People with biopsy-proven glomerulonephritis (GN) as their cause of end-stage kidney disease (ESKD) who undergo kidney transplantation incur significant risk of recurrent GN-related graft failure, but the risk in recipients with ESKD where GN was suspected but not biopsy proven (presumed/advanced GN) and when the cause of ESKD is unknown remains uncertain. Using the Australia and New Zealand Dialysis and Transplant registry, we examined the associations between primary kidney transplant recipients whose ESKD was attributed to: 1) commonly-recurring GN , 2) presumed/advanced GN, and 3) cause of ESKD unknown (uESKD) and GN-related graft failure using adjusted competing risk models. Of 5258 recipients followed for a median of 8 years, 3539 (67.3%) had commonly-recurring GN, 1195 (22.7%) presumed/advanced GN, and 524 (10.0%) uESKD. Compared to recipients with commonly-recurring GN, recipients with presumed/advanced GN or uESKD experienced a low incidence of GN-related graft failure (<1%) and a lower hazard of GN-related graft failure . People with ESKD attributed to either presumed/advanced GN or unknown cause face a very low risk of graft failure secondary to GN recurrence after transplantation. Disease recurrence after kidney transplantation is an important cause of graft loss8 and the ability to inform patients of this risk is one reason why clinicians seek to establish a histological diagnosis in those with ESKD that may be caused by GN9. In practice, a histological diagnosis is frequently not obtained. In some cases with clinical features of GN, a biopsy is not done due to patient refusal or the presence of contra-indications to biopsy such as clotting disorders or small kidneys, and such cases are frequently labelled “presumed GN”. In other cases the biopsy may not show clear features of any particular GN but only advanced interstitial scarring and glomerulosclerosis and in such cases ESRD is frequently attributed to “advanced GN”. In a subgroup of patients with ESKD, the underlying etiology of ESKD is unknown. The incidence of patients with ESKD attributed to presumed GN or “unknown etiology” varies widely, with reported incidence of up to 10%10.Primary glomerulonephritis (GN) is one of the leading causes of end-stage kidney disease (ESKD) in Australia and worldwide, affecting up to 20% of patients commencing renal replacement therapy13. The risks of GN recurrence and recurrence causing graft loss after transplantation remain unknown for patients with presumed or advanced GN and those with an unknown cause of ESKD. The risk of this outcome, placed in the context of other “competing” causes of graft failure including acute rejection, chronic allograft nephropathy and death with graft function, is important for patients and their physicians to understand. We sought to test the hypothesis that patients with ESKD secondary to presumed or advanced GN or an unknown cause have a low risk of GN-related graft failure compared to those with commonly-recurring GN. The primary aim of this study was to compare the risks of GN-related graft failure between kidney transplant recipients with presumed/advanced GN, ESKD from an unknown cause (uESKD) and those with ESKD secondary to biopsy-proven commonly-recurring GN, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry.Several types of GN including IgA nephropathy, membranoproliferative glomerulonephritis (MPGN), focal segmental glomerulosclerosis (FSGS) and idiopathic membranous nephropathy (IMN) are known to recur frequently post-transplantation (i.e. commonly-recurring GN), with up to 50% of those with recurrence experiencing graft failure after a median of 5 yearsThere were 5258 recipients included in this study, of whom 3539 (67.3%) had commonly-recurring GN, 1195 (22.7%) had presumed/advanced GN, and 524 (10.0%) had uESKD. Baseline characteristics of the study population according to exposure groups are shown in Table Mean recipient age and the proportion of deceased donor kidney transplants were greater in recipients with presumed/advanced GN or uESKD as compared to those with commonly-recurring GN. A greater proportion of recipients with presumed/advanced GN or uESKD were indigenous (13–16% vs. 6% with commonly-recurring GN). Biopsies were undertaken to establish ESKD in 19% and 13% of those with presumed/advanced GN and uESKD, respectively, compared to 100% of recipients with commonly-recurring GN. Variability in biopsy practices across Australia and New Zealand are likely, however the ANZDATA registry does not capture these data. The GN subtypes for recipients with commonly-recurring GN are shown in Table A greater proportion of recipients with commonly-recurring GN experienced graft failure from GN recurrence compared to recipients with presumed/advanced GN or uESKD . Compared to recipients with commonly-recurring GN, recipients with ESKD attributed to presumed/advanced GN and uESKD were less likely to experience GN-related DCGF with adjusted sub-distribution HR of 0.28  and 0.20 , respectively  cases of DCGF were attributed to recurrent GN Table . Only 3/Overall graft survival at 5 and 10 years for recipients with commonly-recurring GN was 84% 82–85%) and 67% (65–69%), respectively. This compared with 79% (76–81%) and 60% (57–64%), respectively for recipients with presumed/advanced GN; and 79% (75–83%) and 63% (57–68%), respectively for recipients with uESKD (log-rank p < 0.001). In the unadjusted model, recipients with presumed/advanced GN or uESKD experienced a higher risk of overall graft failure with unadjusted HR of 1.24  and 1.30 , respectively compared to recipients with commonly-recurring GN. However, these associations were no longer significant in the adjusted model  and 0.72 , respectively  and 1.58 , respectively , infection  and cancer  were higher in recipients with presumed/advanced GN and uESKD. Compared to recipients with commonly-recurring GN, recipients with uESKD experienced a higher risk of cancer-related DWFG , but not cardiovascular disease  or infection-related DWFG . There were no associations between presumed/advanced GN and any cause-specific DWFG.Patient survival at 5 and 10 years for recipients with commonly-recurring GN was 94% (93–95%) and 85% (83–86%), respectively. This compared with 88% (85–90%) and 75% (72–78%), respectively for recipients with presumed/advanced GN; and 86% (83–89%) and 75% (70–79%), respectively for recipients with uESKD (log-rank p < 0.001). In the unadjusted model, recipients with presumed/advanced GN or uESKD were more likely to die with unadjusted HR of 1.61  and 1.93 , respectively compared to recipients with commonly-recurring GN. However, these associations were no longer significant in the adjusted model  as the most common cause of DCGL among those with a GN type known to recur, whereas CAN/IFTA, acute rejection, vascular complications and other causes were all more common than GN-related graft failure for those with presumed/advanced GN or uESKD.For a significant proportion of people with ESKD, their cause of ESKD is not determined with certainty. ESKD is attributed to presumed/advanced GN in a proportion of these cases where clinical characteristics suggest GN however a specific diagnosis was not obtained because a biopsy was not performed or was non-diagnostic. Others are classified as ESKD of unknown cause. For both groups, GN remains a possible cause. Given that GN recurrence is one of the leading causes of graft loss after kidney transplantation, understanding the graft outcomes of such recipients would enable a more adequate discussion of risks and benefits, and specifically their risk of GN and GN-related graft failure, prior to kidney transplantation. We found that GN-related graft failure was an uncommon event among these two groups after kidney transplantation, affecting less than 1% after a median follow-up period of 8 years. Over the same period, 5% of those with a type of GN known to recur after transplantation experienced graft failure, which was attributed to recurrence. This finding remained robust after adjustment for potential confounders and thus such patients can be relatively reassured. Consistent with previous literature14. In this analysis, people with presumed/advanced GN or uESKD were no different to those with defined types of GN in terms of their risk of overall graft failure in adjusted models. Here, the higher rates of GN-related graft failure among those with recurring types of GN were negated by higher rates of graft failure attributed to a number of other causes among those with presumed/advanced GN and uESKD. Risks of all-cause mortality were modestly higher for those with presumed/advanced GN and uESKD as compared to known GN, however such differences were accounted for by factors including age and comorbid status and so became non-significant in the adjusted models.In considering transplantation, patients often have concerns beyond the risk that their original kidney disease may recur after kidney transplantation such as the risk of acute rejection, graft failure from any cause and death from cancer or other causes6. Those affected by recurrence incur a two-fold increase in risks of subsequent graft failure7, the majority of which is attributable to recurrence. The vast bulk of affected patients were those with biopsy-proven GN of a type known to recur. Risks for those with presumed/advanced GN are less well reported. In a prospective cohort study of 2606 kidney transplant recipients between 1990–2005, it was shown that only 6% of recipients who were classified as having presumed GN as cause of ESKD had biopsy-proven post-transplant GN, compared to 13% in those whose cause of ESKD was attributed to biopsy-proven GN pre-transplant. However, the authors did not specifically evaluate the risk of GN-related graft loss by GN subtypes3. After excluding