Prevention of depression and anxiety disorders early in life is a global health priority. Evidence on risk and protective factors for youth internalizing disorders indicates that the family represents a strategic setting to target preventive efforts. Despite this evidence base, there is a lack of accessible, cost-effective preventive programs for parents of adolescents. To address this gap, we recently developed the Partners in Parenting (PiP) program—an individually tailored Web-based parenting program targeting evidence-based parenting risk and protective factors for adolescent depression and anxiety disorders. We previously reported the postintervention outcomes of a single-blinded parallel-group superiority randomized controlled trial (RCT) in which PiP was found to significantly improve self-reported parenting compared with an active-control condition .This study aimed to evaluate the effects of the PiP program on parenting risk and protective factors and symptoms of adolescent depression and anxiety using data from the final assessment time point (12-month follow-up) of this RCT.Parents (n=359) and adolescents (n=332) were recruited primarily from secondary schools and completed Web-based assessments of parenting and adolescent depression and anxiety symptoms at baseline, postintervention (3 months later), and 12-month follow-up . Parents in the PiP intervention condition received personalized feedback about their parenting and were recommended a series of up to 9 interactive modules. Control group parents received access to 5 educational factsheets about adolescent development and mental health. Both groups received a weekly 5-min phone call to encourage progress through their program.d=0.51; 95% CI 0.30 to 0.72). When transformed data were used, greater reduction in parent-reported adolescent depressive symptoms was observed in the intervention group . Mediation analyses revealed that these effects were mediated by improvements in parenting . No other significant intervention effects were found for adolescent-reported parenting or adolescent depression or anxiety symptoms. Both groups showed significant reductions in anxiety (both reporters) and depressive (parent reported) symptoms.Intervention group parents completed an average of 73.7% of their intended program. For the primary outcome of parent-reported parenting, the intervention group showed significantly greater improvement from baseline to 12-month follow-up compared with controls, with a medium effect size : 12615000328572; http://www.anzctr.org.au/ACTRN12615000328572.aspx (Archived by WebCite at http://www.webcitation.org/6qgsZ3Aqj). Depression and anxiety disorders are common in young people, with lifetime prevalence rates of 18% and 38%, respectively, in adolescents aged 13 to 17 years ,3. MoreoThe family setting is a strategic target for implementing preventive approaches for adolescent depression and anxiety  disorders. As posited by interpersonal theories of developmental psychopathology, internalizing problems both result from and contribute to disruptions in developmentally salient interpersonal processes (starting with early parent-infant attachment), which in turn interfere with young people’s need for relatedness . From anFor the purpose of prevention, interventions need to target modifiable risk and protective factors . A burgeFor decades, preventive parenting interventions have been developed to capitalize on the influence parents have on their child’s development and adjustment based on the assumption that improving parenting will in turn yield benefits for the child’s mental health . UnfortuHowever, the public health impact of preventive parenting interventions (regardless of child age) is limited by poor uptake and engagement . In partHow to prevent depression and clinical anxiety in your teenager: Strategies for parents (henceforth referred to as the Guidelines)  ,47. InteParent participants registered themselves and their adolescent via the dedicated trial website and provided consent and contact details for their adolescent  and chi-square analyses  were used for these analyses. We also examined potential group differences in follow-up actions taken for adolescents who reported elevated symptoms at postintervention.Analyses were conducted in SPSS version 25 (IBM Corp), with an a priori alpha level of .05. To assess for potential attrition biases, we compared participant characteristics and scores on baseline and postintervention outcome measures between those who completed 12-month follow-up assessments and those who did not. Independent samples d effect sizes with 95% CIs are reported for all analyses.Primary and secondary outcome analyses were conducted on an intention-to-treat basis, using mixed-model repeated measures (MMRM), with an unstructured covariance matrix. MMRM uses all the available data from all the participants, including those who withdrew from follow-up assessments . It is aOwing to the positive skew of model residuals for the SCAS and SMFQ at all occasions, a square-root transformation was applied, which improved the distribution of residuals. All analyses were repeated using the transformed data to check robustness of the results. For most analyses, the results did not change with transformation. When the results did differ, the overall conclusions were made by considering the findings based on both raw and transformed data. For ease of interpretation, raw data have been plotted, with footnotes to indicate where results differed with transformation.To assess for potential mediation of intervention effects on adolescent symptoms by change in parenting, we conducted simple mediation analyses using the PROCESS macro for SPSS ,53. SepaFinally, we conducted post hoc moderation analyses to explore moderation of intervention effects of adolescent age, gender, and baseline symptoms on outcomes. For age and baseline symptoms, the continuous moderator variable  was added to the mixed model as a covariate, including a 3-way interaction term  whose significance constituted a test of a differential effect of the moderator on outcome of the intervention. Significant moderation effects were interpreted using estimated marginal means plotted for values of the covariate  at its 25th and 75th percentile at baseline in the sample. To minimize shared method variance effects for moderation analyses using baseline symptom measures, we used the symptom measure reported by the opposite informant as the moderator variable . For the parenting measures, we conducted 2 moderation analyses, with each of the symptom measures  entered in separate models. Moderation by child gender was assessed in a similar manner using gender as an additional factor rather than as a covariate.The sample’s characteristics have been reported in detail elsewhere  and inclAs shown in 21, [N=359]=9.9; P=.002). In addition, adolescents of parents who completed the 12-month follow-up had significantly higher PRADAS-A scores  at postintervention compared with adolescents of parents who did not complete 12-month follow-up =2.05; P=.04).We examined demographic characteristics and scores on baseline and postintervention measures between participants who completed 12-month follow-up and those who did not. There were no differences on any baseline measures between completers and noncompleters nor were there differences in parent or child demographic characteristics, with the exception of parent education level. Parents who completed the 12-month assessment were more likely to have tertiary-level education than those who did not (χP>.05). There was an average interval of 12.14 days between completion of the adolescent 12-month assessment and the parent 12-month assessment . At 12-month follow-up, dyads in the control group had a significantly shorter interval between completion of adolescent and parent assessments =−2.88; P=.004).The mean time interval between parent baseline and 12-month follow-up was 385.71 days , and the mean interval between parent postintervention and 12-month assessments was 266.66 days . For adolescent assessments, the mean interval between baseline and 12-month follow-up was 376.59 days  and between postintervention and 12-month follow-up was 266.41 days . As reported in the postintervention paper , the widAs reported previously, the mean intended program use by the intervention group (n=179) was 6.85 out of a possible 9 modules. The mean observed usage by the intervention group was 5.17 modules . At the t328.17=4.81, P<.001, with the intervention group showing a significantly greater increase in PRADAS scores from baseline to 12-month follow-up compared with controls . Pairwise comparisons of the 2 groups at 12-month follow-up also indicated a significant group difference , although the effect size was small .Observed scores for all outcome measures at each measurement occasion are presented in rols see . The effd=−0.21; see P>.05). Using transformed data, there was a significant main effect for time over the 3 measurement occasions for the SCAS-P, SCAS-C, and SMFQ-P  but not for the SMFQ-C (P=.12). When raw data were used, there was a significant main effect for time for all symptom measures .As shown in F=9.27; P<.001. However, the comparisons of group differences at each occasion were not significant .The planned contrast of the group × measurement-occasion interaction from baseline to 12-month follow-up was not significant for the PRADAS-A see . There wb=−0.08; 95% CI −0.16 to −0.01) when transformed symptom data were used. However, no significant mediation was found for any of the 4 symptom measures when using raw data =10.23, P<.001. P>.05). Results of the PRADAS moderation analyses suggested that neither child anxiety (SCAS-C) nor depression (SMFQ-C) symptoms at baseline moderated intervention effects on parent reports of parenting =4.40, P=.01. However, as shown in We conducted separate MMRMs for each of the symptom measures, moderated by baseline scores on the opposite informant of the same measure. Of the 4 analyses, only the model of SMFQ-P moderated by baseline SMFQ-C was significant: P>.05; results available from the first author upon request).We ran separate MMRMs for all 6 outcome measures, moderated by adolescent age at baseline and gender (in separate models). None of the 3-way interactions were significant . The observed medium-term effect was despite minimal access to PiP modules by parents between the postintervention and 12-month assessments, so the maintenance of effects is unlikely because of booster effects.This RCT evaluated the medium-term effects of PiP. Consistent with our hypothesis, when compared with parents who received an educational-factsheet control intervention, parents who received PiP reported greater improvements in their parenting behaviors from baseline to 12 months later. These improvements represent reductions in parental risk factors and increases in parental protective factors for adolescent depression and anxiety ,38. NotaContrary to expectations, at 12-month follow-up, there was no robust indication that PiP significantly reduced adolescent depression and anxiety symptoms as reported by either parents or adolescents, compared with the active-control intervention. This is largely consistent with findings at postintervention , suggestIt is possible that the use of an active control in this study, although a methodological strength, may have obscured the benefits of PiP on adolescent internalizing outcomes. Although the educational factsheets in the control intervention did not provide specific personalized parenting strategies in an engaging format (like PiP), they did provide credible information on adolescent development and general advice for parents about how they can best support their adolescent’s development and well-being. For a highly educated and motivated sample of parents, this may be sufficient to produce the improvement in parenting observed in the control group, albeit to a weaker extent than the intervention group, which was maintained at 12-month follow-up. In turn, the improvement in parenting in both groups may explain the significant reduction in reported symptoms (except adolescent-reported depressive symptoms) over time in both groups and, hence, the nonsignificant group difference in change over time. This is notable because many preventive interventions for adolescent internalizing disorders that have demonstrated significant effects were compared with nonactive or no-intervention control groups ,54. AlthContrary to expectation, a significant improvement in parenting was not seen in adolescent reports. This is consistent with findings at postintervention , suggestDivergence in parent and adolescent reports of parenting, especially during early adolescence, is well established and considered to be normative in the developmental literature . From a Results from the mediation analyses were generally consistent with the above findings. Only the mediation hypothesis for parent-reported adolescent depressive symptoms was supported when using transformed data, whereby PiP compared with the control intervention led to greater improvements in parent-reported parenting from baseline to postintervention, which led to greater reductions in parent-reported adolescent depressive symptoms from baseline to 12-month follow-up. Consistent with the parenting pathway proposed by Sandler et al (2011), this mediation suggests that PiP’s effects on parenting may account for a longer-term benefit on adolescent depressive symptoms. Future research is required to examine whether this preliminary finding would be corroborated by other measures of adolescent functioning, such as school engagement and academic performance.In our post hoc moderation analyses, the moderation effect of adolescent-reported baseline depressive symptoms found at postintervention  emerged On the basis of the findings of a recent systematic review of technology-assisted preventive parenting interventions , PiP is The findings of PiP’s effects to date share some similarities to those of other preventive parenting interventions that found developmental cascading effects at long-term follow-up . SpeThis study had various strengths. It evaluated a world-first tailored Web-based parenting intervention to prevent adolescent internalizing problems, using a rigorously designed RCT with an active control group, parent and adolescent informants on all outcomes of interest, low attrition rates that are balanced across groups, and high intervention completion. However, various limitations merit comment. First, despite successfully recruiting a large community sample, there was overrepresentation by mothers and highly educated parents. Although this is a limitation shared by most online preventive parenting interventions , it urgeOverall, this study found that the PiP intervention produced significantly greater improvements than an active control in parenting risk and protective factors associated with adolescent risk for depression and anxiety. The effects persisted for up to 9 months postintervention, reducing the likelihood that they were due to social desirability or short-term priming effects. Findings from the analyses using transformed data and from mediation analyses suggest that PiP may have some benefits for adolescent symptoms that need to be ascertained in future research. However, parent-reported changes in parenting were not reported by adolescents, and there were no robust findings with regard to reductions in adolescent symptoms. Nonetheless, significant reductions in adolescent symptoms were observed over time in both groups. Given these promising findings, the paucity of evidence-based resources for parents of adolescents, and the scalability of the Web-based platform, PiP may be useful as a low-cost, sustainable public health universal prevention program to empower parents for their adolescents’ mental health.


