IS score 1.6–3.5), and high (IS > 3.6) . The chi2 test proved significant in cross-table analysis  patients, these substances were administered, and the mean tacrolimus dosage was 4.1 (±2.6) mg/d. Combination therapy was used in 27 (61.4%) patients, with either MMF . Further, reductions in the number of patients receiving MMF to 11 (25.0%) and glucocorticoids to 10 (24.4%) were documented, and only the number of patients receiving mTORI increased to 15 (34.1%).Following the diagnosis of recurrent malignancy, the number of patients with CNI therapy was reduced to 34 (85.0%), and the mean tacrolimus dosage was 2.9 (±1.9) mg/d. Wilcoxon test revealed the statistical significance of dosage reduction in tacrolimus (p < 0.01). The median time of survival after recurrence was 16.7 (0.53–72.8) months for this group and proved to be significantly improved, compared with the group of patients with unaltered IS with 5.3 (0.13–42.5) months (p = 0.01). This finding was confirmed by Kaplan–Meier analysis   patients of the cohort suffering from rCCA after LT were identified who underwent a reduction in IS and, therefore, were grouped into RIM. Here, the mean IS-score was 3.9 (±2.4) units before and 2.2 (±1.7) units after diagnosis of recurrence ( = 0.02) . The eff = 0.02) . Effect Subgroup analysis of therapeutic approach and handling of IS did not show additional benefit of RIM for patients undergoing resection with a median survival of 19.3 (6.2–72.8) and 6.8 (3.6–23.4) . Similarly, there was no impact of RIM when groups with palliative therapy  or best supportive care  were analyzed individually.p < 0.01) and HR 3.4 , respectively.Multivariate regression analysis using clinical variables with putative empirical effect on oncological course after diagnosis of rCCA after LT confirmed the detrimental effect of grading > G1 and tumor manifestation in lymph nodes (N1 status) for survival after diagnosis of recurrence with HR 7.7  was found. Additionally, the effect of RIM was confirmed, as patients without RIM showed impaired outcomes, with statistical significance in this analysis . MTORI therapy did not show a significant impact, regardless of administration before or after diagnosis of recurrence . Complete multivariate analysis is displayed in Further, statistically significant impaired survival for therapeutic regimens that did not include surgical resection  after rCCA diagnosis, performed in an individualized manner in each case, is able to significantly improve patient survival. According to our current knowledge, there are no data in the literature on this aspect. However, we were able to confirm similar findings for the association of RIM and HCC in a retrospective work published recently . The resBased on our analysis, comparable results were obtained for mHCC/CCA mixed-tumor patients, compared with CCA patients, in terms of recurrence and recurrence rate, although the number of patients may be small and somehow may cause bias.In comparison, Sapisochin et al. demonstrated that mHCC/CCA mixed tumors recurred more frequently than intrahepatic CCA, while Lee et al. reported a comparable recurrence rate between the two tumor types ,10. In cWe found a recurrence rate of 66% in our collective, which is much higher than in patients transplanted for HCC (around 20%) but is consistent with previous studies ,26,27. CIn this study, recurrence was significantly associated with higher UICC stage and N1 status at initial LT. N1 status was also associated with impaired overall survival in multivariate analysis for oncological parameters at LT, highlighting the importance of adequate staging before LT to identify eligible patients in times of organ donor shortage. Previous studies found tumor size, histological parameters, and differentiation to be associated with a high recurrence rate . We did Our multivariate regression analysis for the impact on survival for rCCA after LT showed a statistically significant effect on the impact of RIM in our population. Since treatment options are limited in recurrence besides surgical strategy, RIM should definitely be pursued with close monitoring and in a multidisciplinary approach for rCCA. We believe that individualized IS is necessary and crucial to improve the limited survival of patients.There are only a few studies regarding immunosuppression for LT in CCA and in mHCC/CCA patients. While several studies investigated this association in HCC patients. For example, Rodríguez-Perálvarez et al. showed a more than threefold higher risk of recurrence in the first month after LT when tacrolimus levels are >10 ng/mL. In the context of immunological activity, the first month after LT seems to play an important role in the influence of CNI reduction on relapse . SimilarUsing a scoring system for IS previously introduced by Vasudev et al., we found a striking impact on the level of IS on time and the possibility of recurrence in our cohort of patients after LT for CCA, further condensing the suspicion of a fine line between rejection prevention and disastrous side effects . We beliUnlike in HCC, the importance of acute cellular rejection seems to be rather secondary in the CCA context, although a definite statement is not possible due to the rarity of the diagnosis in the present setting ,34. In aThe limitations of our study are the retrospective study design and the historical patient cohort. Especially since these tumors will continue to be misdiagnosed as HCC before LT. There is a sustained need for research on LT for CCA and mHCC/CCA both for retrospective evaluations with larger patient cohorts and with regard to a prospective study design. Further, the historical patient cohort of 30 years did not allow for differentiated analysis of systemic antineoplastic regimens or subgroups. Additionally, individual indication for RIM was not evaluated and not standardized. Indication for LT in patients with CCA might have been inhomogeneous, and accidental findings of CCA were included in this study as well.Although our historical cohort over a period of three decades with different therapy adjustments of IS inherits heterogenous therapeutical concepts, this circumstance can also be seen as a strength since, firstly, it is known that much higher doses of IS were administered in the past, and secondly, several therapy regimens could be identified, so that the corresponding comparison groups could thus be formed. Still, indications for LT in our patients were highly variable and, in part, time-dependent; therefore, they may not reflect current therapeutic standards.Since the results in the past on CCA and LT were very poor, LT was seen as a formal contraindication ,36,37,38The role of CNI is critical with regard to acute cellular rejection (ACR) and graft loss . HoweverWhile we assessed the use of a restrictive IS (RIM) as important for the overall survival of patients after LT, after a recurrence of malignancy, further reduction inherits the ability to improve following oncological regimens and appears to be safe, as we did not see an increase in rejections or graft loss in patients receiving RIM. Thus, from our point of view, CNI reduction should always be attempted and can be seen as an oncological accompanying measure in the already bleak situation, where options regarding systemic antineoplastic regimens remain poor despite rising efforts ,46. MultWhile LT for CCA remains controversial, oncological, targeted therapies and promising prospects of improved oncological outcomes by, e.g., machine perfusion of grafts, may explore new pathways ,49.We did not examine the pathophysiological mechanisms of this observation, but taking into account that oncogenesis is accompanied by reduced surveillance and identification properties of the immune system, a putative pathway may include the unleashing of immune function with a subsequent enhanced ability for tumor recognition ,51,52. UThus, we conclude that oncological follow-up after LT should switch focus from primarily avoiding rejection to allowing as much immunological stimulation as possible and, therefore, risking undetected, clinically irrelevant liver tissue damage since, otherwise, our observations regarding a correlation between a reduction in immunosuppression and an improved outcome in patients after LT do not seem to be explainable. It is emerging that a protocol for IS dosing before and after relapse plays a role in both CCA and mHCC/CCA.The results of this analysis emphasize the importance of follow-up after LT in terms of earlier detection of tumor recurrence with the possibility of surgical therapy and balanced mild IS according to the rule “as little as possible, as much as necessary”, and a bold reduction in IS in case of tumor recurrence as an important oncologic adjunctive measure.