those who died with a functioning graft, we found that 5% of recipients with presumed/advanced GN experienced GN-related graft failure, compared to 21% in those with commonly-recurring GN, with the majority  being classified as recurrent/de novo IgA nephropathy, FSGS or IMN. Despite the lower risk of GN-related graft failure in those with presumed/advanced GN compared to commonly-recurring GN, the risks of overall graft failure and DCGF were similar. We hypothesised that factors which precluded obtaining biopsy-confirmation of GN as a cause of ESKD may have also prevented a diagnosis of GN post-transplant in the presumed/advanced GN group. Such factors would likely yield an increase in graft failure attributed to CAN/IFTA, as this diagnosis is commonly made on the basis of clinical findings, such as proteinuria and/or declining eGFR, which may also be present in patients with GN4. However, the incidence of graft failure attributed to CAN/IFTA was equal in all groups , of whom less than 1% experienced GN-related graft failure. In our study, recipients with uESKD were less likely to experience DCGF but had a higher risk of DWFG, possibly related to the residual confounding effects of older age and a greater proportion of recipients with comorbid conditions compared to recipients with commonly-recurring GN. However, it is possible that exposure to environmental or occupational toxins may be causal in some cases of uESKD and that these may also contribute to the excess risk of DWFG (including cancer-related DWFG) in this group. It is important to point out that uESKD as reported to the ANZDATA registry represents a constellation of varying diseases with dissimilar causative factors, and likely different to a diagnosis of CKDu, which is a distinct clinical entity in certain countries. A more in-depth review of the occupational and/or environmental exposure to toxins may help to establish the true etiology of uESKD, but this is beyond the scope of registry data.The reported incidence of uESKD (i.e. ESKD without an identifiable etiology or categorized as unknown chronic kidney disease [CKDu] in some countries) may be as high as 25%, often occurring in the absence of significant proteinuria or any identifiable risk factors8. The relatively small number of GN-related graft losses and medium-term follow-up period may potentially have led to erroneous inference and therefore we are unable to generate reliable estimates with certainty.Our study has several strengths and limitations. This is one of the largest cohort studies to examine the association between presumed/advanced GN and uESKD and long-term graft and patient outcomes in the era of modern immunosuppression. In capturing GN post-transplant, we have likely included recurrent and de novo disease, particularly in the presumed/advanced GN and uESKD groups. Selection bias is likely to exist because there may be systematic differences in the selection and listing of ESKD patients with different GN types as well as differences in the management of these recipients pre- and post-transplant. In addition, the cause of ESKD in the registry is assigned to the dominant cause, in the opinion of the nephrologist, which may not always be biopsy proven. Even though multiple confounding factors were adjusted for, it is likely that unmeasured residual confounders such as the severity of comorbidities, intensity of immunosuppression, and treatment of GN prior to transplants, which are not collected by ANZDATA registry may have modified the association between ESKD groups and outcomes. Because histological confirmation is not a requirement of the ANZDATA registry in the reporting of ESKD diagnosis or causes of graft loss, incorrect classification of causes of graft loss could potentially occur. Nevertheless, we have previously shown that a high proportion of cases of allograft failure, which are attributed to GN in ANZDATA registry, are indeed biopsy provenTransplant candidates with presumed/advanced GN or ESKD of unknown cause are at relatively low-risk of incurring graft failure from post-transplant GN, as opposed to those with biopsy-proven GN of a type known to recur. As overall patient and graft survivals were similar between those with GN, presumed/advanced GN and uESKD, we propose that the cause of ESKD should not in general be used to distinguish between the three groups in terms of their access to transplantation.Primary live and deceased donor kidney-only transplant recipients with ESKD secondary to GN or uncertain diagnosis in Australia and New Zealand between 1990–2012 were included. Of 12,859 patients with ESKD who have received primary kidney-only transplants, recipients with ESKD secondary to non-commonly-recurring GN (n = 752) and non-GN causes of ESKD other than uESKD (n = 6803) were excluded. The most common GN type in the non-commonly-recurring group is familial GN (n = 229 [30.5%]), followed by extra/intra-capillary GN (n = 135 [18.0%]), IgA-negative mesangial proliferative GN (n = 107 [14.2%]), Goodpasture’s syndrome  and other GN with systemic causes (n = 162 [21.4%]). In the non-GN causes of ESKD (other than uESKD), 27% were attributed to cystic disease, 23% diabetic nephropathy, 18% reflux nephropathy, 8% vascular disease, 3% analgesic nephropathy and 21% other causes.Of those with commonly-recurring GN, 46 1.3%) were not reported to have biopsy-proven disease and were therefore excluded leaving a final cohort of 5258 recipients for analysis. The Strengthening the reporting of observational studies in epidemiology (STROBE) guideline for reporting is shown in Supplementary Fig. .3% were http://www.anzdata.org.au/forms/ANZDATA/ anzdata_A3_2013.pdf.Recipients were categorised according to the causes of ESKD: 1) Commonly-recurring GN ; 2) Presumed/advanced GN; and 3) uESKD (ANZDATA coded as “uncertain diagnosis”). Categories of ESKD collected by ANZDATA registry are listed in Baseline donor, recipient and transplant-related characteristics included donor age, type and gender; recipient age, gender, race, body mass index (BMI), waiting time pre-transplant, diabetes and coronary artery disease and peripheral vascular disease at time of transplantation; and transplant-related characteristics included peak percentage panel reactive antibody, induction therapy, number of human leukocyte antigen (HLA)-mismatches, total ischaemic time, transplant era and initial immunosuppressive agents.st December 2012. There were no missing outcome data for this study cohort.The primary outcome of this study was GN-related graft failure. Secondary outcomes included overall graft failure, death-censored graft failure (DCGF), death with a functioning graft (DWFG) and all-cause mortality. Data was censored as of 31Data were expressed as number (proportion), mean ± standard deviation (SD) and median and interquartile range (IQR) where appropriate. Comparisons between categories of ESKD were made by chi-square test and analysis of variance (ANOVA) for categorical and continuous variables, respectively. The associations between categories of ESKD and outcomes were examined using adjusted Cox proportional hazards regression or competing risk analyses. The proportional hazards assumptions of all models were checked graphically by plotting the Schoenfeld residuals, and there were no evidence of departures from proportional hazards. The covariates with missing data are shown in the flow chart  were considered as competing risks. The sub-distributional HRs and 95%CI were calculated to estimate the covariate effects on the cumulative incidence. Other covariates included in the competing risk models were identical to those included in the Cox regression models. Statistical evaluation was performed by SPSS V10 software program and STATA version 11. P-values of <0.05 were considered statistically significant.We conducted a competing risk regression for GN-related graft failure, DCGF, DWFG and cause-specific DWFG  taking into account the informative nature of censoring due to competing risk using the method of Fine and GrayThe authors confirm that all data underlying the findings are fully available without restriction. The primary dataset for this manuscript was generated and made available to the authors by the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry, Adelaide, Australia. The ANZDATA Data Use Agreement between the ANZDATA Registry and the authors does not allow the authors to make the data publicly available. The authors confirm that all data underlying the findings can be obtained without restriction from the ANZDATA Registry. The interested researchers are advised to contact the ANZDATA Registry independently (email address requests@anzdata.org.au).Supplementary figure 1


Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9. Published 15, March 2017On publication of our article, we noticed that a penultimate version of Figure 4 was inadvertently resubmitted instead of the final version, along with the penultimate version of the accompanying Supplementary file 2. The final version of Figure 4 is subtly different and is shown below.In addition, the sentence in the Methods describing SuperTOP assays should be slightly modified, as follows:‘For luciferase reporter assays, SuperTOP  was co-transfected with CMV-Renilla as internal control, and assays were performed initially 48 hours post-transfection, but subsequently 24 hours post-transfection ’.The original sentence is given below, for reference:‘For luciferase reporter assays, SuperTOP  was co-transfected with CMV-Renilla as internal control, and assays were performed 48 hours post-transfection’.These corrections do not affect in any way the conclusions of our study.The corrected Figure 4 is shown here:The originally published Figure 4 is also shown for reference:The article has been corrected accordingly.