The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards.Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients.We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT . BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT  (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients.A total of 134 patients were recruited over 47 site-months . The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results.NCT02917551. Registered on September 28, 2016.Clinicaltrials.gov,  The World Health Organization has declared antibiotic resistance a global public health threat, based on rising rates of resistant pathogens and diminishing rates of new antibiotic development . AntimicOur systematic review, national practice survey, and observational studies have documented a lack of evidence to guide optimal treatment durations for bloodstream infections, wide variation in clinical practice, and collective equipoise for a trial of 7 versus 14 days of antibiotic treatment for patients with bloodstream infections –8. ThrouThe Canadian Critical Care Trials Group (CCCTG) and Australian & New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) began the BALANCE trial in the ICU setting. As the majority of patients with bacteremia are cared for on general medical and surgical wards, we began to explore hospital-wide expansion to the full population of hospitalized patients with bacteremia as a means to improve the generalizability and timeliness of the BALANCE RCT. We first conducted a distinct BALANCE pilot trial focused on patients admitted to general hospital wards at the BALANCE central study site. We then expanded this approach to several community and academic hospitals participating in the BALANCE trial .The objectives of this multi-centre BALANCE-Ward pilot RCT were three-fold: (1) to test the feasibility of ward (non-ICU) recruitment into this trial; (2) to compare the patient, pathogen, and outcome characteristics among patients enrolled in the BALANCE-Ward pilot RCT to characteristics in the prior BALANCE-ICU pilot RCT; and (3) to estimate the sample size and non-inferiority margin impacts of merging the BALANCE-Ward pilot with the BALANCE main trial.http://www.randomize.net) with variable block sizes of four to six patients, stratified by site. The intervention related only to the duration of treatment, with patients randomized 1:1 in parallel to 7 versus 14 days of treatment. All other aspects of care  were at the discretion of the clinical team. Participant and clinician blinding and placebo controls were not used given the diversity of pathogens and underlying foci of infection, but allocation concealment was maintained until the seventh day of treatment to mitigate selection bias and differential treatment. The central study team and statistician were blinded to treatment group. The BALANCE-Ward pilot trial was registered separately on Clinicaltrials.gov (NCT02917551), with unique ethics approval at all participating sites, so that enrolled patients could be kept distinct from the main trial until completion of the pilot and evaluation of feasibility.We conducted a pilot RCT of 7 versus 14 days of antibiotic treatment for patients with bloodstream infection, which was identical to our prior BALANCE-ICU pilot RCT , 10, excThe BALANCE-Ward pilot trial was launched at Sunnybrook Health Sciences Centre (SHSC) in October 2016, and then after 1 year extended to five other active BALANCE sites, including The Ottawa Hospital (TOH), Kingston General Hospital (KGH), Hamilton General Hospital (HGH), St. Joseph’s Health Centre (SJHC) Toronto, and North York General Hospital (NYGH).non-ICU ward rather than reported as positive while in an ICU. However, the exclusion criteria were unchanged from the BALANCE pilot RCT: previously enrolled patients, those with neutropenia, organ transplantation, prosthetic valves, endovascular grafts, suspected or documented syndromes requiring prolonged treatment , patients with a single positive culture of a common contaminant organism, or bloodstream infection with Staphylococcus aureus, Staphylococcus lugdunensis, or fungal organisms.The inclusion criteria differed, by definition, from the prior BALANCE pilot RCT , 10 in tPotentially eligible patients were identified through microbiology laboratory reports of positive blood cultures. The site research coordinator screened the medical records of these patients to confirm that they met all inclusion criteria, and no exclusion criteria, and then provided patients with study information materials. Consenting patients could be enrolled any time up to the seventh day of adequate antibiotic treatment .Clostridiodes difficile, and antibiotic resistant organisms) were identical to those collected in the original BALANCE pilot RCT [As per the original BALANCE-ICU pilot RCT, the co-primary feasibility outcomes were (1) recruitment rates and (2) adherence to treatment protocol. Protocol adherence was defined as receipt of 7 ± 2 days of antibiotics or 14 ± 2 days of antibiotics for patients randomized to shorter versus longer duration treatment, respectively. We did not target a specific protocol adherence rate to consider the trial feasible, but sought to determine whether the protocol adherence rate would exceed the rate seen in the BALANCE ICU pilot RCT (77%) . As withilot RCT , 10. IncPatients were followed throughout the hospital stay to a 90-day maximum, with capture of baseline characteristics and outcome information on the same electronic case report form used for the BALANCE main trial. Ninety-day mortality was collected via follow-up phone call 90 days from the index bacteremia.There were no interim analyses or stopping rules within this pilot RCT. As with our initial BALANCE pilot RCT, we planned a priori to maintain blinding of treatment assignment in the BALANCE-Ward pilot RCT . A feasit-test or the Wilcoxon rank sum test were used to compare continuous variables. The Wilson Score method was used to determine 95% confidence intervals. P values were not adjusted for multiple comparisons.Next, we compared these feasibility outcomes to those achieved during our initial BALANCE-ICU pilot RCT . PoissonIf the BALANCE-Ward pilot demonstrated feasibility, we planned to consider merging the ward-based protocol with the ICU-based protocol of the BALANCE main trial. Therefore, we estimated the percentage of recruited patients that would be enrolled from ICU versus non-ICU wards as a function of the percentage of sites expanding to hospital-wide enrolments. Next, we estimated the impact on overall trial sample size and non-inferiority margins as a function of the proportion of anticipated ICU versus ward enrolments at the time of trial completion. For these calculations we estimated the 90-day mortality for ward patients using outcome data from this ward pilot RCT, and we estimated the mortality for ICU patients from up-to-date data from the ongoing BALANCE main RCT. At the time the ward pilot was completed, 600 patients had been enrolled and reached the 90-day endpoint in the BALANCE main trial.We sought to enroll a minimum of 115 patients  , but to S. aureus bacteremia (177). Of eligible patients, 134/605 (22%) were enrolled and randomized  were deemed eligible for enrolment .A total of 134 patients were recruited over 47 site-months .The overall adherence to treatment duration protocol was 125/134 (93%), with minimal variation across study sites: SHSC 103/110, SJHC 15/16, TOH 1/1, KGH 1/2, NYGH 4/4, HGH 1/1 (Table p = 0.010), but had a lower Sequential Organ Failure Assessment (SOFA) score (2(0–3) vs 6 (4–9), p < 0.0001) on the day blood cultures were collected (Table p < 0.0001), and a greater proportion were due to genito-urinary sources of infection  and/or E. coli as a causative pathogen  (Table Patients enrolled in the BALANCE-Ward pilot RCT were older than those enrolled in the ICU pilot RCT (median (IQR) 72(62–82) vs 67(57–78) years, p = 0.65; Table p < 0.001) and more antibiotic-free days by day 28 (14(14–21) vs 14(8–17), p < 0.0001) , which was similar to the 90-day mortality rate in the ICU pilot RCT  , merging ward patients into the main trial would result in an overall mortality rate of 15% if there were equal numbers of ward and ICU patients. Figures In the prior BALANCE-ICU pilot RCT we demonstrated that it was feasible to enroll ICU patients into a trial of 7 versus 14 days of treatment for bloodstream infection , therebyThe BALANCE-Ward pilot RCT documented feasibility with respect to both co-primary outcomes of recruitment rate and protocol adherence. We achieved mean recruitment rates of 2.9 patients per site-month; the median recruitment rate per site per month was lower (1.0) but still met our feasibility target. Similarly, we achieved protocol adherence rates of 93%, which exceeded the 77% adherence rates in the ICU population. On the basis of these co-primary outcomes it appears feasible that the BALANCE RCT could be extended from ICUs to include non-ICU patients. The increased recruitment rate on the wards can be attributed to the larger number of bacteremic patients than those who are in the ICU. The superior protocol adherence rates on the general wards may be due to the lower severity of illness and lower risk of secondary nosocomial infections among these patients with shorter lengths of hospital stay and fewer indwelling devices such as endotracheal tubes and central venous catheters.E. coli as a causative pathogen. On the one hand, merging non-ICU patients with ICU patients into a single trial could be viewed as mixing two heterogeneous populations together. On the other hand, combining these patients together could be considered as reflecting a broader population of patients with bloodstream infection, yielding more generalizable trial results. The ICU and non-ICU pilot trial patients were both infected with a diverse range of Gram negative and Gram positive bacterial pathogens, and each included patients with a diverse range of host comorbidities. Typically a trial based on a specific diagnosis  would be conducted across the full spectrum of severity, including those patients admitted to ICU and non-ICU wards. Conceptually, enrolling both non-ICU and ICU patients captures the full spectrum of bacteremic illness, and the patients are only dichotomized by the location of care within the hospital.As expected, there were some measurable differences in critically ill patients with bacteremia enrolled in the initial BALANCE pilot compared to the patients on the wards who were enrolled in this pilot. The latter were older, had lower severity of illness at baseline, and more commonly had community-acquired bacteremia, genito-urinary sources of infection, and n = 3626) for the BALANCE main trial.The 90-day mortality rate in this pilot RCT 12.8%) was similar to the mortality rate seen in a recently published RCT of 604 patients allocated to 7 versus 14 days of antibiotics for patients with Gram negative bacteremia conducted on non-ICU wards in three centers in Israel and Italy .8% was s, and is Our BALANCE-Ward pilot RCT enrolled patients in six sites, and so we cannot be certain that the recruitment and adherence results would be generalizable to all of the sites involved in the BALANCE main RCT. However, the generalizability is bolstered by inclusion of a mix of both community