BackgroundIn this study, we aimed to assess the effectiveness of omeprazole therapy in the management of acid peptic disease (APD) among type 2 diabetes mellitus (T2DM) patients.MethodologyIn this multicenter retrospective study, electronic medical records (EMRs) of T2DM patients with APD who were prescribed omeprazole between March 2018 and April 2021 at multiple Indian healthcare settings were reviewed. The resolution of APD symptoms was assessed at visit five (120 days after the index visit) and compared to visit one (index visit). Safety was established in terms of reported adverse events during the study period.ResultsOverall, 174 patients were included. The majority of patients (63.8%) were males with a mean age of 48.6 ± 11.03 years. After receiving omeprazole therapy, a significant number of patients reported improvement in symptoms such as abdominal pain (98.2%), epigastric burning (74.2%), altered bowel movements (62.1%), and nausea (80.5%) (p < 0.001 for each). Complete resolution was observed in all patients who complained about flatulence (100.0%) and loss of appetite (100.0%) (p < 0.001 for each). The drug was found to be well tolerated.ConclusionsOmeprazole therapy was well tolerated and highly effective in resolving APD symptoms among T2DM patients receiving fixed oral hypoglycemic agents. Diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by hyperglycemia, depletion of antioxidants, and lipid metabolism changes . The resProton pump inhibitors (PPIs) are the cornerstone of APD treatment and are easily available on prescription as well as over the counter . They arDespite the common usage of PPIs among APD patients, there are limited studies evaluating the effectiveness and safety of these agents among DM patients in Indian settings. Therefore, the present study (PRIDE-1) intends to provide real-world, data-based insights into the effectiveness and safety of omeprazole therapy in managing APD among type 2 diabetes mellitus (T2DM) patients receiving fixed antidiabetic therapy.This was a retrospective, observational study conducted by collecting data from electronic medical records (EMRs) of T2DM patients with APD visiting outpatient settings of Indian tertiary healthcare centers between March 2018 and April 2021.Study populationPatients aged ≥18 years with T2DM who were newly diagnosed with APD (diabetic patients who were diagnosed with APD for the first time at the index visit) and receiving fixed oral hypoglycemic agents (OHAs) for a minimum of three months before visit 1 (index visit) were included in the study. Patients with the same fixed antidiabetic medications and receiving omeprazole (20 mg) for APD for a minimum of four weeks after the index visit were included in the study. However, patients with type 1 DM or gestational DM, those on insulin or other injectables, and T2DM patients treated with H2-receptor antagonists or other PPIs for APD treatment were excluded from the study.Study outcomesThe study outcomes were evaluated at visit 0 (90 days before visit 1), visit 1 (index visit), and visits 2, 3, 4, and 5 . The primary outcome of the study was to determine the clinical improvement, defined as symptomatic relief or resolution of symptoms, i.e., pain in the abdomen, epigastric burning, nausea, flatulence, loss of appetite, and altered bowel movements, etc., at visit 5 compared to visit 1 in APD patients with T2DM receiving omeprazole. Further, safety was assessed in terms of adverse events (AEs) reported during the study period. The secondary outcome of the study was to assess the effect of omeprazole on glycemic control, which was determined as the mean percentage decrease in glycemic parameters , post-prandial blood sugar (PPBS), and random blood sugar (RBS)) at visit 1 compared to visit 0 and at visit 5 compared to visit 1.Statistical analysisData were analyzed using R studio 1.2.1335. Continuous variables such as age and duration were presented as means ± standard deviation (SD) and compared using the t-test/Mann-Whitney U test. Categorical variables such as gender and city/state were presented as percentages/proportions and compared using the chi-square test/Fisher’s exact test. Statistical significance was considered at p-values <0.05.Baseline characteristicsA total of 174 patients with T2DM and APD were included in the study. Overall, the majority of patients were males, i.e., 111 (63.8%) with a mean age of 48.6 ± 11.0 years. Other parameters such as weight, pulse, body temperature, and systolic and diastolic blood pressures are tabulated in Table EffectivenessSymptomatic ReliefThe effectiveness of omeprazole was assessed in terms of the number of patients who reported relief at visit 5 compared to visit 1. At visit 1, abdominal pain (64.9%) and epigastric burning (55.7%) were the chief complaints, followed by altered bowel movements (38.0%), nausea (23.6%), loss of appetite (21.3%), and flatulence (16.6%).The number of patients with abdominal pain at visit 1 (n = 113) was significantly reduced at visit 5 (n = 2), implying that 98.2% of patients had symptomatic relief (p < 0.001). Further, epigastric burning was reported by 97 patients at visit 1, and the number gradually reduced to 25 at visit 5, wherein 74.2% of patients had symptomatic relief (p < 0.001). Improvement in altered bowel movements was reported by 62.1% of patients (the number of patients complaining about the symptom decreased from 66 to 25) (p < 0.001). The patients who reported nausea declined from 41 (at visit 1) to eight (at visit 5), demonstrating that 80.5% of patients got relief from nausea (p < 0.001). Complete resolution was observed in all (100%) patients who complained about flatulence (p < 0.001) as well as loss of appetite (p < 0.001) at visit 5  while the patients were taking only OHAs (p < 0.001). A further significant reduction of 6.1% was observed while patients were taking OHAs along with omeprazole . Similarly, the percentage reduction in the mean FBS level was found to be 19.9% (p < 0.001) from visit 0 to 1, with a reduction of 10.8% from visit 1 to 5 (p < 0.001). In the case of mean PPBS, a marked reduction of 22.4% was observed from visit 0 to 1 (p < 0.001), with a subsequent reduction of 13.1% from visit 1 to 5 (p < 0.001). The decrease in mean RBS levels was noted to be 18.3% , followed by a reduction of 9.2%   compared to placebo  after seven days of treatment. Moreover, omeprazole was found to be significantly (p ≤ 0.003) more effective than placebo for the management of acid regurgitation, dysphagia, epigastric pain, and nausea . A revieIn the PRIDE-1 study, omeprazole, when administered along with OHAs, was found to be relatively safe as no major AE  was observed. This is consistent with the existing literature that states PPIs are relatively safe medications . The risFurther, in this study, a significant improvement in glycemic parameters was observed in patients after taking OHAs (from visit 0 to visit 1). A subsequent marked reduction in glycemic parameters observed from visit 1 to 5 might be attributed to the addition of omeprazole to the existing combination of OHAs. The role of PPI in glycemic control in T2DM patients has been elucidated by their action of lowering gastric acid, subsequently increasing gastrin levels that stimulate beta-cell proliferation and function . ChandraLimitationsThe study was retrospective in nature, due to which the analysis was limited to the information available in existing database records. Further, due to the retrospective design of the study, it lacks the presence of a control group which would have facilitated precise differentiation between the impact of OHAs and omeprazole on APD patients. Additionally, certain symptoms induced by concomitant medications cannot be differentiated from the presenting symptoms of APD.Omeprazole has been widely used to prevent and manage several acid-related disorders. The PRIDE-1 study demonstrated its significant effectiveness in providing symptomatic relief in T2DM patients with APD. Further, omeprazole was found to be well-tolerated among DM patients taking fixed OHAs. It may also potentiate glycemic control in these patients, which needs to be further validated via well-controlled randomized studies.