To examine the effectiveness of systemic chemotherapy following radical hysterectomy for women with intermediate-risk stage IB cervical cancer.n = 223, 40.2%), concurrent chemo-radiotherapy , and radiotherapy alone .This is a retrospective analysis of a previously organized nation-wide cohort study examining 6,003 women with stage IB-IIB cervical cancer who underwent radical hysterectomy between 2004 and 2008 in Japan. Survival of 555 women with stage IB cervical cancer in the intermediate-risk group  were examined based on adjuvant therapy patterns: chemotherapy alone . The most common chemotherapeutic choice was taxane/platinum (52.2%). Women with adenocarcinoma/adenosquamous histology were more likely to receive chemotherapy (P = 0.03), and intermediate-risk pattern was not associated with chemotherapy use (P = 0.11). Women who received systemic chemotherapy had disease-free survival  0.98, 95% confidence interval (CI) 0.52–1.83, P = 0.94) and cause-specific survival  similar to those who received concurrent chemo-radiotherapy on multivariable analysis. Similar results were seen among 329 women with multiple intermediate-risk factors . Cumulative local-recurrence (P = 0.77) and distant-recurrence (P = 0.94) risks were similar across the adjuvant therapy types.The most common intermediate-risk pattern was LVSI with deep stromal invasion (Our study suggests that systemic chemotherapy may be an alternative treatment choice for adjuvant therapy in intermediate-risk stage IB cervical cancer. Worldwide, cervical cancer was the most common gynecologic malignancy in 2012 –5, and tPer the current guidelines set forth by multiple societies, women with early-stage cervical cancer in the intermediate-risk group are recommended to receive postoperative pelvic radiotherapy after surgical treatment in order to reduce the risk of recurrence , 7. WhilDue to these toxicity profiles of radiotherapy use, systemic chemotherapy has been considered as an alternative treatment option for adjuvant therapy after radical hysterectomy for women in the intermediate-risk group –12. WhilThe objective of this study was to examine survival outcomes of women with intermediate-risk stage IB cervical cancer who received postoperative systemic chemotherapy following radical hysterectomy, and compare these outcomes to those women who received radiation-based therapy.n = 223), concurrent chemo-radiotherapy (CCRT) (n = 172), and radiotherapy (RT) alone (n = 160).The selection schema is shown in Figure n = 25, 67.6%). Treatment delay was more common among women who received > 3 cycles compared to those who received ≤ 3 cycles . There were 23 (10.3%) cases with chemotherapy discontinuation in this study population. In the CCRT group  followed by nedaplatin .In the chemotherapy group , the mosRT group , the mosP = 0.18), and the year of diagnosis was not associated with chemotherapy use (P = 0.36). Women with adenocarcinoma / adenosquamous histology were more likely to receive chemotherapy compared to other treatment options: 52.9% for the chemotherapy group, 24.4% for the CCRT group, and 25.6% for the RT group (P < 0.001). Women who received chemotherapy had a lower frequency of tumor with deep stromal invasion compared to the other modalities (P = 0.02). The frequency of large tumors and LVSI were similar across the three groups . Women in the CCRT group had the lowest pelvic lymph node counts among the three groups whereas women in the RT alone had had the lowest para-aortic lymph node counts among the three groups .Patient demographics across the three groups are shown in Table n = 427, 76.9%) followed by deep stromal invasion  and large tumor size . When cases were stratified by the combination of intermediate-risk factors in the whole cohort, tumors with LVSI and deep stromal invasion was the most common pattern  followed by LVSI alone  and deep stromal invasion alone . There were 63 (11.4%) cases that had all three of these intermediate-risk factors.The most common intermediate-risk factor was LVSI . The systemic chemotherapy group had a similar disease-free survival compared to the RT alone group on adjusted models (data not shown).Survival analysis was performed and the median follow-up time of women without survival events was 5.5 years. There were 62 recurrences and 30 deaths due to cervical cancer identified in this study. There were no deaths related to complications from adjuvant chemotherapy or radiotherapy in the cohort. On univariable analysis, adjuvant treatment types were not associated with disease-free survival . Likewise, cause-specific survival was similar between the systemic chemotherapy group and the RT alone group on adjusting models (data not shown).Similarly, adjuvant treatment types were not associated with cause-specific survival  and cause-specific survival  similar to those who received RT alone. Among women who received adjuvant chemotherapy, the number of administered cycles was not associated with disease-free survival  and cause-specific survival . Chemotherapy treatment delay was significantly associated with decreased disease-free survival .When survival was compared between CCRT and RT alone groups, women who received CCRT had disease-free survival .Among women who developed recurrent disease (median follow-up time after recurrence 42.6 months for censored cases and 15.3 months for deceased cases), the second remission rates after salvage intervention were statistically similar across the three groups: CCRT group 20%, chemotherapy alone group 30.8%, and 25% for RT alone group . In this sub-group the results were similar to the whole cohort, and adjuvant therapy was not associated with disease-free survival  and cause-specific survival . Among 229 cases in which the tumor had only one single intermediate-risk factor, LVSI alone had the lowest disease-free survival compared to other factors although it did not reach statistical significance .There were 326 cases in which the tumor exhibited at least two intermediate-risk factors . Women who received postoperative chemotherapy had disease-free survival  and cause-specific survival  similar to those who received CCRT.Results of propensity score matching are shown in The key finding of the study is that systemic chemotherapy use was associated with comparable survival compared to radiotherapy-based treatment in women with stage IB cervical cancer and at least one intermediate-risk factor and without a high risk factor. Moreover, our study found that women who had a single intermediate-risk factor with LVSI alone had a survival outcomes similar to those who had multiple intermediate-risk factors.The effectiveness of systemic chemotherapy as an adjuvant therapy in early-stage cervical cancer in the intermediate-risk group has not been completely studied, and definitive treatment recommendations are currently lacking. Our study findings are similar to prior studies that demonstrated comparable survival outcomes between systemic chemotherapy and CCRT as adjuvant therapy , 11. BecTo date, “classic” criteria of the intermediate-risk group in cervical cancer per the NCCN guidelines require at least two out of the three factors  . Howeverversus multiple risk factors, 87.9% versus 85.9–90.2%). Recurrence risks were minimal when tumors exhibited only large size or deep cervical stromal invasion . Therefore, LVSI alone may need to be considered as an intermediate-risk factor. Further study to validate and prove our results is warranted.Of interest, women whose tumor exhibited only LVSI had survival outcomes similar to those with multiple risk factors  [In a sensitivity analysis, we examined survival outcome of women who received CCRT compared to RT alone. The current guidelines for the intermediate-risk group recommend whole pelvic radiotherapy alone without concurrent administration of chemotherapy, and the use of CCRT is optional , 7. In rGOG-263) . The estThe benefit of offering systemic chemotherapy over radiotherapy is to minimize complications from pelvic irradiation administered after radical pelvic surgery. This rationale was based on a general consensus that demonstrated high complication rates with pelvic irradiation after radical hysterectomy compared to surgery alone . In the versus other treatment types. Indeed, there are various practice patterns for adjuvant therapy in intermediate-risk early-stage cervical cancer in Japan [Strengths of the study included a sample size that is one of the largest in the literature. In addition, the dataset is considerably clear with our rigorous inclusion and exclusion criteria, making interpretation of the results more reliable. However, there are multiple limitations in this study. First, this is a retrospective study that may miss confounding factors in the analysis. For example, we do not know the treatment allocation for chemotherapy in Japan , and thiWeaknesses of the study included that our study population had a fairly favorable survival outcome with the limited number of survival events despite the adequate median follow-up of more than five years. For this reason, an adjustment model with five covariates for cause-specific survival may result in over-adjustment given the number of cervical cancer mortality events. However, two other adjustment models for cause-specific survival were consistent to support the current findings, and this association of chemotherapy and cause-specific survival is likely true. While central pathology review was not performed to confirm that intermediate-risk criteria was met, these surgical-pathological factors are well-established histopathological findings and thus inter-observer-variability is less likely to differ across the pathologists.The intermediate-risk criteria for deep stromal invasion was recorded as outer versus inner half and tumor size was recorded for > 4 versus ≤ 4 cm in this surgical database per the JSGO criteria, and thus, we were not able to apply the Gynecologic Oncology Group (GOG) or Korean criteria for the intermediate-risk in cases where the depth of invasion was defined as outer third . In thisIn summary, our study suggests that systemic chemotherapy can be an alternative effective treatment choice as adjuvant therapy for women with intermediate-risk stage IB cervical cancer. This option can be particularly suitable in patients who are not the best candidates for radiotherapy such as those with pelvic adhesive disease, intraoperative abdomino-pelvic injury, radiation intolerance, and non-compliance for the radiation treatment schedule. Moreover, because increased chemotherapy cycles did not improve survival, and women in the intermediate-risk group have a generally good prognosis, the utility of a reduction in the number of chemotherapy cycles may be considered to minimize the toxicity of chemotherapy. Finally, the current intermediate-risk criteria per the JSGO guidelines need to be revised, as the present criteria may result in overtreatment in cases where the prognosis is generally favorable. Based on our results, at least two risk factors as well as LVSI alone may meet criteria for stratification into the intermediate-risk category. Establishing stricter criteria weighing treatment benefits and risks are warranted.This was a retrospective analysis of the previously organized nation-wide large-scale observational study conducted in 116 Japanese Gynecologic Oncology Group (JGOG) designated institutions –22. We cEligibility criteria for this study were women with stage IB cervical cancer who met criteria for intermediate-risk disease, and received adjuvant therapy following type III radical hysterectomy and pelvic lymphadenectomy. Per the JSGO treatment guidelines for cervical cancer, the intermediate-risk group is defined as cervical cancer in which the tumor is confined to the cervix without parametrial or lymph node involvement, and exhibits any one of the following three factors: large cervical tumor > 4 cm, deep cervical stromal invasion , and LVSI . We limiClinical and tumor information abstracted from medical and pathological records included age, histologic subtype, clinical and pathological stages, tumor size, pelvic and para-aortic lymph node status (including the number sampled), parametrial involvement, deep stromal invasion, LVSI, uterine corpus involvement, ovarian involvement, and the presence of distant metastasis. Adjuvant treatment information included the following three modalities: concurrent chemo-radiotherapy with pelvic irradiation and weekly chemotherapy (CCRT group), systemic chemotherapy alone (chemotherapy group), and whole pelvic radiotherapy alone (RT group). Among women who received chemotherapy, the type of chemotherapy, the number of administered cycles, and toxicity were recorded.Survival information included disease-free and cause-specific survival. Disease-free survival was defined as the time interval between the hysterectomy and the first recurrence. Cause-specific survival was defined as the time interval between the hysterectomy date and death due to cervical cancer. The patients were censored if patients were alive at the last follow-up or had died due to another cause. Among women who developed recurrent disease, locations of recurrence were grouped into local recurrence  and distant recurrence .The primary interest of this analysis was to examine survival of women with intermediate-risk stage IB cervical cancer who received systemic chemotherapy compared to those who received CCRT. The secondary interest of analysis was to assess recurrence patterns based on adjuvant therapy types. A sensitivity analysis was performed to examine cases with at least two intermediate-risk factors by adopting the NCCN guidelines . In addia priori survival factors [versus ≥ 50 years), the second model was adjusted for age and histology type (squamous versus non-squamous), and the third model was adjusted for age, histology, and histo-pathological factors . The magnitude of statistical significance was expressed with an adjusted-HR and 95% CI.The statistical significance of continuous variables among multiple groups was assessed by either the one-way ANOVA test or by the Kruskal-Wallis H test as appropriate. Statistical significance of categorical and ordinal variables was assessed by the chi-square test. The Kaplan-Meier method was used to construct survival curves and cumulative risk curves , and sta factors . In thisWe also performed a propensity score matching to adjust the background differences between the chemotherapy group and the CCRT group. Propensity score for chemotherapy use was computed for each case determined by multivariable logistic regression analysis. In the model, year of diagnosis, age, stage, histology types, extent of lymphadenectomy and tumor factors . An automated algorithm was used for one-to-one matching between the two groups .P-value of less than 0.05 was considered significant. Statistical Package for Social Sciences  was used for the analysis. The STROBE guidelines for a retrospective observational study were consulted to outline this study [All statistical analyses were based on two-side hypothesis, and a is study .