and academic hospitals, as well as sites with long-standing versus recent involvement in the CCCTG. Another limitation is that we cannot predict whether expansion to include non-ICU enrolment will lead to a compensatory decrease in ICU recruitments by diluting study teams’ efforts across broader clinical units. In our six pilot RCT sites, though, we did not see reductions in ICU recruitments. As BALANCE is expanded hospital-wide, we will assess the interplay of ICU and non-ICU recruitment rates over time. The low rate of enrolment of eligible ward patients, and wide variation across sites, suggests that further efforts may be necessary to foster enrolments, including educating ward clinicians about the pre-RCT work which has documented practice heterogeneity and collective clinical equipoise. The BALANCE-Ward pilot RCT experience suggests that sites with infectious diseases engagement on the study team achieve much higher recruitment rates and percent enrolment of eligible patients, and so this will be crucial for future sites considering hospital-wide recruitment. We will also need to track eligible non-enrolled patients, along with recruitment rates and protocol adherence, as a site-specific metric throughout the conduct of the trial.S. aureus bacteremia, and allow us to maximize the benefits while minimizing the harms of antimicrobial treatments for bloodstream infections.The BALANCE steering committee and CCCTG have guided us in conducting step-wise pilots of the BALANCE RCT protocol in the initial ICU population, and now in this non-ICU population, once again confirming the feasibility of the BALANCE trial design on general hospital wards. We have carefully reviewed the one-group findings  with the CCCTG and the BALANCE international steering committee, both of which have strongly endorsed the option for participating BALANCE sites to extend enrolments hospital-wide. Given the success of this non-ICU pilot, no other protocol changes are required to facilitate inclusion of non-ICU patients in the BALANCE main trial. A detailed statistical analysis plan involving the entire cohort will be published before the trial is completed; randomization will be stratified by ICU and non-ICU ward location, and a subgroup analysis will be conducted. The subgroup analyses, by definition, will not be powered to achieve the same non-inferiority margin as the overall BALANCE trial population. However, the achievable non-inferiority margins within the ICU and non-ICU subgroups will still be less than the non-inferiority margins used in recent landmark antimicrobial minimization studies involving patients with serious bacterial infections , 13–15.


We examined the association between pregnancy and life-course lipid trajectories. Linked data from the Nord-Trøndelag Health Study and the Medical Birth Registry of Norway yielded 19,987 parous and 1,625 nulliparous women. Using mixed-effects spline models, we estimated differences in nonfasting lipid levels from before to after first birth in parous women and between parous and nulliparous women. HDL cholesterol (HDL-C) dropped by −4.2 mg/dl  from before to after first birth in adjusted models, a 7% change, and the total cholesterol (TC) to HDL-C ratio increased by 0.18 , with no change in non-HDL-C or triglycerides. Changes in HDL-C and the TC/HDL-C ratio associated with pregnancy persisted for decades, leading to altered life-course lipid trajectories. For example, parous women had a lower HDL-C than nulliparous women at the age of 50 years . Adverse changes in lipids were greatest after first birth, with small changes after subsequent births, and were larger in women who did not breastfeed. Findings suggest that pregnancy is associated with long-lasting adverse changes in HDL-C, potentially setting parous women on a more atherogenic trajectory than prior to pregnancy. Lipids predict future CVD . AlthougThe population-based Nord-Trøndelag Health Study (HUNT), linked with the Medical Birth Registry of Norway, includes data on pregnancy, breastfeeding, and measured lipid values in women from before and up to 41 years after first birth, enabling an examination of changes in lipid levels pre- to postpregnancy. These data enable us to examine, for the first time, the impact of pregnancy on the ratio of TC to HDL-C, which performs as well as or better than other lipid measures in CVD risk prediction –24. UsinHUNT is a population-based open cohort study of adult Nord-Trøndelag county residents designed for a wide range of health-related research. County-wide surveys are conducted roughly every decade, with three completed at the time of this analysis. This analysis was restricted to the second and third surveys in which lipids were sampled: HUNT2 (1995–1997) and HUNT3 (2006–2008). During the surveys, participants received an extensive health assessment that included blood sampling, clinical measurements, and questionnaires . All curWe linked HUNT data to the Medical Birth Registry of Norway, which includes all births in Norway from 1967  through Participants’ ages ranged from 20 to 60 years during measurements. Among parous women, 2,488 women had at least 1 measurement before their first birth , including 747 women with measurements both before and after first birth . Nonfasting lipids were measured from serum samples. For technical details about TC, HDL-C, and triglyceride measurements, see supplemental Table S1. We calculated non-HDL-C as TC minus HDL-C and the TC/HDL-C ratio. LDL cholesterol (LDL-C) was not analyzed because the Friedewald formula , typical1) family history of CVD ; 2) smoking status at the age of 20 years, defined as ever versus never smoked daily prior to or at the age of 20 years, to approximate prepregnancy smoking behavior for parous women; and 3) highest obtained education level. HUNT3 did not collect education level and was instead derived from work titles for 13% of women based on recommendations from Statistics Norway (1) BMI, 2) smoking status, 3) alcohol use, 4) vigorous leisure-time physical activity, and 5) oral contraceptive use. Time-varying covariates were measured at the time of lipid assessment either from HUNT2 and HUNT3 clinical examinations (in the case of BMI) or HUNT2 and HUNT3 questionnaires . We obtained additional information about first births, including maternal age and preterm status (<37 weeks gestation), from the birth registry and breastfeeding length after first birth  from HUNT questionnaires. We additionally obtained self-reported information about menopause transition and hormone replacement therapy  from HUNT questionnaires.Covariates were collected during HUNT surveys and were selected based on the causal diagram shown in supplemental Fig. S2. We used data from all HUNT questionnaires, including HUNT1 (1984–1986), to identify the following time-invariant covariates: s Norway . We alsoWe used linear mixed-effects models to estimate lipid trajectories as a function of age, accounting for the timing of a woman’s first birth. Age was modeled using restricted cubic splines with four knots located at ages 23, 37, 46, and 57 years based on prespecified quantiles of the age distribution, as recommended by Harrell . Two variP in supplemental Methods equation 1) and an interaction between parity and the spline terms, allowing the age-related splines to differ throughout the life course based on final parity status. We chose final rather than updated parity status because nulliparous and parous women are likely to be different even before the latter give birth, given observed associations between infertility and lipid levels , nulliparous women represented background age and secular trends independent of parity. These analyses included an indicator of final parity status . Fully adjusted results from these models included updated BMI, alcohol use, physical activity, and oral contraceptive use as well as maternal age and preterm status of first birth. Both baseline and updated covariates were multiply imputed using fully conditional specification  to obtain estimates of the short-term effect of the first birth on lipid levels and to describe differences in this effect estimate by length of breastfeeding . The short-term effect of the first birth was estimated based on the discontinuity between predicted trajectories before first birth and predicted trajectories after first birth  to verify that our main results, which included some women with only one measurement, were consistent with within-woman changes in lipids observed among women with more than one lipid measurement. First, we replicated the lipid trajectory models among women with repeated measures to verify that our results could be interpreted as within-woman life-course trajectories. Second, we compared the within-woman change in lipid levels from HUNT2 to HUNT3 for women who had one or more births during the ∼11 year interval to the within-woman lipid changes for women who remained nulliparous during the interval using a difference-in-differences approach . We addiAmong 21,312 study participants born between 1940 and 1974 (study population 1), 8% were nulliparous throughout the follow-up period, at which point the youngest were 38 years old. Nulliparous and parous women had similar age distributions, but nulliparous women were less likely to smoke or consume alcohol and more likely to participate in vigorous physical activity . However, women who breastfed >6 months after first birth still experienced a decrease in HDL-C and an increase in the TC/HDL-C ratio after first birth, even after adjusting for updated covariates . Women with a birth between HUNT2 and HUNT3 experienced a decrease in HDL-C and an increase in TC/HDL-C compared with women who did not give birth during the ∼11 year period, with a magnitude similar to associations seen in the main analysis . Lipid trajectories were also similar after adjusting for menopause and hormone replacement therapy use .We found that women who bore children had more positive lipid profiles before first birth compared with women who remained nulliparous throughout life. However, this advantage changed at first birth, when new mothers had a decrease in HDL-C and an increase in the TC/HDL-C ratio compared with nulliparous women. Our findings suggest that adverse changes in HDL-C and TC/HDL-C associated with pregnancy persist across a woman’s life course. In addition, the specificity of the timing of the change in these lipid profiles suggests that pregnancy itself causes the drop in HDL. Adverse changes after pregnancy were present after adjusting for a variety of behavioral changes associated with a first birth, including higher BMI, lower alcohol use, less physical activity, and less oral contraceptive use. Although longer breastfeeding appeared to moderate adverse changes in HDL-C and the TC/HDL-C ratio after pregnancy, women who breastfed for >6 months still experienced worse lipid profiles postpartum compared with prepregnancy levels.The magnitude of the drop in HDL-C associated with first pregnancy of −4.2 mg/dl is consistent with previous studies that examined short-term changes in lipids from prepregnancy to postpartum , 6, 7, 9Our study is the first to report the association between parity and the TC/HDL-C ratio, which has been found to have a stronger independent predictive power for CVD over its