For 35 (55.6%) individuals, diagnosis of 22q11.2 deletion syndrome (22q11.2DS) followed diagnosis of an offspring, with disproportionately fewer individuals had major congenital heart disease (CHD) in that transmitting parent subgroup. The regression model indicated that major CHD, in addition to previously identified factors, was a significant independent predictor of reduced reproductive fitness. There was evidence of persisting diagnostic delay and limited prenatal genetic testing. The findings indicate that pregnancy loss is an important health issue for adults with 22q11.2DS. CHD and/or its absence is a factor to consider in reproductive outcome research. Further studies are warranted to better appreciate factors that may contribute to reproductive outcomes, including technological advances. The results suggest the need for ongoing efforts to provide optimal education and supports to individuals with 22q11.2DS, and their clinicians, around reproductive issues and early diagnosis.The 22q11.2 microdeletion and its associated conditions could affect reproductive outcomes but there is limited information on this important area. We investigated reproductive outcomes in a sample of 368 adults with typical 22q11.2 deletions , and without moderate-severe intellectual disability, who were followed prospectively. We examined all reproductive outcomes and possible effects of diagnosis as a transmitting parent on these outcomes. We used logistic regression to investigate factors relevant to reproductive fitness (liveborn offspring). There were 63 (17.1%) individuals with 157 pregnancy outcomes, 94 (60.3%) of which involved live births. Amongst the remainder involving a form of loss, were seven (5.77%) stillbirths, significantly greater than population norms ( The 22q11.2 microdeletion affects nearly one in 2000 live births and causes 22q11.2 deletion syndrome (22q11.2DS), the most common, and one of the most clinically relevant, of microdeletion syndromes , there cSeveral conditions associated with 22q11.2DS, including those present from early in development such as congenital heart disease (CHD) or intellectual disability (ID), and those that arise later such as psychotic illness, may be expected to affect reproduction ,6. In coThe aim of this study was to examine reproductive outcomes in a large, well-characterized sample of adults with 22q11.2DS where data were available on pregnancy and pregnancy outcomes. We investigated possible effects of diagnosis that occurred only after diagnosis of an offspring. We also evaluated possible predictors of live births in 22q11.2DS. Based on previous literature  we hypotn = 406), as this is a subgroup less likely to have pregnancies (and there were none in this subgroup). The sample for this observational cohort study comprised 368 adults with 22q11.2DS , all with a typical 22q11.2 deletion, confirmed by clinical genetic testing using a standard probe and fluorescence in situ hybridization (FISH) or genome-wide microarray, and followed longitudinally ,11. We eFor this adult 22q11.2DS sample, we recorded lifelong data for any pregnancies among study participants or, for male participants their female partners, obtained as a routine part of initial and follow-up assessments. These included age at pregnancy, reproductive outcomes, conception method , natural conception), and partner and relationship characteristics. Advanced maternal age was defined as ≥35 years. Stillborn was defined as the birth of a fetus at ≥20 weeks gestation, with no signs of life at birth. We also recorded whether individuals were ascertained as transmitting parents, i.e., receiving a diagnosis of 22q11.2DS through follow-up testing after determination of a 22q11.2 microdeletion in an offspring or through an affected pregnancy. As before, we examined data recorded for key phenotypic features ,10, inclThe study was approved by the local research ethics boards of the Centre for Addiction and Mental Health and University Health Network, which are affiliated with the University of Toronto. Informed consent was obtained in writing for all participants.t-tests, as appropriate, including those to investigate possible effects of diagnosis of 22q11.2DS as a transmitting parent. For reproductive outcomes, we searched for comparable Canadian population-based norms and identified those for stillbirths (for 1991–2020) as a proportion of all deliveries [Analyses included descriptive statistics: Chi-square, Fisher’s exact, and liveries  to compaA logistic regression model was constructed to analyze factors of relevance to reproductive fitness in 22q11.2DS . Multicollinearity analyses to identify any potentially correlated variables in the model showed that variance inflation values did not exceed 1.5, suggesting there were no issues with multicollinearity. p values < 0.05.Analyses were performed using R version 4.1.3 software , including rms and lmtest packages for the regression analysis ,15, or Sn = 48, 76.2% vs. n = 15 male, 23.8%, χ2 = 15.32, p < 0.0001). The demographic and clinical features of these 63 adults are summarized in Of the 368 adults with 22q11.2DS studied, there were 63 (17.1%) with a history of at least one pregnancy. Significantly more were female (p = 0.3485). For the comparable subgroup not diagnosed as a transmitting parent , diagnoses of 22q preceded 36 of 55 (65.5%) pregnancies. Examining for possible effects on pregnancy findings of diagnosis with 22q11.2DS as a transmitting parent, we found that there were 35 (55.6%) individuals in this subgroup . None ofThere were 157 outcomes of these 156 pregnancies (one twin pregnancy resulted in one live birth and one spontaneous abortion): 94 (60.3%) live births, 34 (21.2%) spontaneous abortions, 22 (14.1%) therapeutic abortions including two late-term terminations for nonviable fetuses, and 7 (4.5%) stillbirths. p = 0.0002). In this 22q11.2DS sample, spontaneous abortions appeared consistent with the high end of Canadian population-based estimates (21.2% vs. 15–25%) [For all nine pregnancies involving a stillbirth or otherwise fatal anomaly there were multiple features highly consistent with a 22q11.2 microdeletion. Only two of the eight from the molecular era received a molecular diagnosis of a 22q11.2 microdeletion . For a recent stillbirth, prenatal ultrasound findings contributed to obtaining a postnatal diagnosis and subsequent parental diagnosis. However, few of the 63 individuals in the sample with pregnancies were known to have ever had genetic prenatal testing or screening for a 22q11.2 deletion at any pregnancy [ 15–25%) , and the 15–25%) . 2 = 9.75, p = 0.0018). Extending reproductive outcomes to age 2 years, there were four (4.21%) infant deaths, all with severe congenital cardiac abnormalities, two with confirmed, and two deemed retrospectively likely to have had 22q11.2 microdeletions. For the 51 parents with a 22q11.2 microdeletion who had liveborn offspring, median parental age at first live birth was 25.7 years (range 17.0–35.0) for 39 mothers, and 31.4 years (range 22.5–37.5) for 12 fathers. Twenty-seven (52.9%) of these parents with 22q11.2DS  had two or more liveborn offspring; 18/27 were in the transmitting parent subgroup. Of the 94 liveborn offspring, 28 (29.8%) were born to an individual at median age 26.6 (range 21.3–35.0) years who had been diagnosed with 22q11.2DS for reasons other than as a transmitting parent. Of these offspring, 11 (39.3%) have a 22q11.2 microdeletion. This was a significantly lower proportion than the confirmed 71.2% (47 of 66) for those born to an individual diagnosed with 22q11.2DS as a transmitting parent  were married or had a long-term (>1 year) partner at the time of the birth of their first offspring; two of these were arranged marriages. Of these 43, 29 67.4%) subsequently separated from this partner. Of the 27 individuals with two or more liveborn offspring, 17 (63.0%) had the same partner for each of these offspring. Of the 51 families where one parent had 22q11.2DS, 12 (23.5%) had received support from Child Protective Services (Children’s Aid Society in Ontario). This support ranged from one-time encounters to issues related to child custody that sometimes involved identifying an alternative living situation for the child 7.4% subs.n = 39, 76.5% female) adults with at least one liveborn offspring to the 317  with no liveborn offspring (p = 0.0906) amongst those with liveborn offspring. As hypothesized, individuals with no liveborn offspring were younger, and less likely to be female, or to have a psychotic illness or mild ID  of the variance of this likelihood and correctly classifying 84.5% of this sample of 368 adults with 22q11.2DS. The results showed that, while accounting for effects of the other four variables, younger age, psychotic illness, male sex, mild ID, and major CHD were each independent negative predictors of having liveborn offspring in 22q11.2DS.The logistic regression model to assess the likelihood of having at least one liveborn offspring was statistically significant (χThe results of this study demonstrate that only a minority of women and men with 22q11.2DS have a history of pregnancy (on average 2.5 per person), even though individuals with moderate to severe intellectual disability were not included, and over half of the individuals with a pregnancy history were diagnosed to have a 22q11.2 microdeletion on the basis of a new diagnosis in an offspring. The outcomes of the 156 pregnancies involved substantial losses, including spontaneous abortions (miscarriages), stillbirths , and infant deaths, most likely attributable to the 50% risk of transmitting the 22q11.2 microdeletion at each pregnancy. The results indicate that, in this sample, there was limited to no known uptake of available prenatal genetic testing, including that for a 22q11.2 microdeletion. There was also no indication that elective terminations were common, and indeed may be somewhat less common amongst individuals with 22q11.2DS than population norms. Direction and relative effect sizes of previous findings that male sex, major neuropsychiatric issues  and older age affect the likelihood of having liveborn offspring in this genetic condition were confirmed . Importan = 158) [For individuals with 22q11.2DS, the elevated prevalence of stillbirths, about 9-fold greater than population-based expectations, is consistent with previously reported results using an overlapping but much smaller sample  . The resn = 158) ,20. Simin = 158) ,22, suggn = 158)  may indeThe low uptake of prenatal genetic testing, and relatively low prevalence of elective termination, in our cohort appear comparable to previous reports ,23. AmonOur findings further confirm the association of male sex and major neuropsychiatric phenotypes with lower reproductive fitness in 22q11.2DS , and thaWhile this study used the largest sample yet to investigate reproductive outcomes and fitness among adults with 22q11.2DS, the sample size of those with pregnancies remains relatively small. Due to diligence in tracking down elderly parents of our adults with 22q11.2DS for standard genetic testing, combined with following our cohort prospectively, the pregnancies analyzed span over six decades. The fact that over half of the individuals with pregnancies in our sample were diagnosed with 22q11.2DS following the diagnosis of an affected offspring is an ongoing ascertainment issue in the field, and applies not only to reproductive outcomes but also to other research. To our knowledge, no previous study of reproductive outcomes has reported this important ascertainment parameter. Reproductive outcomes will also be affected by temporal factors, including new technologies and their uptake ,33, and This study demonstrates that although individuals with a history of pregnancy are relatively uncommon, adverse reproductive outcomes, especially stillbirth, are relatively common in 22q11.2DS. Most of these adverse outcomes are likely to be related to transmission of the 22q11.2 microdeletion. Any possible role of the maternal 22q11.2DS phenotype amongst pregnant individuals, and possible effects of partner choice, genetic background, and other factors including possible interactions between maternal and fetal phenotypes, will require further study to discern. Ensuring follow-up parental testing after prenatal, pediatric and later new diagnoses of a 22q11.2 microdeletion could facilitate these studies. Confirming that male sex, and the 22q11.2DS neuropsychiatric phenotype, and also that major congenital heart disease, adversely affect reproductive fitness may prompt further study of selective advantage and disadvantage in 22q11.2DS. Such studies may benefit from comparisons with unaffected siblings. Given the numbers, it is likely that multicentre prospective studies would be necessary to better understand other factors of lower effect size that may contribute to reproductive outcomes in 22q11.2DS, such as the 22q11.2 deletion extent. This work supports further research to investigate factors that affect reproductive choices, pregnancy outcomes, and parenthood in 22q11.2DS. Moving forward, increased access to advanced molecular diagnostic and NIPS for 22q11.2 microdeletions ,33, and In summary, results of this study have important clinical and research implications for adults with 22q11.2DS and their families, and for service providers and researchers, including those in obstetrics and maternal fetal medicine. Further research is needed about reproductive outcomes for individuals with 22q11.2 microdeletion and other rare genomic disorders that are increasingly detectable.


A total of 85.7% of patients in the intermittent fasting 5:2 plus group lost more than 5% body weight, vs. 58.5% in the daily calorie restriction group (p = 0.008), and 45.2% lost more than 10% body weight, vs. 14.6% in the daily calorie restriction group (p = 0.005). No serious adverse events were reported in the three groups. The intermittent fasting 5:2 plus program more effectively led to weight loss than daily calorie restriction in the short-term in Chinese patients with overweight or obesity. A longer-term prospective randomized controlled trial is needed.To retrospectively review the efficacy of intermittent fasting 5:2 plus program (30% of energy requirements on fast days and 70% of energy requirements on nonfasting days) in Chinese patients with overweight or obesity. This retrospective cohort study evaluated weight loss outcomes of patients treated with 12 weeks weight loss program in clinic. Adults with overweight or obesity participated in intermittent fasting 5:2 plus, daily calorie restriction (70% of energy requirements every day) or daily calorie restriction with meal replacement  programs for 12 weeks. The primary objective was to compare the weight loss of three groups. The primary outcome measure was the change in the % total weight loss. A total of 131 patients  were included, and the mean weight loss was 7.8 ± 4.4% after 12 weeks. The intermittent fasting 5:2 plus group ( The worldwide obesity prevalence has increased significantly, and China has the largest population of obesity ,2. IntenThe mechanisms of IF in weight loss and metabolic health are complex and include enhancing defenses against oxidative and metabolic stress, eliminating or remediating damaged molecules and improving insulin resistance ,9,10. IFCurrently, in clinical practice IF programs provide 30–40% of energy requirements on fasting days and 100% or ~125% of energy requirements on nonfasting days . A previEnergy restriction on nonfasting days with alternate-day fasting model was shown to be effective in previous study . HoweverThis was a retrospective analysis of 12-week weight loss data. Data from electronic database of patients with overweight or obesity receiving 12 weeks of weight loss intervention at the Peking Union Medical College Hospital (PUMCH) from 1 July 2018 to 1 July 2020 were reviewed. The patients with overweight or obesity receiving different weight loss interventions were included. (1) Intermittent fasting 5:2 plus group: the patients were provided approximately 30% of their energy requirements on fasting days (two non-consecutive days a week) and 70% of their total energy requirements on nonfasting days. (2) Daily calorie restriction (CR) group: the patients were provided approximately 70% of their total energy requirements per day. The targeted percentages of energy derived from fat, protein, and carbohydrates were 20%, 20%, and 60%, respectively. The average eating