We performed a systematic review and meta-analysis to identify predictors of serious clinical outcomes after an acute-care evaluation for syncope.We identified studies that assessed for predictors of short-term (≤30 days) serious clinical events after an emergency department (ED) visit for syncope. We performed a MEDLINE search  and reviewed reference lists of retrieved articles. The primary outcome was the occurrence of a serious clinical event  within 30 days. We estimated the sensitivity, specificity, and likelihood ratio of findings for the primary outcome. We created summary estimates of association on a variable-by-variable basis using a Bayesian random-effects model.We reviewed 2,773 unique articles; 17 met inclusion criteria. The clinical findings most predictive of a short-term, serious event were the following: 1) An elevated blood urea nitrogen level ; 2); history of congestive heart failure ; 3) initial low blood pressure in the ED ; 4) history of arrhythmia ; and 5) an abnormal troponin value . Younger age was associated with lower risk . An abnormal electrocardiogram was mildly predictive of increased risk .We identified specific risk factors that may aid clinical judgment and that should be considered in the development of future risk-prediction tools for serious clinical events after an ED visit for syncope. There are over 1.3 million annual events of syncope (transient loss of consciousness with rapid and spontaneous recovery10According to the 2017 American College of Cardiology (ACC) / American Heart Association (AHA) / Heart Rhythm Society (HRS) Syncope Guidelines, accurate risk prediction using the clinical examination  is fundamental to guiding diagnostic and disposition decisions.13Multiple research groups have proposed objective risk-stratification scores, each with different combinations of predictors.To address this evidence gap, we performed a systematic review and meta-analysis to describe the diagnostic test characteristics of initial history, physical exam, ECG, and selected tests.We performed a systematic literature review and meta-analysis that complied with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.We conducted English-language searches in MEDLINE using a combination of the terms “syncope” and “risk” in any field. We considered papers published between January 1, 1990, and July 1, 2017. We also manually reviewed the reference lists of relevant studies. Titles and abstracts for all articles were screened by one of the authors (BCS). The full text of potentially eligible studies was reviewed by the entire study team.Inclusion criteria included the following: 1) Patients presenting to an ED after a syncope event; 2) serious, short-term (≤30 days) clinical outcomes  were reportedWhat do we already know about this issue?The emergency department evaluation relies on careful history, examination, electrocardiogram, and selective testing to evaluate patients presenting with syncope.What was the research question?What are the predictors of serious clinical outcomes after an acute-care evaluation for syncope?What was the major finding of the study?The strongest predictors included age, cardiac co-morbidities, hypotension, and abnormal biomarkers.How does this improve population health?We identified specific risk factors that may aid in clinical evaluation and risk prediction for patients undergoing ED evaluation for syncope.We excluded studies that included non-ED referral populations  or that were conditioned on prior testing (e.g. electrophysiology or tilt-table test) or pre-existing co-morbidities . Because the focus of this review was to aid short-term decision-making relevant in the ED, we excluded studies that only had data on long-term (>30 days) outcomes. We excluded studies that had implausible results (defined as OR >20).For each included article, we evaluated for potential bias with a modified version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) Criteria,Papers provided varying degrees of covariate information, and the method of extraction varied with the type of information: direct, for papers that provided exact counts for contingency tables; direct after rounding, for papers that provided percentages instead of counts; and extrapolated, for papers that provided ORs and 95% CIs  and negative (LR−) for predictor variables. We did not assess diagnostic performance of specific risk scores, as two meta-analyses have previously addressed this issue.27We numerically assessed the level of heterogeneity of effect sizes via the mean posterior standard deviation of random effects on the log-odds ratio scale. Smaller (larger) values indicate less (more) heterogeneity. Values very close to zero would suggest a fixed-effects model , while values above 2.5 would signal a problem with the data or the model. We visually assessed heterogeneity with L’Abbé plots.Initial Medline and manual screening identified 2,773 potentially eligible studies, and we identified seven additional studies through citation reviews. Seventeen articles met our inclusion criteria and were included in the systematic review .4,15,16,Rates of serious outcomes after an ED evaluation syncope ranged from 1.2–36.2% (interquartile range 6.7–16.9%). There was heterogeneity in the definition of serious outcomes across studies  and whetPre-existing co-morbidities predictive of short-term outcomes included a history of congestive heart failure  and prior arrhythmias . Younger age was variably defined . Other symptoms, including traumatic injury after syncope, palpitations, position, effort, chest pain, and absence of prodromes, had non-significant LR+ and LR−.Hypotension was variably defined . Measurement heterogeneity would likely result in a conservative bias toward a null finding.Third, most of the studies did not exclude patients with outcomes identified during the ED evaluation. The majority of serious clinical conditions are identified during the initial ED evaluation for syncope,Finally, we performed a meta-analysis on univariate predictors of outcomes, and it is likely that these factors are not independent of each other. This limitation underscores the importance of developing risk scores that account for the correlations among potential predictors.We identified specific risk predictors of short-term clinical events after an ED evaluation for syncope. Individual risk factors, symptoms, exam findings, and test results in isolation are modestly predictive of risk. These findings should be used to supplement clinical judgment and inform the development of novel risk scores.