component lipid measures , 23, 40,The use of a nulliparous comparison group is a strength of this study, as it allowed us to distinguish the change after pregnancy from any background age or secular trends in our population. Previous cross-sectional studies that compared nulliparous and parous women postpartum have generally found lower lipid levels among parous women after they deliver, consistent with our findings , 41, 42.Our findings that breastfeeding may moderate the short-term adverse changes in HDL-C levels associated with pregnancy is consistent with findings from the CARDIA study . HoweverA limitation of this study is the lack of repeated measurements for all women. By including women who contributed only one measurement, we were able to examine a much larger span of time postpartum than had previous studies. However, such trajectories, constructed of both longitudinal and cross-sectional data, may not reflect an individual woman’s trajectory across her life course, as there is the potential for secular trends to influence the shape of trajectories. Such concerns should not affect the comparisons of parous and nulliparous women, who experienced the same secular trends. We also found similar results after restricting our analysis to the 47% of women with repeated measurements, suggesting that it is reasonable to estimate within-woman changes from these trajectories.Another limitation of our study is the nonfasting collection of lipids. Although we controlled for the time since last meal in all analyses, we lacked information on the content of the last meal, which may have affected triglyceride measurements but likely had a minimal effect on other lipid measures , 46. ThiWe also were unable to adjust for statin use, which may have altered the shape of lipid trajectories. However, rates of use were low among 20 to 60 year olds during our study period , and usaAs with other studies on this topic, we found that the difference in HDL-C after pregnancy was still present after adjusting for changes in BMI and a variety of lifestyle factors postpartum , 9, 10. These findings suggest that pregnancy is associated with a lasting adverse change in HDL-C that sets parous women on a more atherogenic trajectory than they had before pregnancy. Extrapolating from Hartz et al. , the 4.2


To conduct an indirect treatment comparison of patients with high-volume mHSPC and a cost analysis between Abi-ADT and Doc-ADT therapies in China.The Bucher technique for indirect treatment comparison was used. A cost analysis was conducted from both healthcare and patient perspectives.The indirect treatment comparison demonstrated no significant difference in PFS for Abi-ADT versus Doc-ADT . Doc-ADT therapy costs less than Abi-ADT, with potential savings of up to RMB 887,057 per patient from the healthcare perspective and RMB 226,210 per patient from the patient perspective.No significant differences in PFS between Doc-ADT and Abi-ADT therapy for patients with high-volume mHSPC. Doc-ADT therapy is a cost-saving alternative to Abi-ADT in China. Prostate cancer is the most common cancer for men worldwide . It alsoIn China, due to the low rate of prostate-specific antigen screening to detect cancer at an early stage, a panel of local clinical experts reported that most Chinese patients at the time of diagnosis had high-volume metastatic hormone-sensitive prostate cancer (mHSPC), which included the presence of visceral metastases, a bone-metastasis burden categorised by site  or by a high number of lesions, or a combination of these .The treatment for men with mHSPC has historically included androgen deprivation treatment (ADT), which can be accomplished by surgical castration or medical suppression of testicular function with synthetic analogues of gonadotropin-releasing hormone . The addIn summary, the main objective of our study is to determine the comparative efficacy and costs of Doc-ADT and Abi-ADT therapies in the treatment of patients with high-volume mHSPC. To achieve this goal, we first updated the NMA outcomes of the two treatments. We then performed an economic evaluation comparing Doc-ADT and Abi-ADT therapies in China through a cost analysis from both healthcare and patient perspectives.Studies of adults with high-volume mHSPC comparing the efficacy of Doc-ADT or Abi-ADT to ADT alone were identified. Only randomised controlled trials (RCTs) were included. PubMed and Cochrane Library were searched for trials published in English, and the Chinese databases CNKI and WanFang were searched for studies published in Chinese. Search terms were derived from the Wallis study and updated from August to November 2017. Table Two reviewers (SQ and YL) independently extracted all data from the eligible trials. For each included trial, we extracted the characteristics of the participants and the interventions, efficacy and safety outcomes, the sample size  in each arm, numerical results, and loss to follow-up data.We assessed the risk of bias in each included trial using the Cochrane Collaboration’s Risk of Bias tool .The Kaplan–Meier (KM) survival data of Doc-ADT and Abi-ADT were reconstructed by applying Guyot’s method , which uI2 statistics. The pooled results are presented in the form of forest plots.The hazard ratio (HR) of response to Doc-ADT and Abi-ADT versus ADT alone was calculated independently using Review Manager 5.3  software. A random effect model was used due to the clinical heterogeneity inherent in the data. Heterogeneity among the studies was assessed using Chi square and An indirect treatment comparison was performed to assess the clinical effects of Doc-ADT and Abi-ADT using ADT as the common comparator arm. We used Bucher’s successive pairwise approach , which hAmong 235 identified studies, 4 papers from 3 clinical trials were eligible for inclusion: the CHAARTED , LATITUDOverall, 1895 patients with high-volume mHSPC were included in the analysis; 354 (18.7%) patients received Doc-ADT, 597 (31.5%) received Abi-ADT, and 944 (49.8%) received ADT alone.2 for a maximum of six [In the Doc-ADT trials (CHAARTED and GETUG-AFU 15), the patients in the experimental arm received docetaxel 75 mg/mm of six  cycles. m of six . The quaI2= 24%, heterogeneity Chi square p = 0.25, 2 trials, 696 patients) for Doc-ADT versus ADT alone and 0.60  for Abi-ADT versus ADT alone  for Doc-ADT versus ADT alone and 0.47  for Abi-ADT versus ADT alone .Patients with mHSPC were included in the model. Based on disease progression, we defined three health states in the model: progression-free survival (PFS), progressed disease (PD) and death. The model began with 1000 patients. At any given time, a patient would be in one of the three states. A patient could remain in PFS (or PD) or advance to PD (or death) during each cycle, and the patient sample was followed until death. The length of each cycle was 1 month. Direct medical costs were considered, including the costs of the drugs , hospitalisation costs for chemotherapy, ADT cost per month, laboratory test costs, and costs associated with adverse events (AEs). All costs were discounted 3% annually. Model development and the data analysis were conducted using MicrosoftThe numbers of surviving patients, patients with clinical progression and deceased patients each month were obtained by fitting OS and PFS survival curves of the CHAARTED trials ADT arm. Parametric functions were assessed based on model goodness of fit using Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) as well as a visual assessment of each parametric function. Log-logistic and Log-normal distribution were selected for the OS and PFS curve respectively based lowest AIC and BIC value. Then, the HRs from NMA were applied to reconstruct the curve for Abi-ADT and Doc-ADT arms Fig. .Fig. 3PaFor patients with clinical progression, the second-line treatment varied widely across the two therapies. Based on the Sweeney 2015 study [2) was calculated as 0.0061 × height (cm) + 0.0128 × weight (kg) − 0.1529. An average height of 161.5 cm and an average weight of 61.8 kg, reflecting a typical Chinese adult [The unit costs of docetaxel and prednisolone/prednisone were extracted from the IQVIA China Hospital Pharmaceutical Audit (CHPA) database, which was updated in the first three quarters of 2017. Because abiraterone acetate has been included in the national negotiation drug list in China, we used the negotiated price as its drug cost. Weighted average dosages from the included trials were calculated and entered into the cost analysis. Body surface area  were conducted to collect information regarding other medical resource use and cost data related to the two therapies. Other costs included the hospitalisation costs for chemotherapy, ADT cost per month, laboratory test costs, and the costs associated with AEs. Patients receiving docetaxel required hospitalisation, while patients treated with abiraterone acetate did not. The hospitalisation costs for patients receiving docetaxel included hospital bed fees and the cost of preventive drugs for chemotherapy. All patients required regular examinations, including routine blood tests, blood biochemistry and liver function tests. The incidence of AEs was obtained from the included clinical trials and is listed in the Table We compared the cost between Doc-ADT and Abi-ADT therapies from both healthcare and patient perspectives.From the healthcare perspective, we calculated the total medical costs of Doc-ADT and Abi-ADT therapies. From the patient perspective, only patient co-payments were considered. Under the current insurance policy , using Shanghai as a reference, an average patient co-pay rate of 25% was applied for outpatients, including all the costs associated with Abi-ADT treatment, and 15% for inpatients, including all the costs associated with Doc-ADT treatment.Uncertainty is usually associated with input parameter values of an economic model, which may derive from clinical trials, observational studies or in some cases, expert opinions. Therefore, sensitivity analyses were performed to examine the stability and robustness of the results.One-way sensitivity analysis (OWSA) was performed for all parameters. The results were recalculated by adjusting one input (parameter) at a time to determine how the model results were affected. The input was specified as multiple point estimates and was adjusted manually. Most parameters included in the one-way sensitivity analyses were adjusted by ± 20%, and the cost data for AEs derived from clinician interviews were adjusted by ± 100%. Because the drug cost of abiraterone used was the negotiated price, its future price cannot be increased. Therefore, only the lower limited unit cost of abiraterone acetate was considered in this analysis. The OWSA results are displayed in a tornado diagram.To quantify the level of uncertainty in the output of the analysis, we also conducted a probabilistic sensitivity analysis (PSA). In the PSA, 1000 Monte Carlo simulations were performed to test the effect of uncertainty on the base case results for costs. Model input was specified as a distribution and was obtained from the literature. The results are displayed in a histogram for the frequency distribution of cost differences.The expected total costs were RMB 399,844 per patient for Doc-ADT therapy and RMB 1,286,900 per patient for Abi-ADT therapy, with a potential saving of up to RMB 887,057 per patient. Especially, the expected drug costs before clinical progression were RMB 130,786 per patient for Doc-ADT therapy, which is much lower than that for Abi-ADT therapy with RMB 1,230,951 per patient. Although the second-line treatment costs after clinical progression for Doc-ADT therapy is higher than those for Abi-ADT therapy, the total cost for Doc-ADT arm is still much lower  patients received Doc-ADT, 597 (31.5%) patients received Abi-ADT, and 944 (49.8%) patients received ADT alone.The indirect treatment comparison demonstrated no significant difference in PFS for Abi-ADT versus Doc-ADT .A cost analysis over a lifetime survival projection was conducted based on the updated systematic review and indirect comparison. The related medical cost was derived from the local setting.The cost analysis indicated that Doc-ADT therapy costs less than Abi-ADT, with potential savings of up to RMB 887,057 per patient from the healthcare perspective and RMB 226,210 per patient from the patient perspective.No significant differences in either PFS or OS exist between Doc-ADT and Abi-ADT therapy for patients with high-volume mHSPC. The cost analysis revealed that Doc-ADT therapy is a cost-saving alternative to Abi-ADT in China.