frequency was defined as 5 times a day, including breakfast, lunch, dinner and two extra meals with fruit or yogurt at 10 AM and 4 PM. (3) Daily calorie restriction with high protein meal replacement (HP) group: the patients were provided approximately 70% of their total energy requirements per day. The targeted percentages of energy derived from fat, protein, and carbohydrates were 30%, 30%, and 40%, respectively. Approximately 50% of protein was provided by whey protein isolate powder as a meal replacement for breakfast and a snack in 4 PM. One scoop (23.2 g) of whey protein a meal replacement contained of 88.8 kcal, 20.0 g protein, 0.5 g fat, 0.6 g carbohydrate and 0.084 g sodium . These patients were asked to complete 150–300 min of moderate-intensity aerobic or resistance exercise per week. And several behavioral strategies were also advised and consisted of reducing high-fat food consumption, having regular eating times, having an average eating frequency of 5 times a day, eating vegetables and protein first and carbohydrates later, increasing the number of chewing cycles, self-weighing every day, avoiding prolonged periods of sitting, exercising every day and going to sleep early. Data on weight and body compositions were collected when the patients were reviewed in clinic every 4 weeks. Dietary education was provided by trained registered dietitians or physicians in clinic.2, and (3) a 12-week weight loss intervention. Patients were excluded if they could not complete the 12-week weight loss intervention. The patients with type 1 or 2 diabetes, cardiovascular events, or cancer were excluded. The study was approved by the Ethics Committee of PUMCH .The inclusion criteria were as follows: (1) 18–70 years old; (2) BMI > 25 kg/mThe primary objective was to compare the weight loss effects of three groups for 12 weeks of weight loss. The primary outcome measure was the change in the % total weight loss (TWL). The secondary outcome measures were the fat mass (FM): total mass (TM) ratio and the fat free mass (FFM): total mass (TM) ratio. The body weights, body mass index (BMI) and body compositions of patients were measured after fasting for 8 h at 0 and 12 weeks with multi-frequency segmental bioelectrical impedance analysis . Weight loss was defined as the initial weight minus the final weight. The % TWL was defined as the difference between the initial weight and final weight divided by the initial weight.Clinical data such as age, sex, weight and body compositions at 0 and 12 weeks were collected from an independent electronic database. Data on adverse events were collected from the patients’ self-reported complications. The serious adverse events were define as death, pancreatitis, cholecystitis, serious abdominal pain of unknown aetiology. Data were abstracted and inputted independently by 2 trained investigators to ensure consistency and integrity. Disagreements on information were resolved by consensus or by retrieving further information from the electronic database.t test for normally distributed variables or Wilcoxon test for nonnormally distributed continuous variables. A two-tailed p value of less than 0.05 was considered statistically significant. Statistical analyses were performed with SPSS software .For the sample size calculation, IF was shown to reduce body weight by 6% in previous papers . We calcn = 107) were female. The mean body weight was 84.8 ± 16.4 kg, with a mean BMI of 30.7 ± 4.7 kg/m2. The baseline characteristics of patients were comparable among three groups  (p < 0.001).At week 12, the weight change from baseline was 7.9 ± 5.0 kg in the IF group, 7.5 ± 3.6 kg in the HP group and 4.7 ± 3.4 kg in the CR group  . The % Tp = 0.008 and 0.005, respectively) (p = 0.650), proportion of subjects with more than 5% weight loss  and more than 10% weight loss  between the IF group and HP group.There were also significant differences in percentages of more than 5% weight loss and more than 10% weight loss among groups  . Comparet tests for differences within groups, t = 10.203, p < 0.001). 41 were in the daily calorie restriction group, the weight change from baseline was 4.7 ± 3.4 kg . 48 were in the daily calorie restriction with high protein meal replacement group, the weight change from baseline was 7.5 ± 3.6 kg . As shown in After 12 weeks of weight loss intervention, 131 patients lost an average of 6.8 ± 4.3 kg and had a 7.8 ± 4.4% reduction in body weight. The changes in weight, BMI, FM/TM and FFM/TM were shown in p = 0.257, 0.597 and 0.985, respectively).During follow-up, all patients were interviewed face-to-face every 4 weeks. No serious adverse events were reported in the three groups. The common self-reported complications were constipation (6.8%), fatigue (5.3%) and hair loss (4.6%). There were no significant differences in the rates of constipation, fatigue and hair loss among the three groups , and the % TWL was higher in the HP group than in the CR group. This finding is consistent with the outcomes of previous studies. Meal replacement programs for weight loss were associated with eliminating choices, controlling portions and enhancing adherence ,20,21. OTherefore, in addition to reduced calorie intake, other mechanisms may underlie the weight loss observed with IF. Several mechanisms of IF have been reported, such as metabolic switching, metabolic adaptations, enhanced mitochondrial health and blunted inflammation ,10,36. IIn previous studies, the common adverse effects of IF included dizziness, headache, nausea and temporary sleep disturbances . Partici2 were enrolled in this study, and we cannot generalize the benefits of the 5:2 plus program in other populations. For example, in lean, healthy adults, intermittent fasting was shown to less effectively improve postprandial indices of cardiometabolic health and reduce body fat mass than CR in a randomized controlled trial [There are several limitations in our study. First, this was a retrospective cohort study, and the study group assignment was not randomized, although the baseline characteristics were comparable among groups. A prospective randomized controlled trial is needed in the future. Second, this is a short-term study and the duration of 12 weeks was relatively short. The effects of weight loss were superior in 8-week or 12-week time-restricted feeding interventions compared with CR interventions ,43, but ed trial .Nonetheless, to our knowledge, this is the first exploratory study to examine the weight loss effect of 12-week intermittent fasting 5:2 plus intervention in Chinese patients with overweight or obesity. The findings of this study could help adults with overweight or obesity select an appropriate intervention for short-term weight loss.The intermittent fasting 5:2 plus program led to effective weight loss in the short-term in Chinese patients with overweight or obesity. A longer-term prospective randomized controlled trial is needed.


There is evidence that metabolic syndrome (MetS) is common in chronic psychosis but also exists in the early stages.To study the prevalence and course of MetS over a period of 2 year after a first episode psychosis. To determine whether there may be differences in its prevalence according to the type of antipsychotic used over two years.A sample of 300 patients participate in the PEPsNa Early Intervention Programme. SMet was determined at baseline and at 6, 12, 18 and 24 months. The type of antipsychotic used at each assessment moment is collected . Adult Treatment Panel III (ATP III) criteria were used to define MetS.The prevalence of MetS at baseline is 4.44% and increases to 7.96% at 6 months, 10.1% at 12 months, 8.62% at 18 months and 9.01% at 24 months. The prevalence of MetS increases at 6 (p<0.021) and 12 months (p<0.003) compared to baseline and then remains stable. Only at 6 months assessment there are significant differences (F-Ficher p<0.022) in the presence of MetS (15.8%) in the paliperidone group treatment .Metabolic syndrome (MetS) exists from the early stages of psychosis and increases in the first 6-12 months and remains stable thereafter. The type of antipsychotic treatment only seems to have an influence at 6 months, with no differences at other follow-up times.No significant relationships.