Pre-eclampsia often has detrimental health effects for pregnant women and their fetuses, but whether exposure in the womb has long-term health-consequences for children as they grow up remains poorly understood. We assessed overall morbidity of children following exposure to either mild or severe pre-eclampsia up to 30 years after birth and related disease risks to duration of exposure, i.e. the time from diagnosis to delivery.We did a registry-based retrospective cohort study in Denmark covering the years 1979–2009, using the separate diagnoses of mild and severe pre-eclampsia and the duration of exposure as predictor variables for specific and overall risks of later disease. We analysed 3 537 525 diagnoses for 14 disease groups, accumulated by 758 524 singleton children, after subdividing deliveries in six gestational age categories, partialing out effects of eight potentially confounding factors.Exposure to mild pre-eclampsia appeared to have consistent negative effects on health later in life, although only a few specific disease cases remained significant after corrections for multiple testing. Morbidity risks associated with mild pre-eclampsia were of similar magnitude as those associated with severe pre-eclampsia. Apart from this overall trend in number of diagnoses incurred across disease groups, hazard ratios for several disorders also increased with the duration of exposure, including disorders related to the metabolic syndrome.Maternal pre-eclampsia has lasting effects on offspring health and differences between exposure to severe and mild pre-eclampsia appear to be less than previously assumed. Our results suggest that it would be prudent to include the long-term health prospects of children in the complex clinical management of mild pre-eclampsia. Pre-eclampsia is part of a pregnancy specific syndrome defined clinically by new-onset hypertension and multi-organ failure; it complicates 5–8% of all pregnancies worldwide with potentially life threatening consequences for both mothers and children . Pre-eclThere is general consensus on the optimal expectant management of severe pre-eclampsia before 34 weeks gestation , 3, wherThe etiology of pre-eclampsia remains largely unknown and many have attempted to elucidate why a disease that is both damaging for mother and child does in fact exist. Pre-eclampsia has been shown to be long-term detrimental for maternal health as it increases risk of cardio-vascular diseases and type-2 diabetes later in life and incurs an increased likelihood of developing again in later pregnancies . The staEvolutionarily hypotheses have been proposed as well to explain the conundrum of why pre-eclampsia has not been removed by natural selection despite the potentially severe impact on female reproductive success, especially in populations with natural birth rates before medical intervention and management was possible. First, pre-eclampsia has been suggested to be a by-product of selection for large brain size in the hominin lineage . Endowinvice versa, as, for example, in IGF2 and its receptor [Alternatively, pre-eclampsia may be the result of an imbalance in the tug-of-war between paternal and maternal interests in resource provisioning to an unborn child. Trivers  recognizreceptor . Effectsreceptor  or as pareceptor .Both parent-offspring theory in the sense of Trivers and parental antagonism in the sense of Haig are affected by the probability of parental promiscuity in the population, but in different ways. A higher probability of future maternal offspring being half siblings aggravates parent-offspring conflict because, from an offspring’s perspective, the relatedness difference between self (100%) and future full- (50%) or half-siblings (25%) is 2:1 and 4:1, respectively. However, when both parents are diploid, parental antagonism should be absent in populations with 100% monogamy. Paternal imprinting  is thus expected to be driven by the population-wide probability of serial monogamy or promiscuity, which imposes selection for compensating maternal imprinting  at other loci , 18, 21.In an earlier study, we provided a partial answer to the question of why pre-eclampsia may have been maintained in ancestral human populations by showing that mortality and morbidity in children of mothers with slightly elevated blood pressure in the first trimester were significantly lower relative to control pregnancies without any hypertension diagnoses. However, these correlations reversed when hypertension diagnoses continued during the second and third trimester . This coIn the present study we used the same Danish public health data to address a complementary question that has so far remained unexplored, asking whether the duration of exposure to maternal pre-eclampsia may have lasting consequences for offspring health. This question is of interest both for the clinical management of pre-eclampsia, and evolutionarily because it explores the degree to which hypertension related disorders during pregnancy have a common cause as expected when unbalanced parental conflict drives the continued existence of these pregnancy disorders. Because recent research has indicated that the umbilical cord in pre-eclamptic pregnancies has increased atherosclerosis of the endothelium at birth , there aWe linked data from the Civil Registration System with the Danish National Patient Registry, Fertility Database, Birth Registry and Cause of Death Registry, via PNR numbers . We extracted information on all singleton births from 1 January 1979 to 31 December 2009, yielding 1 872 192 births by 1 004 129 mothers. We excluded births with missing values for one or more key variables such as PNR number, birth weight, birth length, gestational age, maternal birth-related diagnoses such as gestational diabetes, sequential births with short birth interval, child PNR numbers matching more than one mother, and pre-pregnancy diagnoses that could directly affect the risk of pre-eclampsia , which gave us a final cohort of 758 524 births by 413 594 mothers. Possible causes and consequences of caesarean sections could not be included in our analyses because they were not registered before 1996 and registration did not become diagnose-specific until 2004. The available data allowed us to extract information on all offspring diagnoses yielding 3 537 525 diagnoses across the maximally 30 years of follow-up. Offspring morbidity thus covered all diagnoses received through hospitalization and ambulant visits from birth to end of follow-up time (31 December 2009) with a minimum of 4 years of follow-up time.In Denmark, medical services are free of charge and all residents have access to the same health care. This also applies to pregnant women, who are by default enrolled in a program with regular visits to a midwife and general practitioner, fetal ultrasound scans, advice on how to lose weight when deemed desirable, encouragement to give up smoking, etc. When registered as patients, all mothers and offspring in our study receive a medical evaluation and a diagnose code when referred or admitted to the hospital. These diagnoses are all registered (following ICD-8 from 1979 to 94 and thereafter ICD-10) in a hierarchical system with main disease categories, subcategories and further subcategories where appropriate. In our present study, morbidity refers to all diagnoses grouped primarily according to the 14 major disease groups defined by the WHO see  excludinFor statistical analyses, we categorized births into three groups based on diagnoses of pre-eclampsia see : mild prTo ensure that data for fetuses exposed to both mild and severe pre-eclampsia would not be confounded across categories, we excluded women in the mild pre-eclampsia group who progressed into severe pre-eclampsia during the same pregnancy. We also excluded a residual group consisting of women diagnosed with unspecified pre-eclampsia (ICD 8 code 63709 and ICD 10 code DO149) due to inconsistencies in the diagnostic criteria, and women with any form of pre-eclampsia that progressed into eclampsia (ICD 8 code 63719 and ICD 10 code DO15) or the post-partum disease HELLP syndrome (ICD 8 code 63799 and ICD 10 code DO142). The final pre-eclampsia sample thus consisted of 28 471 births (23 920 with mild pre-eclampsia and 4551 with severe pre-eclampsia), while the unexposed cohort consisted of 704 013 births without any of these hypertensive disorders .Table 1We stratified births into six categories based on gestational length: extremely preterm 20–27 weeks, very preterm 28–33 weeks, preterm 34–36 weeks, early term 37–38 weeks, full term 39–40 weeks and post-term 41–44 weeks. Due to low sample sizes in week 20–27  we only included the results from this category in the h(t) is dependent on n covariates , where the effect is measured by the size of the respective coefficients , its mathematical expression becomes h(t) = h0(t) exp b1x1 + b2x2 + … + yxyb. Thus, h(t) is the probability (relative to controls) that an offspring at time t is diagnosed with a disease within one of the 14 disease groups. The changeover between ICD-8 and ICD-10 coding did not affect the diagnostic criteria, but the easier ICD-10 registration method increased the number of reported diagnoses. To compensate for this effect, we added the covariate ‘year’ to all our analyses to substantiate the general assumption that overall hazards remained constant through time.We used Cox proportional-hazard regression (R version ×64 2.15.3 (2013-03-01)—‘Security Blanket’, package Survival) to estimate hazard ratios and their confidence intervals, which correspond to the chance of being diagnosed at any point within a given time period relative to controls. When a hazard function 3)) adjusted for gestational age (birth weight cut-offs 200 and 6500 g). For birth weight, Z-scores (birth weight—mean/SD) were calculated based on the national reference intrauterine growth curve for Denmark and are presented separately as these are often used in perinatological practices [We used three models based on Cox proportional-hazard regression. Model 1 is a combined analysis where both women with mild and severe pre-eclampsia were included, whereas models 2 and 3 are comparable multivariate analyses focusing on women with mild pre-eclampsia and women with severe pre-eclampsia, separately. The combined Model 1 analysis of hazard ratios associated with exposure to mild and severe pre-eclampsia partialed out the covariates maternal and paternal age at delivery, parity , maternal education , sex of the child , number of days of pre-eclampsia , year of delivery  and ponderal index  tested the extent to which child morbidity was affected by the duration of exposure to either mild or severe pre-eclampsia, because these separate effects have not previously been analysed. All covariates specified above for the Model 1 analysis were also included in the Model 2 and 3 analyses. We present the effects of exposure duration for mild and severe pre-eclampsia side-by-side to facilitate comparison, but the effects of the other covariates only for the combined Model 1 analysis as these effects remained very similar in the two additional models.P-values were adjusted for multiple testing by FDR and we tested for homogeneity of variances for the hazard ratio response variables in each of the five classes of gestational age. There were no significant deviations from homogeneity, neither in the Model 1 analysis , nor the Model 2 and 3 analyses , which allowed