The primary cytotoxic effects of anticancer drugs like idarubicin, a chemotherapeutic agent, are not limited to neoplastic cells; they also produce similar effects in normal cells. In this study, we hypothesized that the combination of idarubicin-bromelain could make cancer cells more susceptible to cytotoxicity and genotoxicity.To test our hypothesis, the optimal concentrations of idarubicin and bromelain were combined and incubated in the HL-60 cancer cell line and normal human mononuclear leukocytes (PBMC) for 24, 48, and 72 hr. Cytotoxicity and genotoxicity were evaluated by measurement of ATP cell viability test, DNA damage, Caspase-3, Acridine orange/ethidium bromide (AO/EB), and DAPI fluorescent dyes in both cell types.P<0.05). DNA damage and Caspase-3 levels (except for 24 hr) were also higher in the HL-60 cell line in comparison with PBMC and were statistically significant (P<0.05). The percentages of apoptotic images obtained by DAPI and AO / EB morphological examination were increased in both cells, depending on the combination dose.The combination of idarubicin-bromelain significantly reduced cell proliferation in the more potent HL-60 compared to PBMC in all incubation times (Based on these results, it can be concluded that idarubicin combined with bromelain produces more cytotoxic effects in low concentrations in comparison with when it was used per se in the HL-60 cells. Conversely, it was found that this combination in PBMC caused less cytotoxicity and less genotoxicity. Taken together, it can be said that this new combination makes cancer cells more sensitive to conventional therapy. The formation of leukemia is a complicated process that is defined by the separation of differentiation anomalies and proliferation, resulting in leukemic clonal expansion and a block in maturation . IDA, whAnanas comosus L., family Bromeliaceae), is a phytochemical-including mixture of proteolytic enzymes and non-protease constituents. BRO is defined as a medical component because of its anti-carcinogenic effects, inhibition of platelet aggregation, fibrinolytic activity, anti-inflammatory effects, cytokine and immune system regulatory effect, drug absorption enhancing effect, mucolytic effect, digestive effect, wound healing effect, and regulatory effects in the hemostatic system  was purchased from Selleckchem . Bromelain, DMSO, and, unless mentioned otherwise, other chemicals were purchased from Sigma-Aldrich . RPMI 1640 was purchased from Gibco . The Cell Titer-Glo™ Luminescent cell viability assay kit was purchased from Promega . Caspase-3 Human Instant ELISA™ Kit was purchased from Thermo Fisher Scientific .Drug preparationBRO solutions of different concentrations were prepared according to literature , 15. FinIsolation of human PBMC and leukemia cellsThe human peripheral blood sample was obtained from a young (28 years old), healthy, non-smoking volunteer. Healthy volunteers provided informed, written consent before participating. The study was approved by the Ethical Committee of Clinical Research of the University of Gaziantep, and it was conducted in accordance with the Declaration of Helsinki. . PBMC separation processes and live cell count experiments were carried out as described previously . The IC50 values of incubation times  were calculated separately. After carrying out the cell viability assay, three different doses of BRO and three different doses of IDA were chosen to include doses above and below the IC50 values determined for the PBMC and HL-60 cell lines and the combinations were created. All experiments were replicated three times.The CellTiter-Glo Luminescent Cell Viability Assay was utilized to determine cell viability in HL-60 and PBMC cells. Cells were treated with or without different concentrations of BRO, IDA, and their combinations . After 2DNA damage determination by alkaline comet assayet al. with minor modifications  developed by Singh ications , 22. Theeviously . The expDetermination of caspase-3 assayA Caspase-3 assay was performed to investigate the apoptotic activity of IDA and IDA-BRO combinations in the HL-60 cell line and PBMC. Caspase-3 levels were measured using a commercial ThermoFisher Scientific Caspase-3 Human Instant ELISA Kit. The test samples were run in duplicate as three replicates. The results were expressed in ng/ml.AO/EB fluorescent stainingAO/EB fluorescent staining to assess morphological differences in the HL-60 cell line and PBMC was performed as described in literature . After tDAPI fluorescence stainingThe fluorescence intensity, as a result of nuclear fragmentation and chromatin condensation in the detection of apoptotic cells by DAPI staining, is stronger than that of normal cells. After the incubation periods, the DAPI fluorescence staining method was carried out as described previously . The morStatistical analysisP-value<0.05 was considered statistically significant.Statistical analyses were performed using SPSS for Windows, Version 20.0 software . The results are represented as a mean±standard deviation. Data in all experiments were analyzed for statistical significance using analyses of variance . A Mann-Whitney U test was used to compare the two groups. The relationship between the parameters was investigated by a Spearman correlation analysis. A Cell viability assay50 values of IDA (0.01-20 μM) and BRO (0.01-20 mg/ml) were determined separately for each cell to generate the combination . These results revealed morphological changes and shrinkage of cells leading to cell apoptosis included by the IDA-BRO combination in human PBMC and HL-60 cell lines.It was found that while the early apoptotic, late apoptotic, and necrotic cell rates in the IDA-BRO combinations during three incubation periods in both cell lines increased in a concentration-dependent fashion, the normal cell rate decreased and was statistically significant (DAPI fluorescence stainingP<0.05).The fluorescence intensity, as a result of nuclear fragmentation and chromatin condensation in the detection of apoptotic cells by DAPI staining, is stronger than that of normal cells . It was The balance between the therapeutic and toxicologic effects of a chemical compound becomes an important parameter in the pharmacological applicability of that component . Many cyMany studies of cancer cells show that the combined use of anti-carcinogenic materials and chemotherapy agents that are already used generally generates additive and synergistic effects , 30. In In our study, we found that an IDA-BRO combination concentration-dependently generated more cytotoxic effects on the HL-60 cell line compared to PBMC after 24, 48, and 72-hr incubation periods. The cytotoxic effect of IDA/BRO combinations in the HL-60 cell line in all of the incubation periods was higher than the cytotoxic effect created by a single concentration of IDA. The fact that the cytotoxic concentrations formed in the HL-60 cell line by idarubicin, which executes its cytotoxic effect by inducing cell death processes through nuclear DNA or by causing intracellular free radical formation, were not seen in PBMC suggests that this is caused by antioxidant defense systems and DNA repair mechanisms in the lymphocyte cell culture. These results are important findings in terms of showing the necessity for higher idarubicin concentrations in order to create cytotoxic effects in lymphocyte cells as compared with HL-60 cells.There is a linear correlation between DNA damage and cell death in high concentrations of idarubicin , 17. Somet al., it was reported that idarubicin induced the apoptotic pathway through caspase-3/7 in Jurkat leukemia cells and HL-60  could help optimize conventional chemotherapy further.The findings of our research may be a guide for the development of new approaches, identification of new molecules and


Furthermore, when subcategorized based on pathological diagnosis, both BCC and SCC patients had higher levels of IL-27 in their sera compared to controls . However, these levels were not different among SCC and BCC patients. According to our results, it seems that IL-27 is involved in antitumor immune responses in NMSCs. On the other hand, these observations might be indicative of this cytokine involvement in NMSC tumorigenesis and progression. Therefore, administration of this cytokine for therapeutic purposes in patients with such conditions should be erred on the side of caution.IL-27 has been shown to have both tumor promoting and suppressing functions. IL-27, with its diverse influences on immune responses, has not been studied extensively in nonmelanoma skin cancers (NMSC), including Squamous and Basal Cell Carcinomas (SCC and BCC), and its roles in tumor initiation, progression, and its probable use in NMSC treatment have yet to be unveiled. A cross-sectional analytical study was designed to investigate the serum levels of IL-27 in NMSC patients in comparison to normal individuals. Levels of IL-27 in the sera of 60 NMSC patients along with 28 healthy controls were measured by means of quantitative enzyme-linked immunosorbent assay (ELISA). In this study we observed that IL-27 serum levels were significantly higher in NMSC patients in comparison to healthy individuals (0.0134 Attempts for identifying mechanisms underlying carcinogenesis have resulted in discovery of many aspects of tumor immune responses, many of which are already being used in therapeutic protocols for different malignancies . HoweverAmong cytokines being investigated for probable therapeutic applications, IL-27 has been shown to have both tumor promoting and suppressing functions, depending on the characteristics of the target neoplasm –6. IL-27Several reports have demonstrated IL-27 exerting direct and indirect inhibitory effects on neoplastic cells. Studies have shown the tumor restricting effects of this cytokine on pediatric leukemias , 9, lympIn spite of well-documented antitumor activities for IL-27, tumor promoting effects have been reported for this cytokine, as well. In contrast to pediatric leukemias, a study has shown