Behçet's disease is a multisystem vasculitis whose pathogenesis remains unclear. Although usually described in young adults, it may begin in childhood. The diagnosis is clinical, based on international criteria. The limitations of early diagnosis are related to the progressive onset of symptoms and the variety of differential diagnoses at this age in the absence of a pathognomonic diagnostic test.To report the epidemiological features of our series and to compare the 2015 pediatric criteria with the 2014 and 1990 international criteria.This is a monocentric, retrospective study of 31 children over an 11-year period from January 2011 to December 2021. All patients suspected with Behcet's disease by a pediatric rheumatologist were included in the study, the 2014 international criteria “ISG 2014” being the gold standard classification criteria used in our center.p = 0.002) compared with the 2014 international criteria taken as gold standard, as well as the 1990 international criteria with a respective sensitivity and specificity of 52.6% and 91.7% (p = 0.034).31 cases of Behcet's were collected. The mean age was 10 years (5.5–16) ± 2.87 years. A female predominance is noted with a sex ratio F/M of 1.21. A quarter of the patients were from a consanguineous marriage and 38.7% had a family history of Behcet disease. Mucocutaneous manifestations were represented by recurrent oral aphthosis 87.1%, genital aphthosis 29%, pseudofolliculitis 48.4%, erythema nodosum 6.5% and acne lesions 3.2%. The pathergy test was positive in 1 case. Ocular involvement was reported in 29% and joint involvement in 45.2%. Thromboembolic complication was seen in 9.6% and neurobehcet in one patient. The HLA B51 antigen was present in 45.2% of cases. In our series 38.7% respond the pediatric criteria, while 61.3% met the 2014 international criteria and 35.5% met the 1990 international criteria. The 2015 pediatric criteria have respectively a sensitivity and specificity of 63.2% and 100% (p = 0.002).Our study highlights a female predominance, a high rate of consanguinity and familial Behcet. The sensitivity and specificity of the 1990 pediatric and international criteria appear to be better than those of 2014, with a more significant trend for the 2015 pediatric criteria (


The aim of this study is to evaluate the efficacy and toxicity of image-guided high-dose rate (HDR) interstitial brachytherapy (ISBT) for the reirradiation of cervical cancer within a previously irradiated area.3 (range: 26.9–208.3 cm3), and the median treatment-free interval (TFI) was 13 months (range: 3–93 months).Twenty-three consecutive patients with cervical cancer were reirradiated with curative intent using brachytherapy (BT) with or without external beam irradiation. The median biologically equivalent dose in 2-Gy fractions (EQD2) for reirradiation was 64.0 Gy (range: 31.3–95.1 Gy), and the median cumulative EQD2 (for primary treatment and reirradiation) was 152.4 Gy (range: 97.8–200.9 Gy). The average clinical target volume was 82.9 cmThe median follow-up time was 19 months (range: 2–59 months). The complete response rate after reirradiation was 56.5%. The 1-, 2- 3-, and 4-year post-relapse survival (PRS) rates were 65.2%, 43.5%, 33.8%, and 27.1%, respectively. The median reirradiation EQD2 D2cc of rectum and bladder was 39.5 Gy (range = 14.6–96.2 Gy) and 52.1 Gy (range = 29.1–114.2 Gy). The median cumulative EQD2 D2cc of rectum and bladder was 115.0 Gy (range = 84.4–189.3 Gy) and 130.5 Gy (range = 95.5–173.5 Gy). During follow-up, nine (39.1%) patients had experienced grade 3 or 4 late toxicities. Grade ≥3 rectal toxicity occurred in three patients (13.0%). Grade ≥3 urinary toxicity occurred in five patients (21.7%). One patient (4.3%) had both grade ≥3 urinary and rectal toxicity. Tumor volume, TFI, tumor invasion organ number, and local control were significant prognostic factors adversely affecting OS.For recurrent cervical cancer after radiotherapy, reirradiation of HDR-ISBT is feasible, even if the local tumor invasion is large, with a good chance of survival and acceptable side effects. Cervical cancer is the fourth most common malignancy and the fourth leading cancer-related death in women worldwide . The recThe retreatment of recurrent cervical cancer that develops in a previously irradiated field is a complex challenge for gynecologic oncologists . Surgery3 (D2cc) rectum and sigmoid colon was 70–75 Gy, and that of the bladder was 90 Gy  occur within a previously treated volume, following radical or adjuvant RT for cervical cancer. Fifteen patients were not suitable for pelvic exenteration, and the others refused surgery for fear of surgical trauma. Twelve patients had LR identified by pathological examination, and the rest had LR confirmed by pelvic MRI and positron emission tomography (PET)/CT. Twelve patients were initially treated at other hospitals, and detailed doses of organs at risk (OARs) could not be obtained. When brachytherapy is used, radiation doses to the rectum and bladder should be limited to 65% and 75% of the tumor dose, respectively . The limas 90 Gy . For patDuring reirradiation, the tumor location of some patients was too far from the vulva, leading to the use of external radiation therapy when the metal needles could not reach. Conformal EBRT was delivered to the tumors with a 0.7-cm margin using high-energy 6-MV photons with 1.8- to 2-Gy fractions to total doses of 30.0–50.4 Gy. The local tumor is the target of EBRT. The medical linear accelerator that we used is Varian Varianix-4702.The radiotherapy positioning system was Varian Eclipse 13.5. One hundred percent of the prescribed dose of EBRT was considered while calculating doses delivered to the tumor and the OARs.192 HDR brachytherapy machine, Oncentra brachytherapy planning system, and metal needle implantation are from Elekta, Sweden. The HDR ISBT was performed twice a week, 4–7 fractions in total, and 6–7 Gy for each fraction. Because of the large tumor volume and/or wide scope of invasion, ISBT was performed by freehand metal needle placement under CT guidance, resulting in excellent dose coverage. The patient underwent lumbar anesthesia in the operating room. After receiving anesthetic drugs, the patient was transferred to the large-caliber CT room dedicated to the Radiotherapy Department through a transfer bed. The anesthesiologist accompanied the patients all time to monitor vital signs. First, an intrauterine tandem was implanted in the uterine cavity. Then, some parallel and oblique metal needles  were inserted into the tumor and lateral extensions at different degrees angled to the vagina at a width and depth of approximately 10 mm as initial implantation. The insertion position and number of these oblique needles were decided by T2-weighted MRI  planning in all patients. All the patients have pelvic MRI before brachytherapy. The Ir3D plans were reported in high-risk clinical target volume (HR-CTV), defined as the cervix and the involved parametrium, vagina, vulva, urethra, pelvic wall, rectum, and bladder. The following dose–volume parameters were calculated for the HR-CTV and OARs (bladder and rectum): the percentage of the CTV receiving 100% of the prescribed dose (V100) and the dose that covered 90%, 98%, and 100% of the target volume . We calculated the D2cc of the rectum and bladder. The total doses (EBRT and HDR-BT) were recalculated as the biologically equivalent doses to 2-Gy fractions (EQD2) using the following equation: EQD2 = nd (d + α/β/2 Gy + α/β), where n = the number of fractions, d = dose (Gy) per fraction . For primary BT, the dose delivered by the two-dimensional (2D) treatment plan was calculated at point A and the rectum and bladder reference points, based on International Commission on Radiation Units and Measurements (ICRU)89 report .All time intervals were calculated from the final day of treatment. The tumor response was assessed 2 months after the reirradiation. The complete response (CR) was defined as the disappearance of the tumor, and the partial response (PR) was defined as a reduction of at least 30% in the sum of the maximum diameters of the tumor. Stable disease (SD) was defined as when none of the above conditions is applicable. Local control (LC) was defined as the length of time from the end of treatment to LR. The post-relapse survival (PRS) was calculated from the date of relapse diagnosis to the date of death for disease or the date of the last follow-up.The bladder and rectum complications were scored using the Radiation Therapy Oncology Group Acute and Late Radiation Morbidity Scoring Criteria .P-values<0.05 were considered statistically significant.PRS curves were derived from Kaplan–Meier estimates and compared using the log-rank test. The influence of potential prognostic factors on the risk of failure was assessed using a Cox model. 