comparison of the 14 disease groups across the 5 gestational age categories.P-values. The weighted and unweighted samples sizes produced almost identical results, so we only report the former. Absolute risks of being diagnosed with diseases after exposure to either mild or severe pre-eclampsia, compared to the unexposed controls, were also calculated per gestation category and evaluated for differences with Mann–Whitney U tests using P < 0.05 as significance threshold. Model diagnostics and standard tests  were performed in all analyses to check for violation of the Cox proportional-hazard regressions. No covariates showed any significant tendencies towards non-linearity.To elucidate overall morbidity risks of exposure to mild or severe pre-eclampsia, we performed Z-transformed combined probability tests with and without weighted sample sizes (R package survcomp 1.1.6) using the disease specific We report means ± SD for a set of maternal and paternal covariates that potentially affect the incidence of mild or severe pre-eclampsia diagnoses and for a set of offspring response variables that are potentially affected by these maternal diagnoses. We then evaluate hazard ratios for child morbidity, again separately for exposure to either mild or severe pre-eclampsia and for the five (pre- to post-term) gestational age categories. We further evaluate the differential effects per disease and gestational age category for three offspring covariates , four parental covariates  and for the duration of exposure to pre-eclampsia, always comparing pre-eclampsia diagnoses with unexposed control pregnancies. Finally, we assess the isolated effect of duration of exposure to mild and severe pre-eclampsia (models 2 and 3) after partialing out the same set of covariates reporting the hazard ratio per day of exposure per disease class per gestational age category.1, 727931 = 932, P < 0.0001; unexposed vs. severe PE: F1, 708562 = 86.25, P < 0.0001), had lower parity , and had fewer years of education . Also the fathers were younger when a pregnancy was affected by pre-eclampsia   .1, 727907 = 12.5, P = 0.0004) and substantially reduced after severe pre-eclampsia  compared to children that were not exposed to pre-eclampsia  and by ca. 3 weeks for severe pre-eclampsia   . Further 0.0001)  showed tP-values analysis, where only week 28–33 for mild and severe pre-eclampsia and week 34–36 for severe pre-eclampsia remained non-significant. Absolute risk estimates showed higher risks across all gestation categories when exposed to mild or severe pre-eclampsia compared to unexposed children. Children exposed to mild pre-eclampsia appeared to have consistently higher absolute risks than children exposed to severe pre-eclampsia, but this was only  significant for week 28–33  and week 39–40   see . The res.04) see , but the.04) see  across t.04) see .The average ages of being diagnosed within the 14 main disease groups are concentrated in childhood and early adolescence, both for unexposed children and for children exposed to mild or severe pre-eclampsia see , indicatP = 0.003, <0.001, 0.02 and 0.02  and matrigenic  effects on fetal provisioning , 17, 24,The alternative ultimate hypothesis driven by the need to sustain early human brain development , 12 and It has recently been suggested that pre-eclampsia may be mitigated by the peripheral T regulatory cells (pTreg) that evolved to provide a stronger maternal-fetal tolerance in placental mammals . As pre-per se is also linked to later learning difficulties in basic school (age 6–15) and risk of not completing an education [It is known that the mild pre-eclampsia syndrome may be recurrent across pregnancies of the same women with negative implications such as fetal growth restriction and placental abruption , comorbiducation , so expoducation .The organ systems most sensitive to mild pre-eclampsia exposure appear to be the neurological system, eyes and ears and the respiratory system  and S5. For clinical practice our results imply that the management of mild pre-eclampsia by expeditious delivery after 37 weeks may reduce life-time morbidity while also preventing progression of maternal perinatal disease—inferences that appear to match the results from the seminal HYPITAT trial  but see.Because of the large sample sizes, our cohort study based on a complete census of all live births and subsequent medical diagnoses in Denmark during three decades allowed for sufficient statistical power to detect small effects. As hospitalizations are most common before age 10 and after age 45 (except for pregnancy-related reasons and deliveries .Although we could partial out more potentially confounding effects than most other public health studies, we had no data on maternal body mass index and smoking, factors that have previously been shown to increase the risk of pre-eclampsia , and we Mostly of clinical relevance, antihypertensive treatment may itself negatively affect neurocognitive development of children, as suggested by recent studies that incriminated all three standard drugs in Denmark: methyldopa, labetalol and nifedip , 49, revFinally, we would like to stress that the likelihood of our results having predictive value for other populations will depend on the neonatal and general obstetric support available at delivering units. We therefore expect that our results may be valid for other affluent societies, but that they are not directly transferable to developing countries.Supplementary DataClick here for additional data file.


People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. The efficacy of HCV treatment has significantly improved in recent years with the introduction of direct-acting antivirals (DAAs). However, DAAs are more costly than pegylated-interferon and ribavirin (PegIFN/RBV). We aimed to assess the cost-effectiveness of four HCV treatment strategies among PWID and treatment scale-up.An individual-based model was used describing HIV and HCV transmission and disease progression among PWID. We considered two epidemiological situations. A declining epidemic, based on the situation in Amsterdam, the Netherlands, and a stable HCV epidemic, as observed in other settings. Data on HCV incidence, prevalence, treatment setting and uptake were derived from observed data among PWID in Amsterdam. We assessed the incremental cost-effectiveness ratio ) of four treatment strategies: 1) PegIFN/RBV; 2) sofosbuvir/RBV for genotype 2–3 and dual DAA for genotype 1–4; 3) Dual DAA for all genotypes; 4) Dual DAA with 3x treatment uptake.In both types of epidemic, dual DAA therapy was most cost-effective strategy. In the declining epidemic, dual DAA yielded an ICER of 344 €/QALY while in the stable epidemic dual DAA led to cost-savings. Scaling-up treatment was also highly cost-effective. Our results were robust over a range of sensitivity analyses.HCV treatment with DAA-containing regimens is a highly cost-effective intervention among PWID. Based on the economic and population benefits of scaling-up treatment, stronger efforts are needed to achieve higher uptake rates among PWID. People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection  as shariTreatment with pegylated-interferon and ribavirin (PegINF/RBV) became available after 2001 with an overall sustained virological response (SVR) ranging from 33–79% . Among PNew all-oral treatment regimens with direct-acting antivirals (DAAs) are highly effective, with SVR rates reported up to 95–100% . A cost-Beyond the costs, the cost-effectiveness of HCV treatment may depend on several factors such as HCV-screening uptake and whether PWID with a re-infection after successful HCV treatment are re-treated. The type of HCV epidemic may also influence the cost-effectiveness. In a stable epidemic, with a stable PWID population inflow and HCV incidence, transmission is on-going and treatment may prevent new infections (treatment as prevention). In contrast, in a declining epidemic as observed among PWID in the Netherlands , small pAn individual-based model describing demographic changes and infection dynamics of HIV and HCV was employed. This model was used previously to study the effects of harm reduction policy on the spread of HIV and HCV in Amsterdam , as wellWe considered two epidemiological scenarios. For the first epidemiological scenario, the declining HCV epidemic, demographic parameters were estimated from the ACS . In AmstAs the Dutch epidemiological situation is not representative for the majority of countries, we made a counter-factual scenario to explore the impact of the type of epidemic on the cost-effectiveness of DAAs in a more general setting. The model demographics were adapted to obtain a stable HCV and HIV epidemic. The number of new PWID entering the population was set at 4 per month; resulting in a stable population size of approximately 1,500 PWID (this number is comparable to the peak of the Amsterdam PWID population size as in 1985). Risk behavior of PWID in this scenario was similar to that at the start of the Amsterdam epidemic. In contrast to the declining epidemic, syringe sharing frequency did not decline over time. Prior to the introduction of HCV treatment, we ran the model until all variables reached their equilibrium distributions.In HCV screening in both epidemics was based on the situation in Amsterdam, where PWID attending harm-reduction programs (HRP) have been routinely offered screening for HCV and HIV since 2001. Around 75% of PWID living in Amsterdam received or had received methadone substitution therapy  and, basIn 2005, a special unit to treat HCV-RNA positive PWID with PegIFN/RBV was launched outside a hospital setting in Amsterdam (DUTCH-C project); details of this project have been previously described . In summDutch treatment guidelines currently recommend a combination of two DAAs  for genotype 1 and 4 and either dual DAA therapy or sofosbuvir (SOF)/RBV for genotype 2 and 3 . The folTreatment with PegIFN/RBV (24 weeks G2-3 and 48 weeks G1-4): standard treatment in the Netherlands until November 2014. This strategy is used as a comparator strategy to calculate the cost-effectiveness of DAAs.SOF/RBV for G2-3 (weighted average 22 weeks) and dual DAA for G1-4 (12 weeks).Dual DAA therapy for all genotypes (12 weeks).Dual DAA therapy for all genotypes with a three times higher treatment uptake.HCV-treatment uptake in our study is based on PegIFN/RBV treatment among PWID within the DUTCH-C project which was limited by the eligibility for PegIFN/RBV treatment and the manpower available given the long treatment durations. Based on reduced treatment duration and fewer side effects with DAA-containing regimens, we believe that with the same health-service capacity, a higher treatment uptake could be attained. Therefore a strategy with a higher uptake with dual DAAs was also assessed incrementally. SVRs for DAAs are mainly based on clinical trial data as limited real-world results were available . We assuUtilities were based on an UK Health Technology Assessment Report . We multWe adopted a healthcare perspective in our study. Healthcare utilization and costs associated with HCV disease state were subdivided based on treatment outcome: no SVR (untreated or unsuccessfully treated) or SVR after treatment . HealthcTotal costs and effects ) were calculated by adding up all costs and QALYs over a 15-year time horizon (from 2015 onwards), among PWID with a chronic HCV infection and PWID who were screened and treated during the modeled