that IL-27 improves survival of adult Acute Myeloid Leukemia (AML) cells and decreases their responsiveness to chemotherapeutic agents . Other sThe significance of the immune system in nonmelanoma skin cancers (NMSC), including Squamous and Basal Cell Carcinomas (SCC and BCC), has been long recognized, mainly based on the increased incidence of these neoplasms in organ transplant patients receiving immune-suppressants and immunomodulation due to ultraviolet light . IL-27, A cross-sectional analytical study was designed to investigate the serum levels of IL-27 in NMSC patients in comparison to normal individuals. A total of 60 patients with histopathologic diagnosis of SCC or BCC, who consented to be involved in the study, were enrolled from a dermatology clinic affiliated with Shiraz University of Medical Sciences. Their demographics, past medical history, and family history were gathered from clinical documents. Patients with previous history of any neoplastic or autoimmune diseases, and those with metastatic NMSC were excluded from the study. The comparison group consisted of 28 age-sex matched nonaffected individuals from the same geographic area with no history of malignant or autoimmune diseases and signs of infection at the time of sampling. The Medical Ethics Committee of Shiraz University of Medical Sciences approved that this study was in agreement with the Declaration of Helsinki principles [5 ml of venous blood was collected from each participant. The blood samples were centrifuged and the obtained sera were stored at −80°C until analysis. Levels of IL-27 in the sera were measured by a quantitative enzyme-linked immunosorbent assay (ELISA) kit  according to the protocols described by the manufacturer.Statistical Package for Social Sciences  was used for data analysis. Variables with normal distribution are presented as mean ± standard deviation (SD), otherwise as median. Frequencies are presented as percentages. Mann–Whitney U-test, Kruskal-Wallis, and Dunn's post hoc test were used to analyze the differences among groups. P< 0.05 was considered statistically significant.A total number of 60 NMSC patients and 28 healthy age-sex matched individuals, as controls, were involved in the study. The mean age of NMSC patients was 67.60±12.82 years, and male to female ratio was 3:1 (45:15). The most frequent diagnosis was SCC . Other clinicopathological features of the NMSC patients are presented in  versus 0.0008 ng/ml; P<0.001). In subgroup analysis according to pathologic diagnosis, serum levels of IL-27 were not different between SCC and BCC patients (P=1.000). However, we observed that SCC patients had higher levels of IL-27 in their serum in comparison to controls . The same was true when comparing IL-27 serum levels of BCC patients with controls . No other significant difference in IL-27 circulating levels was observed among different subgroups of patients  of NMSC presence.Although many studies suggested IL-27 administration for cancer immunotherapy , its the


Heterocycles are important class of structures, which occupy a major space in the domain of natural and bioactive compounds. For this reason, development of new synthetic strategies for their controllable synthesis became of special interests. The development of novel photoredox systems with wide-range application in organic synthesis is particularly interesting. Organic dyes have been widely applied as photoredox catalysts in organic synthesis. Their low costs compared to the typical photocatalysts based on transition metals make them an excellent alternative. This review describes proceedings since 2015 in the area of application of metal-free, visible-light-mediated catalysis for assembling various heterocyclic scaffolds containing five- and six-membered rings bearing nitrogen and oxygen heteroatoms. Heterocycles are a very important class of structural motifs that can be found in many pharmaceuticals and natural products ,2,3. NumDuring the last years, application and development of visible-light-mediated catalysis in organic chemistry became a topic of immense importance ,9. It isTo create heterocyclic scaffolds, comprehensive photocatalytic strategies based on various metal complexes have been already disclosed ,18,19,20This article presents the coverage of the recent advances in the application of metal-free, visible-light-mediated catalysis for assembling five- and six-member heterocyclic scaffolds containing nitrogen and oxygen heteroatoms. We are mainly focusing on the new metal-free photochemical reactions discovered after the year 2015 in the synthesis of aromatic and non-aromatic heterocycles. The article is organized into three chapters, which describe synthetic strategies for the preparation of nitrogen-containing heterocycles, oxygen-containing heterocycles, and heterocycles containing more than one heteroatom.N-, O-, S-, or other heteroatoms. Among the reaction strategies that lead to heterocycles, many of them use heavy metals, or require harsh reaction conditions . T. T62 to adiation b. Firstl64 followed by intramolecular cyclization gives radical 66, which is then deprotonated by phenoxyl anion 67 to radical anion 69. Formed intermediate 69 undergoes another photocatalytic cycle with the excited state of eosin by SET leading to the final product 63 in moderate to good yields (up to 80%).Fragmentation of the intermediate N-acyloxylphthalimides 71 with vinyl azides 70 in the synthesis of various phenanthridine 72  cyclization with maleimide 105 to form intermediate 109. Finally, aromatization of 109 leads to the desired product 106 in up to 94% yield 2S2O8 as a terminal oxidant. General mechanism for this transformation is disclosed in 120 and sulfate radical anion forms intermediate 123, which undergoes intermolecular addition to the triple bond of alkyne 121 with the formation of radical 124. Next, intramolecular radical addition to the carbonyl oxygen forms a five-membered O-heterocycle 125 radical. Finally, oxidation of 125 by MB•+ followed by deprotonation leads to the final product 122.Similar to euticals ,55, attreuticals . Lei elaals . F. F129 vi128 various γ-lactams or pyrrolidines can be prepared as well  cycloaddition of nitrone 165 with alkyne 161 provides the product 162.Woo group  unveiledynes 161 a. Descri authors b. Excite166 in the presence of the triphenylpyrylium 8c catalyst and molecular oxygen as the oxidant, promoted by compact fluorescent lamp (p-F)PPT act as both an electrophilic catalyst and a photocatalyst due to the fact that reaction works also in the dark, although less efficient. The authors proposed a possible mechanism for this transformation  and produces the radical 172. Subsequent oxidation of the compound 172 to the iminium ion by molecular oxygen or excited catalyst followed by intramolecular cyclization yields the final product 167.1,2,4-Oxadiazole derivatives besides exhibiting biological activities have also found application in light-emitting diodes (OLEDs) . Due to ent lamp a. Opposiormation b. Reacti174 and phenyl disulphide  tolerates also many functional groups. In 12 by blue LED irradiation generates the active oxidant (PC+*), which accepts an electron from substrate 174, generating cation radical intermediate 176. Subsequent cyclization and proton loss affords cyclic radical intermediate 177. Finally, hydrogen atom transfer from thiophenol 178 generates product 175 and a thiyl radical 179. The thiyl radical 179 is presumed to re-oxidize the acridine radical catalyst (PC•), regenerating catalyst in its ground state.This mild and efficient protocol leading to the products 183 and in situ conversion of formed fluorophosgene for the synthesis of carbamates, carbonates, and urea derivatives 184  is excited under irradiation followed by intersystem crossing (ISC) providing 3RB*. Subsequent energy transfer from triplet RB catalyst to oxygen produces reactive singlet oxygen 1O2 responsible for the oxidation of the compound 188 into the final product 187.Quinazolines are another class of heterocyclic compounds extensively studied. Itoh et al. described the synthesis of quinazolines ydes 186 a 82]. A. A187 un189 and aldehydes 190 into heterocycles 191, but in different reaction conditions [2-catalyzed dehydrogenation/aromatization of amines under photoredox conditions. In this context, a corresponding amine formed upon cyclization of diamine 189 and aldehyde 190 is dehydrogenated and aromatized to the product 191. A broad range of functional group can be used and desired products can be prepared in up to 91% yield. In addition to the diamine and aldehydes coupling, multisubstituted quinazolines and benzimidazoles can also be obtained by the radical cyclization of N-alkyl-N’-arylamidines catalyzed by Rose Bengal 7 in the presence of CBr4 and K2CO3. Tang group demonstrated that the given methodology tolerates a wide range of functional groups with a higher reaction efficiency [More recently, Das group also demonstrated cyclization of the diamines nditions  . Alternatively, the radical 198 can undergo intramolecular cyclization with the aromatic ring (path b) leading to the undesired product 199 in trace amount. The radical 200 undergoes another intramolecular cyclization producing conjugated radical 201, which after oxidation by the Eosin Y cation radical (EY•+) forms intermediate 202. Final product 194 is obtained by the deprotonation of intermediate 202.The suggested mechanism is depicted in 203 easily undergoes intramolecular cyclization using Eosin Y 11a as photoredox catalyst and green light source . Secondly, electron transfer from Eosin to tert-butyl hydroperoxide (TBHP) generates t-butyloxy radical and OH−. Subsequent hydrogen atom removal from 214 produces sulfur-centered radical 215, which undergoes addition to the double bond of 207 and produces radical intermediate 210. Intramolecular cyclization cascade delivers radical 212, which is oxidized by EY•+ to the cationic intermediate 213 through a single-electron-transfer route regenerating the same EY in its ground state. Finally, deprotonation of 213 gives the expected product 209.Quinazolinone structure is another important structural unit in heterocyclic chemistry ,2,3. Idrenes 207 a. PresenIn addition to the given examples, other heterocycles containing multiple heteroatoms like imidazopyridines  or oxadiIn this review, recent advances in the synthesis of nitrogen and oxygen heterocyclic compounds via a metal-free visible-light-induced catalysis have been discussed. It has been shown that various metal-free organic dyes are effective photo-redox catalysts in the synthesis of many structurally different heterocycles containing one or more heteroatoms. Both non-aromatic and aromatic heterocyclic units are readily accessible by using visible-light-mediated catalysis in a straightforward modular way. Reported works indicate that organic dyes capable of visible-light-spectra absorption act as an attractive alternative to the transition-metal complexes. The variety of the presented examples indicates the potential use of the described methodologies in organic synthesis, drug discovery, or materials science. Moreover, the use of inexpensive organic, transition metal-free catalysts makes described protocols very practical and hold promise for broader application in industry and scientific community.