3. Eleven patients had the number of tumor invasion organ including bladder, rectum, and pelvic wall greater than 1. The tumors of the other 12 patients did not invade the bladder, rectum, or pelvic wall.There were 13 patients’ tumors that reached CR after radiotherapy, nine had PR, and one had SD , and the median cumulative EQD2 for primary treatment and reirradiation was 152.4 Gy (range = 97.8–200.9 Gy) . Five of them were NED, one was AWD, five were dead of oncologic disease (DOD), and one died due to cardiac sudden death. A total of 13 patients had CR in remission status after therapy, and the average follow-up time was 31.8 months. Among them, six were NED, one was AWD, three died due to LR or distant metastasis, two died due to complications of treatment, and one died due to cardiac sudden death. The treatment characteristics are detailed in , 43.5% (95% CI = 23.3%–62.1%), 33.8% (95% CI = 15.6%–53.1%), and 27.1% (95% CI = 10.2%–47.3%), respectively. The survival curve of PRS after re-radiotherapy is shown in The median primary RT EQD2 D2cc of rectum and bladder was 73.5 Gy (range = 22.8–93.1 Gy) and 80.2 Gy (range = 22.8–106.0 Gy) , and the median percentage volume of 100% prescription dose was 93.1%. This result suggests that freehand ISBT has better dose–volume histogram parameters for large volume tumors than conventional ICBT.Liu et al.  reported131Cs and 198Au as an isotope of PIB. The 2-year success rate for reirradiation using PIB was 67.3%. Grade 3 to 4 toxicities were observed in eight patients (16.7%). However, the limitation in this series is the fact that majority of recurrences in this series were small volume, with an area of 6 cm3. In our study, the average CTV was 88.5 cm3.Permanent interstitial brachytherapy (PIB) is also a viable and potentially durable treatment modality that can be used to treat recurrent pelvic malignancies in the field of previous irradiation. Feddock et al.  reported3 (39.7–136.9cm3), the mean EQD2 of reirradiation was 69.8 Gy (51.3–95.1 Gy), the mean EQD2 calculated for primary RT and reirradiation was 157.3 Gy (143.3–184.4 Gy), and the mean follow-up time was 32 months (20–46 months). One patient underwent transverse colostomy prior to reirradiation for rectal invasion. Hence, the rectal dose of this patient was not calculated. The average bladder and rectum doses of re-radiotherapy were 52.5 Gy (40.9–66.3 Gy) and 41.5 Gy (35.9–47.6 Gy), respectively. The median EQD2 calculated for primary RT and reirradiation of bladder and rectum were 136.0 Gy (90.5–148.8 Gy) and 120.0Gy (101.8–126.0 Gy), respectively. Two patients had a grade ≥3 urologic radiation response , and one patient had a grade ≥3 gastrointestinal radiation response  , the mean tumor volume was 77.5cmdiation) . In our 3, no pelvic lateral wall invasion, volume before BT< 7.5 cm3, and the prescribed dose > 64 Gy were positive predictors. Mahantshetty et al.  for the publication of any potentially identifiable images or data included in this article.XR conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. YF performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. ZL analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. XL conceived and designed the experiments, performed the experiments, and approved the final draft. LQ performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. YL performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. HL performed the experiments, authored or reviewed drafts of the paper, and approved the final draft. YB performed the experiments, authored or reviewed drafts of the paper, and approved the final draft. TW conceived and designed the experiments, performed the experiments, analyzed the data, authored or reviewed drafts of the paper, and approved the final draft. All authors contributed to the article and approved the submitted version.This work was funded by the National Key Clinical Specialty Capacity Building Project , Jilin Province Financial and Health Project , Jilin Provincial Department of Finance , and Jilin Province Medical and Health Talent Special Project (2019SCZT010).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


SD) affects economic return for turkey production and can impact performance parameters. In this study , Nicholas Select hens  were randomly placed in 1 of 4 SD treatments of 30, 40, 50, or 60 kg/m2 in open rooms (67.5 m2) with 4 replications per treatment. Feeder and drinker space were equalized on a per bird basis. Air quality was measured, and ventilation was adjusted to equalize ammonia and carbon dioxide levels across all rooms. Group BW and feed consumption were measured on d 0 and wk 3, 5, 8, and 11. BW gain and mortality corrected feed-to-gain ratio were calculated. Mortality and culls were recorded daily and necropsied for cause of death. At wk 8 and 11, flock uniformity was evaluated (30 birds/replicate). Data were analyzed using regression analyses in SAS 9.4 . An ANOVA was performed for air quality  and a Tukey's range test was used to separate means. Differences were considered significant when P ≤ 0.05. Carbon dioxide and ammonia were consistent across treatments for both blocks. At wk 11, BW decreased linearly as SD increased (P = 0.05). There was a tendency for overall BW gain to decrease linearly as SD increased (P = 0.06). Feed consumption decreased as SD increased during wk 8 to 11  and from wk 0 to 11 . SD had no impact on feed efficiency, mortality, or uniformity. Total aggression related mortality and culls were highest in the 30 kg/m2 treatment . A brief economic analysis was performed utilizing commercial poult and feed costs and income at marketing. Net room income increased as SD increased . The results indicate that high SD negatively impacted turkey hen final BW and feed consumption, but no effect was observed on feed-to-gain ratio, percent mortality, or uniformity.Stocking density ( SD) has many effects on turkey production parameters, including performance, health, welfare, and producer profitability. It can have adverse effects on turkey performance such as BW, feed efficiency, and mortality. These effects can negatively impact economic return but can also indicate birds are experiencing stress or poor wellbeing. The majority of studies assessing SD in turkeys have focused on turkey toms. The most current literature on the effects of SD in turkey hens was published 22 yr ago. Though these studies provided valuable information, there have been many advances in genetic selection for improved growth rate and feed efficiency since then. When evaluating SD, some studies have altered group size and maintained floor space (Stocking density (or space  while otor space . For theP < 0.06) for higher mortality rates with increasing SD observed in the studies by Though there has been more extensive research with broiler chickens, the available literature focusing on turkeys found that as SD increased, BW of toms and hens decreased . However2CO) levels can also be directly related to SD due to increased respiratory output  were arranged in a randomized complete block design, with 2 trial blocks allowing for increased replication. Each trial (block) consisted of 2 room replicates per SD treatment. The study was conducted at the University of Saskatchewan Poultry Centre in a floor housing facility that includes separate, and independently controlled rooms for environmental parameters.Four SD treatments  were randomly selected and placed in 1 of the 4 SD treatments. The number of birds placed in each treatment was calculated according to the final predicted BW of 7 kg for turkey hens at 11 wk of age . An addi2). Brooder rings (7.0 m in diameter) with wood shaving bedding (7–10 cm thick) and heat lamps were used for the first 10 d. Wheat straw (10–13 cm depth) was utilized for bedding during the rearing period. Feed was provided ad libitum using aluminum tube feeders with a pan diameter of 36 cm for the first 40 d and a large pan diameter of 44 cm for the remaining time. During the first 7 d, humidifiers were utilized to maintain relative humidity at a minimum of 50%  white  during the first 3 wk of the trial. At wk 8, mortality rates were low, and space was opened to maintain the estimated final SD for each treatment. In block 2, birds were removed from each treatment at wk 9 due to