period. The ICER was calculated by dividing the difference in costs between two strategies by the difference in QALYs and represents the incremental cost associated with an additional QALY gained following a strategy that is more effective than the comparator strategy . We applStrategies were compared incrementally (among each other) to identify the most cost-effective strategy. According to WHO guidelines, a strategy can be considered highly cost-effective when the ICER is < = 1 times the Gross Domestic Product (GDP) per capita and as cost-effective when the ICER < = 3 times GDP/capita . The DutWe performed one-way deterministic sensitivity analyses to assess the impact of certain model parameters on the ICER in the declining epidemic. The following sensitivity analyses were done: fibrosis progression 2x the base transition probability, 0.70 SVR probability for F3-F4 in the SOF/RBV strategy (instead of 0.90), 40% never screened for HCV (instead of 20%), higher and lower utility values , 20% and 50% lower DAA costs, excluding costs specific for PWID care, and a 0% discount rate for the costs and effects. A probabilistic sensitivity analysis using 1,000 bootstraps was also performed to reflect uncertainty in the costs and utilities parameter valuesWe calculated the cost-effectiveness of increased treatment uptake, by treating 100 PWID per year with dual DAA in Amsterdam (the declining epidemic); corresponding to an estimated 6% treatment uptake rate among HCV-RNA positive PWID in 2015. PWID specific treatment costs were doubled in this scenario analysis.Treatment with dual DAAs was the most cost-effective strategy (strategy 3) and is highly cost-effective (ICER = 344 €/QALY) . As illuTreatment with dual DAA in a stable epidemic was the dominant strategy and led to cost-savings . Eleven Dual DAA therapy remained highly cost-effective throughout the deterministic sensitivity analyses and ICERs were comparable to the main analysis. Although when DAA costs are 20% or 50% lower, and when fibrosis progression is twice that of the baseline scenario, this strategy becomes cost-saving . On the When 100 PWID were treated annually in the declining epidemic, dual DAA remained highly cost-effective when compared to PegIFN/RBV . This scenario led to a 23% and 6%, reduction of chronic HCV prevalence over a 15-year period for G1-4 and G2-3, respectively; though in 2029, chronic HCV prevalence was still estimated at 18% for G1-4.We determined the cost-effectiveness of four HCV treatment strategies among PWID in a stable and a declining HCV epidemic. This study showed that treatment with DAA-containing regimens for PWID is a highly cost-effective intervention, irrespective of the type of epidemic. Although dual DAA therapy was most cost-effective, the two other DAA-treatment strategies fell also below the WTP. Sensitivity analyses showed that our ICERs were very robust. These analyses provide economic support for the treatment of PWID with DAAs.Our results are in line with other cost-effectiveness studies with sofosbuvir-containing regimens among chronically HCV-infected individuals –62. HagaAlthough DAA-containing treatments are cost-effective, treating only 15 PWID annually will probably not contain the epidemic in an on-going transmission setting (stable epidemic) as only a slight decrease in chronic HCV prevalence was observed with dual DAA in this epidemiological setting. When treatment is scaled-up  more new infections were averted (31 vs. 11 with baseline uptake) and HCV RNA prevalence decreased 17% for G1-4. Martin et al. also showed that current treatment uptake in England was unlikely to achieve observable reductions in HCV prevalence, while scaling up treatment  could lead to a substantial reduction . HoweverOur analyses have several limitations. First, SVR for DAAs are mainly based on clinical trials with relatively small sample sizes. However, a recent real-life study showed comparable SVR rates as those observed in clinical trials . Second,There are also several strengths in this study. First, we used an individual-based transmission model which took re-infections into account and thus the population benefit of HCV treatment; particularly important for countries with on-going HCV transmission. If re-infections are not taken into account, the burden of HCV might be underestimated. Second, our study is mostly based on observed data from Amsterdam on incidence, prevalence, mortality, HCV treatment uptake, and real-world DAA prices. Also, we took screening and a treatment setting specific for PWID into account, which is usually not included in recent cost-effectiveness studies for DAA-containing regimens –62, 64. In conclusion, DAA-containing regimens are highly cost-effective among PWID, irrespective of the type of HCV epidemic. Given the current evidence, dual DAA therapy should be considered the standard recommended HCV treatment, not only because of its higher efficacy but also the lower net costs compared to other DAA regimens , 63. AlsS1 File(DOCX)Click here for additional data file.


In 2014, UNAIDS announced the 90-90-90 treatment targets to curb the HIV epidemic by 2020: 90% of people living with HIV know their HIV status, 90% of people who know their HIV status access treatment and 90% of people on treatment have suppressed viral loads. Monitoring and evaluation are needed to track linkage and retention throughout the continuum of care. We propose a systematic review and meta-regression to identify the different methodological approaches used to define the steps in the HIV care cascade in sub-Saharan Africa (SSA), where most people with HIV live, and to assess the proportion of participants retained at each step.We will include cohort and cross-sectional studies published between 2004 and 2016 that report on the HIV care cascade among adults in SSA. The PubMed, Embase and CINAHL databases will be searched. Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility and extract data. Disagreements will be resolved by consensus or consultation with a third reviewer. We will assess the number and proportion of individuals retained in the HIV care cascade from HIV diagnosis to linkage to care, engagement in pre-ART care, initiation of ART, retention on ART, and viral suppression. The data will be analysed using random effects meta-regression analysis. Publication bias will be assessed by funnel plots.This review will contribute to a better understanding of the HIV care cascade in SSA. It will help programs identify gaps and approaches to improve care and treatment for people living with HIV and reduce HIV transmission.PROSPERO CRD42017055863The online version of this article (doi:10.1186/s13643-017-0562-z) contains supplementary material, which is available to authorized users. In 2014, UNAIDS proposed the 90-90-90 Fast-Track treatment targets to curb the HIV/AIDS epidemic. These targets stipulate that, by 2020, 90% of people living with HIV worldwide should know their diagnosis, 90% of these people should be on antiretroviral therapy (ART), and 90% of these persons  should be virally suppressed  The cascade can be used to evaluate HIV programme performance and serve as a monitoring tool to identify gaps and opportunities for specific interventions to improve outcomes . In sub-Few studies have evaluated the methods used to define the HIV care cascade in low- and middle-income countries, or in SSA . A previThis systematic review protocol was written following the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines . The PRIThe first aim of this systematic review is to describe the different concepts and methodologies used in the published literature to define the steps in the HIV care cascade in SSA. The second aim is to obtain comparable measures of the number or proportion of people retained in the different steps of the HIV care cascade, based on the findings from the first aim.We will include cohort and cross-sectional studies with data collected between January 2004 and March 2016 in any country in SSA  as the PMTCT care cascade differs substantially from the general HIV care cascade , 34. We The primary outcome is the concept, methodology and definition used to identify a reported stage of the cascade. We will describe these narratively and classify studies into suitable groups.):HIV diagnosis (UNAIDS 90-90-90 treatment target)Linkage to pre-ART careRetention in pre-ART careStart of ARTRetention on ARTOn ART (UNAIDS 90-90-90 treatment target) withSuppression of viral load (UNAIDS 90-90-90 treatment target)The secondary outcomes include the number or proportion of persons retained at each cascade step  for HIV and AIDS and key terms ‘cascade’, ‘continuum’, ‘linkage to care’, ‘retention in care’ and ‘ART initiation’ were cross-referenced with terms associated with 62 African countries  and de-duplicated. We will use Microsoft Excel  to record outcomes of the selection process.Two reviewers will independently screen studies in two stages: title/abstract screening, followed by full text screening. A checklist with the eligibility criteria will be developed and pilot-tested on a random sample of 20 studies. Titles and abstracts will then be reviewed against the eligibility criteria by AG and FV. We will obtain full texts of all potentially eligible articles. Two reviewers will independently apply inclusion criteria  on a random sample of 10 articles and revised as needed. Two reviewers will independently read each article and extract the relevant data. Both sets of data will be entered into Epidata version 3.1 . Any discrepancies in the extracted data will be resolved by consensus, in discussion with a third reviewer (CM or ME) if necessary. We will contact study authors to resolve any information that is not clear.Study characteristics ;Study setting (location and type of facilities);Characteristics of study populations ;Definitions and methods used to construct cascade;The number or proportion of persons diagnosed with HIV (90-90-90 treatment target), linkage to pre-ART care, retention in pre-ART care, on ART (90-90-90 treatment target), virological suppression (90-90-90 treatment target);Clinical and laboratory data , TB status, other co-infections and comorbidities).The data items for extraction will be informed by items reported in the PRISMA statement –39. We wp values from tests of between-study heterogeneity. We expect substantial between-study heterogeneity, and the focus of the subsequent analyses will therefore be on the identification and exploration of sources of heterogeneity. We will explore associations between proportions at each step and country, setting  and study characteristics  using random intercept logistic meta-regression  models. These models avoid the biases that arise when Normal-Normal models  are applied to logit or arcsine-square root transformed proportions . (DOCX 33 kb)Additional file 2:Complete cascade including all steps. A) HIV care cascade as defined by the WHO, B) Assessment of ART eligibility within the HIV care cascade. ART, antiretroviral therapy; D, denominator; LTP*, loss to programme (pre-ART); LTP**, loss to programme (post-ART); N, nominator; PLD, population level denominator; PBD, programme-based denominator. (JPG 5616 kb)Additional file 3:Search strategy . (PDF 79 kb)Additional file 4:Study eligibility form. (PDF 114 kb)