Background: Delay discounting (DD) refers to the decrease of a present subjective value of a future reward as the delay of its delivery increases. Major depressive disorder (MDD), besides core emotional and physical symptoms, involves difficulties in reward processing. Depressed patients often display greater temporal discounting rates than healthy subjects. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique applied in several countries to adult patients with treatment resistant depression. Studies suggest that this technique can be used to modulate DD, but no trial has assessed its effects on depressed patients. Methods: In this open-label uncontrolled trial, 20 patients diagnosed with MDD and at least stage II treatment resistance criteria underwent 20 HF-rTMS sessions over the dorsolateral prefrontal cortex . Pre-post treatment DD rates were compared. Effects on impulsivity, personality factors, and depressive symptoms were also evaluated. Results: No significant effect of HF-rTMS over the left dlPFC on DD of depressed individuals was observed, although rates seemed to increase after sessions. However, treatment resulted in significant improvement on cognitive impulsivity and depressive symptoms, and was well-tolerated. Conclusion: Despite the limitations involved, this pilot study allows preliminary evaluation of HF-rTMS effects on DD in MDD, providing substrate for further research. Major depressive disorder (MDD) is a widespread psychiatric disease that will become the leading worldwide cause of years living with disability by 2030 according to the World Health Organization (WHO). Episodes of depression, in addition to core emotional and physical symptoms, also involve difficulties in reward processing . A reducDelay discounting (DD) or temporal discounting are terms that refer to the decrease of a present subjective value of a future reward as the delay of its delivery increases . The degTendency for impulsive choices and inability to delay gratification can stand in the way of one’s fulfillment of long-term plans. Individuals have different discount rates, and the more one devaluates a future reward as a function of its delay, the less influence this reward will have on one’s present choices . In an eThe behavioral balance between cautious and risky decisions critically involves the prefrontal cortex (PFC). This cortical area has been implicated in decision-making processes based on reward values and effort calculations of multiple choices to promote goal-directed behavior ,17. ActiEvidence suggests that non-invasive brain stimulation over the dlPFC can improve risk taking, reward seeking, computation of values, as well as other processes involved in impulsive behavior . TranscrModulatory effects of TMS on DD are promising, as suggested by a recent review and meta-analysis on studies involving healthy adult participants, with a significant mean effect size for the left dlPFC as the target . AnotherStudies assessing TMS effects on the DD of clinical populations remain scarce. Sheffer and colleagues  delivereAs far as we know, no study has assessed rTMS effects on DD in depressed individuals. We have therefore conducted an open-label uncontrolled pilot study to evaluate whether rTMS applied to the dlPFC could reduce DD in MDD patients who have not shown satisfactory clinical progress with medication. We hypothesized that rTMS would decrease temporal impulsivity of these patients, along with the expected improvement on their depressive symptoms. The primary objective was to analyze changes in baseline DD rates after 20 rTMS sessions. As secondary outcome measures, we also investigated (i) the neuromodulatory effects of a single rTMS session on baseline DD scores; (ii) the effects of 20 rTMS sessions on general impulsivity, (iii) on personality traits, and (iv) on depressive symptoms; (v) possible correlations of DD rates with the other psychiatric measures; and (vi) DD rates correlations with sociodemographic characteristics.The study was conducted at the psychiatric department of the University Hospital of Besancon, France, and aimed to enroll all eligible volunteers that met inclusion criteria. The inclusion criteria were as follows: (i) men and women over 18 years old, with (ii) diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, and (iii) at least stage II treatment resistant criteria ,29. ExclIn this open-label uncontrolled trial, all subjects underwent the same procedure. Patients received 20 sessions of high frequency rTMS (HF-rTMS), delivered twice a day over a period of two weeks (sessions were performed by E.H. or D.B. from Monday to Friday). The protocol was approved by the French Committee of Protection of Persons (CCPPRB Reference No.: 04/380) and authorization was given by the General Health Administration (DGS 2005/0030). Investigations were conducted in line with the principles from the Declaration of Helsinki. Signed written informed consent was obtained from all patients before study enrollment.A Magstim Super Rapid2  with an air-cooling figure-of-eight coil was used. The rTMS was administered at 10 Hz during 5 s, with 25 s between trains, and at 110% MT over the left dlPFC per 20 min session (2000 stimuli per day). The coil was angled tangentially to the head. The placement to stimulate the left dlPFC was 5 cm anterior to the hand motor area, in a parasagittal line. Tolerability and side effects were assessed both verbally, during and after sessions, and through a Visual Analogue Scale (VAS) applied by the end of sessions. The VAS assessed the patient’s perception on pain, mood, fatigue, and motivation.Measures on DD rates were collected at three points in time: prior to stimulation sessions (baseline scores), immediately after the first session, and after 20 sessions. DD was assessed by the 27-item Monetary Choice Questionnaire (MCQ), based on Kirby’s DD inventory . The MCQFurthermore, measures of impulsivity, personality traits, and severity of depressive symptoms were collected prior to stimulation sessions and at the end of 20 rTMS sessions. Impulsivity was evaluated by the French version of the Barratt Impulsiveness Scale (BIS-10) ,31, a 34Depression severity was assessed by both the Montgomery–Åsberg Depression Rating Scale (MADRS) —filled bkD, where V represents the subjective value of the delayed reward, A is the amount of the delayed reward, D is the delay, and k is the coefficient that estimates the subjective discounting rate for the given delayed reward. The hyperbolic function is more efficient than the exponential model of discounting, since it better integrates discount variations for decisions concerning rewards in the short and in the long run [K-values were generated by the 27-item MCQ Automated Scores [DD rates are based on the hyperbolic function V = A/1 + long run . K-valued Scores  for smaln)” column.Our sample was composed of 9 women (45%) and 11 men (55%), with a mean age of 54.4 (SD ± 9.854) years. All patients had been using antidepressant medications for at least 4 weeks: 18 of them were on antidepressant monotherapy (selective serotonin reuptake inhibitor (SSRI) = 7, serotonin and norepinephrine reuptake inhibitor (SNRI) = 7, tricyclic antidepressant (TCA) = 3, tetracyclic antidepressant (TeCA) = 1), and two patients had a combination of two antidepressants (SNRI with TeCA = 2). Mean baseline scores and demographic data are displayed on p < 0.0125) was assessed. The median values apparently increased after rTMS sessions (p = 0.0293). However, analysis showed that there was no statistical significance , but no significant change was observed . There was a significant reduction on cognitive-impulsivity scores (p = 0.0071) as displayed in The analysis of the impact of 20 rTMS sessions on the BIS-10 considered four scores: BIS-10 total score and cognitive-, motor-, and non-planning-impulsivity subscales scores (p < 0.01) was observed  were significantly reduced in both assessments  at the end of 20 rTMS sessions (Depressive symptoms assessed by the MADRS and the QIDS-SR16 (sessions .p < 0.05) between pre-post 20-rTMS-session discounting rates and scores of other psychiatric measures. The agreeableness score on the BFI-Fr was negatively correlated to k-values for medium rewards , while the non-planning-impulsivity subscale from the BIS-10 was positively correlated to k-values for large rewards . No other significant correlations were found. Baseline psychiatric scores, age, and gender of participants had equally no significant influence on pre-post 20 rTMS discount rates.Spearman’s rho test revealed significant correlations —was observed, although no significance of the effect was obtained. Methodological differences between our trial and previous trials with healthy participants [Interestingly, as we analyzed data from pre-post 20 HF-rTMS sessions, an apparent increase on temporal impulsivity—especially for medium rewards  may lead to a better understanding on rTMS effects. Other targets could also be explored in accordance with depression biotypes and their particular connectivity dysfunction  as theraDespite the limitations involved in this study, the results allow a preliminary evaluation of rTMS effect on temporal impulsivity in depressed individuals meeting treatment-resistant criteria. Nevertheless, further research concerning MDD and DD is required. Merging TMS with brain-imaging methods, performing randomized controlled trials, and associating measure instruments on impulsivity may help us better understand the effect of neuromodulation on temporal impulsivity in depression.