low mortality up to that age, to achieve the final predicted SD at wk 11.mF:G) were calculated for each of these time periods. Flock uniformity was determined by individually weighing a subsample of birds (30 birds/replication) at wk 8 and 11. After the bird replacement period (d 1–3), all mortality and culls were recorded daily and sent for necropsy to an independent diagnostic laboratory, and all mortality and morbidity results were then categorized by cause (Body weight and feed consumption were measured by collecting group (room basis) BW and feeder weights on d 0 and wk 3, 5, 8, and 11. Feed consumption and mortality corrected feed-to-gain ratio (by cause . Basic e2) was measured 3 times per wk using a handheld CO2 meter  and ammonia was monitored once per wk until differences were noted, then twice per wk. Ammonia was measured using Dräger-Tubes and a handheld pump . If CO2 levels varied by 20% or ammonia differed by 5 ppm between rooms, ventilation was adjusted in each individual room to match air quality between all density treatments  and average weekly room temperatures were calculated over the course of each block. From d 1, carbon dioxide  with rooms as the replicate unit. Data were checked for normality (Univariate Procedure) and all mortality data were log transformed (log +1) prior to regression analyses, and reported means were back transformed. Regression analyses were conducted using the Regression Procedure (Proc Reg) and Surface Response Regression Procedure (Proc RSReg) to determine if there were either linear or quadratic relationships between SD and the performance parameters being evaluated . An ANOVA was performed for air quality and room temperature data using the Proc Mixed Procedure and Tukey's range test was used to separate means (SAS 9.4). Differences were considered significant if 2.All results are presented in terms of the final estimated SD. The actual SD achieved at 3, 5, 8, and 11 wk of age is shown in P = 0.05) as SD increased . Stocking density did not affect turkey hen BW gain for 0–3, 3–5, 5–8, and 8–11 wk (P = 0.06) to decrease with increasing SD.At placement, poult BW was similar across all treatments and no differences in BW were observed at wk 3, 5, or 8 . At 11 w 8–11 wk . OverallP < 0.01) as SD increased . Overall feed consumption, from 0 to 11 wk of age, demonstrated a quadratic relationship (P = 0.04) with the lowest feed consumption in the 60 kg/m2. Mortality corrected F:G ratio was unaffected by SD for 0–3, 3–5, 5–8, 8–11, and 0–11 wk of age  in the low SD treatment of 30 kg/m2 . Total aggression related mortality and culls were highest in the low SD of 30 kg/m2  and lowest in the 60 kg/m2 treatment .Total mortality and culls as a percentage of turkey hens placed was not affected by SD . Total m2, respectively. At 11 wk of age, there were 47.50, 43.33, 51.67, and 45.00% within 5%, 77.50, 80.83, 85.83, and 79.17% within 10%, and 93.33, 95.83, 93.33, 93.33% within 15% of the mean for SD treatments 30, 40, 50, and 60 kg/m2, respectively.Turkey hen flock uniformity, presented as the percentage of birds found within 5, 10, or 15% of the mean room BW was not affected in relation to SD at 8 or 11 wk of age. At 8 wk of age, there were 43.33, 49.17, 47.50, and 48.33% of hens within 5%, 79.17, 75.83, 75.00, and 79.17% within 10%, and 90.83, 94.16, 93.33, and 88.33 within 15% of the mean for SD treatments 30, 40, 50, and 60 kg/m2 concentrations did not differ between treatments for either block . Similarly, average ammonia concentrations did not differ between treatments for both blocks . It is important to note that rapid increases in CO2 and ammonia occurred when external ambient temperatures were extremely low as both blocks took place during winter in Saskatchewan, Canada. This resulted in rapid increases in CO2 and ammonia as ventilation was reduced to maintain internal temperatures and prevent unwanted chilling of the birds. However, the rapid increases were accounted for by increasing the ventilation once the weather allowed. No differences were noted for average room temperature for each SD treatment from 1 to 11 wk (Carbon dioxide and ammonia concentrations (ppm) for block 1 and block 2 are shown in to 11 wk .Table 8AP < 0.01). The net income was CA$1706.88, CA$2283.41, CA$2723.20, CA$3144.22 per room replicate for the 30, 40, 50, and 60 kg/m2 treatments, respectively.The basic economic analysis was performed using poult cost, feed cost, number of birds shipped, and bird meat income as seen in 2, whereas the Certified Humane program suggests a maximum standard of 36.6 kg/m2  at 12 and 16 wk of age when the final predicted SD was closer to being achieved. Similarly, the BW results from this study demonstrate differences at 11 wk of age when the target SD was achieved suggesting that older birds (11 wk and older) are more impacted by high SD resulting in slower growth. These effects on growth may be related to poor mobility, reduced floor space, and increased stress. Gait scores indicated that more birds in the 60 kg/m2 treatment had an identifiable abnormality that did not affect overall function (11 wk) and a higher incidence of footpad dermatitis   . The pood 11 wk)  could mad 11 wk) . Additioeatments  at wk 11eatments .The studies that have examined the effect of SD on feed consumption in turkeys have focused on turkey toms, however, it is an important parameter to examine as it directly affects economic return and growth. Previous studies have found that feed consumption in toms decreased as SD increased between various periods within the range of 12 to 20 wk of age  and over2 treatment were at the feeder despite a higher incidence of FPD  from 4 wk of age and older in toms (2) (2), indicating lack of feeder space as a confounding factor. However, there may have been other confounding factors contributing to the results observed in previous studies which would serve as stressors to the birds and may affect feed efficiency. In the current study, internal room temperature and air quality were consistent across treatments and ventilation was adjusted when differences were noted, which may help reduce the impact of SD on F:Gm. 2) in one of 2 of their experiments. The authors suggest that the effect seen in the first experiment at high SD was because it was conducted in winter with curtain sided barns compared to summer for the second experiment. Therefore, the amount of energy and feed required to thermoregulate and maintain body temperature would have resulted in poorer feed efficiency. Without confounding factors of room temperature and feeder space in this study, feed efficiency was less likely to be impacted by SD.Feed efficiency demonstrated no relationship with SD. Previous literature found that feed efficiency was poorer at high SD (60 kg/m in toms  which ma in toms . Feed eftoms (2) . These s2), however, P < 0.06) for higher mortality with increasing density (29.4–60.9 kg/m2). P = 0.09) where aggression related mortality increased linearly with decreasing SD at wk 12 to 16 in toms. The authors suggest that birds at low SD may be more active compared to birds at high SD when floor space is reduced , production, health, and welfare parameters are important when developing SD guidelines to ensure the welfare of birds is maximized without compromising economic return. Additionally, this economic analysis did not consider management and labor costs, equipment damage, or potential carcass condemnations, thus not accurately depicting the true effects of high SD on economic return.2 is more beneficial to turkey hens raised to 11 wk of age as it ensures efficient production, health, and wellbeing. However, continuous monitoring of CO2 and ammonia is important to ensure that air quality or environmental conditions are not negatively affecting the health of the birds. This recommendation is based on maintaining good air quality by managing ventilation and barn temperatures.In conclusion, high SD negatively impacts some aspects of turkey hen performance to 11 wk of age. It was hypothesized that high SD would negatively affect BW, feed consumption, feed efficiency, and flock uniformity due to reduced space allowance and environmental stressors. It was also hypothesized that at low SD there would be more aggression. Although feed efficiency and uniformity were unaffected by SD, growth and feed consumption were negatively impacted at high SD and higher aggression related mortality and culls occurred at low SD. By assessing performance, health, and behavior, it is evident that a moderate density of around 40 to 50 kg/m