One hundred and seventy-two women were followed-up in pregnancy, at birth and at 17 weeks post-partum. Three in five  initiated breastfeeding. At 17 weeks post-partum, 23.8% (n41) were exclusively or partially breastfeeding and over a third  of all mothers were at risk of distress. In multivariate analyses, independent predictors of distress included: low maternal resilience : 7.22 ); unsatisfactory partner support ); older age ); and breastfeeding ). Routine assessment of emotional wellbeing and targeted interventions are needed to promote a more healthful transition to motherhood among women in Ireland.This study aimed to examine factors associated with maternal wellbeing at four months post-partum in the Irish context. Socio-demographic, health behaviour and infant feeding data were collected in pregnancy, at birth and at 17 weeks post-partum. Maternal distress, body image and resilience were measured at 17 weeks post-partum. Binary logistic regression predicted maternal distress and statistical significance was taken at  The transition to motherhood is associated with, and most often accompanied by, feelings of maternal joy. However, it is also a time of increased vulnerability and possible distress for women , as theyMaternal distress impairs daily functioning ,6 and inCompared to other European countries, Irish women are a singular population when breastfeeding practices are examined . Irish wBreastfeeding is a unique component of the post-partum period, where its presence and absence both carry physical, psychological and socio-cultural implications for mothers ,13. GiveEthical approval for this prospective observational study was obtained from the Coombe Women and Infant’s University Hospital and Dublin Institute of Technology.Women were recruited by the lead author whilst waiting in community antenatal clinics in the Coombe Women and Infants University Hospital. Eligible women were those who: had a healthy singleton pregnancy; were at least 24 weeks pregnant; were available in hospital for follow-up after labour; and were willing to be contacted in the post-partum period for follow-up via a home visit. Written informed consent was obtained from all participants for all elements of data collection.A questionnaire was administered in the clinic for pregnant participants to self-complete. This questionnaire collected socio-demographic and health behaviour data, to include: age; nationality; parity; education level; marital status; folic acid supplementation practices; and smoking and alcohol status. The questionnaire also included the validated Tilburg Pregnancy Distress Scale (TPDS) .The TPDS  is a 16-To reduce withdrawal rates and record infant feeding practices, participants were followed-up in hospital after giving birth. The lead author checked hospital records daily to identify those women who had consented to participate in the study and had given birth to a healthy term infant in the previous 24 h. The lead author visited these women on the ward, re-introduced herself and asked them if they were still happy to be contacted at 17 weeks post-partum. The method of infant feeding initiated and the method of infant feeding on discharge from hospital were documented from each mother’s medical record. Standard definitions were used to categorise infant feeding methods .A home visit was arranged during the week in which infants turned 17 weeks of age. During the visit, mothers completed quantitative questions on infant feeding practices and maternal health behaviours. Maternal wellbeing was also assessed using the Mother and Baby Interaction Scale (MABISC) , an eighThe ten-item MABISC assesses maternal distress and potentially suboptimal mother-infant bonding over the month prior to its completion . Scale iThe eight-item BSQ (version 8b) measures body shape concern over the 7 days prior to its completion . ParticiThe 14-item Resilience Scale measures resilience, confidence and ability to persevere . Resiliet-tests, and associations with categorical variables were assessed using 2 × 2 cross-tabulations, where the Chi-squared statistics test assessed statistical significance. Variables which were significantly associated with maternal distress in these univariate analyses were included in multivariate analyses. Binary logistic regression was used to predict maternal distress. The Forced Entry Method was used, whereby all predictor variables were tested in one block to assess their predictive ability whilst controlling for the effects of other predictors in the model. Statistical significance was taken at p < 0.05.IBM SPSS for Windows, version 22  was used for analysis. Normally distributed data were summarised numerically using the mean and standard deviation (SD). Non-normally distributed data were summarised numerically using the median and interquartile range (IQR). To identify factors associated with maternal distress at 17 weeks post-partum, univariate and multivariate analyses were conducted. Associations with continuous variables were determined using Independent Samples n8 infants admitted to intensive care and n29 mothers availed of the early discharge service). Of the 233 eligible mothers, 172 (73.8% follow-up rate) consented to follow-up at 17 weeks post-partum  of this sample of 172 women were multiparous. A quarter  smoked until their pregnancy was confirmed, 7.6% (n13) smoked all throughout pregnancy, and 22.1% (n38) consumed alcohol during their pregnancy. Only a third  supplemented with folic acid in line with recommendations [Over half  mothers initiated breastfeeding upon the birth of their infant. The median length of stay in hospital was 48.2 (37.8) h, and by discharge, the proportion of women exclusively breastfeeding had decreased to 37.2% (n64). A further 15.7% (n27) were combination feeding, and almost half  were solely formula feeding upon discharge.Three in five , the majority  reported that their partner was completely supportive of their decision to breastfeed. One in eight  reported that their partner was mostly supportive and one mother (0.9%) reported that her partner was not supportive of her decision to breastfeed. Less than half  reported putting specific breastfeeding supports in place prior to the birth of their infant .Of those who initiated breastfeeding (n26), with a further 8.7% (n15) combination feeding their infant. Over three-quarters  were solely formula-feeding their infant at this time.By 17 weeks post-partum, the proportion of mothers exclusively breastfeeding had decreased to 15.1% (n43) of the 172 women followed-up in the post-partum period had met or exceeded the cut-off [n48) were distressed according to the negative affect subscale of the TPDS, and one in ten  were distressed on the partner involvement subscale.A quarter  were coping well and not distressed (n48) were at risk of distress and one in twelve  met cut-offs for a high probability of distress. Of note, different scales were used to determine the prevalence of distress at each time point.At 17 weeks post-partum, almost two-thirds  of mothers had no body shape concern at 17 weeks post-partum. A quarter  had mild body shape concern and 14.0% (n24) and 7.0% (n12) had moderate and marked body shape concern, respectively. At 17 weeks post-partum, 13.3% (n23) of mothers had low levels of resilience and 86.6% (n149) had high levels of resilience.Over half  were compared with those of mothers experiencing some degree (high probability/at risk) of distress at this time  (p < 0.01); multiparous (p = 0.02); breastfeeding (p < 0.01); or distressed by her partner’s involvement (or lack thereof) in pregnancy (p = 0.02). Distress was also more likely if a mother had low resilience (p < 0.01).The characteristics of women who experienced no distress at 17 weeks post-partum  . From th2  = 43.15, p < 0.01), four of the six independent variables included made a statistically significant contribution to the model. The strongest predictor of distress at 17 weeks post-partum was low resilience. Mothers with low resilience scores were over seven times more likely , to include: low maternal resilience; suboptimal partner support; older age; and, breastfeeding. In particular, the association between breastfeeding and distress was somewhat unexpected, where breastfeeding women were almost 3 times more likely to experience distress at 17 weeks post-partum when compared with non-breastfeeding women.Breastfeeding is often regarded as a challenging demand of motherhood , particuMeedya and colleagues  identifiA positive antenatal intention to breastfeed has been strongly and consistently associated with breastfeeding initiation and duration ,24. PregWhen significant discrepancies between expectations and reality arise, disillusionment with breastfeeding can manifest, increasing the likelihood of maternal distress . HoweverSupporting women to support themselves is especially important in light of the recent decision to cease all funding for, and activities related to, the Baby Friendly Health Initiative (BFHI) in Ireland . The BFHGiven the widespread lack of standardised support at hospital-level , social In addition to external support from health professionals and partners, it is also important that women view themselves as a source of support, in that they possess the resilience and equanimity to manage the responsibility of being the sole food provider for an infant . Low matResearch has demonstrated the effectiveness of using mindfulness and cognitive behavioural therapy techniques to enhance maternal resilience and elicit clinically significant reductions in distress, depression and anxiety ,36,37,38Perseverance with breastfeeding, despite its associated physical and emotional challenges, has been well-documented ,12,26. AFinally, regardless of the infant feeding decision made, it is important that all women are appropriately supported throughout their transition to motherhood. Women with low resilience levels, suboptimal partner support, or who were older, were also more likely to feel distressed in this study. Many of the factors discussed here, support breastfeeding secondary to supporting a woman’s overall emotional wellbeing ,37,40. ABefore drawing conclusions, the study strengths and limitations must be considered. The data presented were collected as part of a longitudinal observational study conducted in County Dublin and its surrounding counties. Strengths of the study include the lack of inter-observer variation and the use of validated instruments to measure different aspects of maternal wellbeing. The MABISC has been shown to have satisfactory internal consistency and convergent validity with the more widely used Edinburgh Post-partum Depression Scale (EPDS) and Post-partum Bonding Questionnaire (PBQ) . AlthougThe relationship between breastfeeding and many sociodemographic and health behaviour characteristics has been examined in the Irish context ,11,23,41Adequate physical, emotional and practical preparation for breastfeeding is paramount to its successful initiation and maintenance. Pregnant women planning to breastfeed should be empowered with practical and evidence-based information on feeding techniques and positioning, in addition to information on troubleshooting common breastfeeding challenges. All women should also be supported to attain and maintain a healthy body and frame of mind prior to giving birth. If this preparation among women is further bolstered by a well-prepared maternal support network, women can approach motherhood, whether it is for the first or subsequent time, in an informed manner which safeguards their wellbeing and that of their infant.