Studies to examine the associations of gestational weight gain (GWG) with offspring weight status during infancy are needed, especially among Asian populations. We examined 801 mother–infant pairs from a prospective cohort study in China to assess the associations of total and trimester-specific GWG with early infant weight status. We used linear mixed effects models and linear regression models to examine the longitudinal and time-point associations of GWG rate (kg/week) with infant growth measures (z-scores of body-mass-index (BMIZ), weight-for-age (WFAZ) and length-for-age (LFAZ)) at birth, 1, 3, and 6 months. Greater total GWG rate was associated with higher BMIZ  per 1 kg/week increase in GWG) and higher WFAZ ) across the first 6 months of life. GWG rate in the first two trimesters but not in the third trimester was positively associated with infant BMIZ. The association between GWG rate and infant BMIZ was significant at all timepoints and more pronounced in normal weight women and among male infants. In conclusion, greater GWG rate is positively associated with offspring BMIZ in the first 6 months of life, the association is mostly driven by GWG in the first two trimesters. The epidemic of childhood obesity is a global challenge . In ChinFurthermore, the effects of GWG programing childhood weight status may vary according to the timing of weight gain during pregnancy. First and second trimester weight gain primarily represents maternal fat deposition, which may increase the placental transfer of nutrients from mother to fetus, while third trimester weight gain reflects fetal growth which may influence fetal body composition . Most prIn addition, existing studies have reported sex-specific effects of pre- and postnatal exposures such as pre-pregnancy weight status , smokingTo address these gaps, we investigated associations of total and trimester-specific GWG rate with offspring weight status during early infancy in a prospective pre-birth cohort study in China, the Born in Shenyang Cohort Study (BISCS). We hypothesized that: (1) greater GWG rate would be positively associated with weight status of infant; (2) early pregnancy (first and second trimesters) GWG would have stronger associations with infant weight status; (3) the association of GWG with infant weight status would differ by infant sex or pre-pregnancy women weight status.We established a multicenter prospective pre-birth cohort, “Born in Shenyang Cohort Study (BISCS)”, to examine associations of prenatal factors in relation to maternal and child health. Between April and September 2017, we enrolled healthy single pregnant women at 21–24 weeks gestation at 54 hospitals and community healthcare centers which are all the maternity clinics for antenatal visit in the urban area of Shenyang, northeast of China. We included women with singleton pregnancies, gestational age <24 weeks, and who had no plans to move away in the next three years. Among 2068 women, 1338 agreed to participate in the study and 1260 had a live singleton birth . All motWe conducted in-person visits with mothers during the second trimester (mean ± SD: 22 ± 1.2 week) and third trimester (mean ± SD: 34.5 ± 1.9 week). We also conducted home visits with mothers and infants within 7 days after birth, and research visits at the child development clinics at ages 1, 3, and 6 months. We collected socio-demographic, environmental, behavioral, and clinical information from mothers and children via questionnaires and medical records, and performed anthropometric measurements.n = 3) or delivery at <34 weeks of gestation [n = 5). Of the 926 eligible mother-child pairs, we further excluded from the present analysis, those without data on gestational weight, or any weight records within 4 weeks preceding delivery (n = 125). A total of 801 mother-child pairs were included in the present study .nt study . We compWe defined total GWG as the difference between self-reported pre-pregnancy weight and last recorded weight before delivery. We obtained a median of 10 (range 5 to 17) weight records over the entire duration of pregnancy. We calculated GWG rate (kg/wk) as total GWG divided by the number of gestational weeks at delivery. We defined the first two trimesters as the duration from the date of the last menstrual period to day 196 (28 weeks)  of pregnWe extracted weight and length at birth from medical records. Trained pediatricians measured the child’s length and weight during research visits at ages 1, 3, and 6 months using calibrated infant stadiometers  and weighing scales . We measured length and weight twice to the nearest 0.1 cm and 0.01 kg respectively, and calculated the mean of the two measurements.We calculated offspring BMI by dividing infant weight in kilograms by the square of height in meters measured at birth and 1, 3, 6 months of age. We calculated age- and sex-specific z-scores for BMI (BMIZ), weight (WFAZ), and length (LFAZ) based on the World Health Organization (WHO) child growth reference .2), normal-weight (18.5 kg/m2 ≤ BMI < 23 kg/m2) or overweight/obese (BMI ≥23 kg/m2) using WHO references for Asian population [We measured mother’s height at the initial prenatal visit using a calibrated stadiometer . Mother’s pre-pregnancy BMI was calculated by dividing self-reported pre-pregnancy weight in kilograms by the square of measured height in meters. Father’s BMI was calculated on self-reported height and weight. Both mother’s pre-pregnancy BMI and father’s BMI were categorized as underweight  with infant sex- and age- specific z-score for BMI, weight and length from birth to 6 months using linear mixed effects (LME) models, which takes into account within-subject correlation of repeated measurements and at the same time allows for incomplete outcome measurement . We fittWe also used multivariable linear regression models to examine associations of total and trimester-specific GWG rate as well as the pre-pregnancy weight status with infant sex- and age-specific z-scores for BMI, weight and length at each time point . The full model adjusted for pre-pregnancy BMI, maternal age, race, parity, educational attainment, household income, smoking status, and paternal BMI. We tested interactions of GWG rate with pre-pregnancy BMI category and infant sex in relation with infant growth measures by including corresponding interactions into the models. Furthermore, we performed stratified analyses to investigate the association of GWG rate with infant size among women of different pre-pregnancy weight status. In addition, we also stratified analyses according to infant sex to identify sex-specific associations of total and trimester-specific GWG rate with infant growth.For sensitivity analyses, we used weight-for-length z-scores (based on the WHO child growth reference) as outcomes to be compared with BMI z-scores as outcomes in the LME analysis. We also adjusted for infant variables that might mediate associations of GWG with outcomes, including mode of infant feeding, television viewing status, and secondhand smoke exposure at the age of 1 month.p-value <0.05 was considered statistically significant.To get a full sample, multiple imputation was used to fulfill the missing values in linear regression models. We performed all analyses using Stata S.E. version 13 . A two-side There were no significant differences in demographic  or clinical characteristics  across quartiles of total GWG . Comparep for interaction <0.05). In normal weight women, total GWG rate was positively associated with offspring BMI z-score at birth, 1 month, 3 months, and 6 months. In underweight women, total GWG rate was positively associated with offspring BMI z-score only at age of 3 months. No associations were observed between total GWG rate and offspring BMIZ in overweight/obese women.In stratified analyses by pre-pregnancy weight categories , we founAmong male infants, total GWG rate and GWG rates in the first two trimesters were associated with infant BMI z-score at birth, 3, and 6 months . HoweverIn this prospective birth cohort study in China, we found that the rate of gestational weight gain was positively associated with offspring BMI z-score across early infancy. The association was largely driven by GWG in the first two trimesters rather than the third trimester. The observed associations were more pronounced in normal weight women and in male rather than female infants.Our findings provide additional evidence to the existing literature on the relationship between trimester-specific GWG and offspring weight status in the early stages of life. Although a previous study examined the association between trimester specific GWG with infant birthweight in the Asian population, our study is the first study to assess associations of trimester-specific GWG on offspring weight status across early infancy in Asia. Our findings may help develop intervention strategies focused on controlling the rapidly increasing prevalence of childhood obesity in Asia.Our results are consistent with previous studies ,12,24 thOur findings confirmed previous studies ,22,25 thTaken together, these findings suggest that the early pregnancy period is a highly sensitive period for fetal adiposity programing, consistent with the fact that fetal adipose tissue begins to develop around 14–16 weeks of gestation . GreaterTo our knowledge, no previous studies have assessed sex-specific associations of GWG with child weight status after birth. In our study, greater total GWG rate was positively associated with infant BMI z-score at 3 and 6 months in male but not female infants. These sex differences could be due to the differences in adiposity related hormones (such as leptin and testosterone) between male and female infants ,50,51. FThe strengths of our research include a population-based prospective design, collection of weight status at multiple timepoints during pregnancy, and repeated research-standard measures of offspring length and weight status during early infancy. The study was based on the understudied Asian population, which has both high prevalence of excessive GWG and rapidly increasing pace of childhood obesity. Our research also has several limitations. First, pre-pregnancy weight status was based on self-reports and thus subject to recall bias, although previous studies have reported high correlations between self-reported and measured pre-pregnancy weight ,22. SecoIn summary, we found that GWG rate was positively associated with early infancy weight and BMI z-score, but not with length. Normal weight women are more likely to have infants with higher BMI z-score if they had greater weight gain during pregnancy, thus they should pay more attention to control weight gain. Associations were stronger in male infants. Given that boys in China are approximately twice as likely to have obesity, and the rate of obesity is rising much faster than in girls , more at