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Objective To develop in vitro fertilization (IVF) prediction models to estimate the individualized chance of cumulative live birth at two time points: pretreatment (i.e., before starting the first complete cycle of IVF) and posttreatment (i.e., before starting the second complete cycle of IVF in those couples whose first complete cycle was unsuccessful). Design Population-based cohort study. Setting National data from the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System. Patient(s) Based on 88,614 women who commenced IVF treatment using their own eggs and partner’s sperm in SART member clinics. Intervention(s) Not applicable. Main Outcome Measure(s) The pretreatment model estimated the cumulative chance of a live birth over a maximum of three complete cycles of IVF, whereas the posttreatment model did so over the second and third complete cycles. One complete cycle included all fresh and frozen embryo transfers resulting from one episode of ovarian stimulation. We considered the first live birth episode, including singletons and multiple births. Result(s) Pretreatment predictors included woman’s age (35 years vs. 25 years, adjusted odds ratio 0.69, 95% confidence interval 0.66–0.73) and body mass index (35 kg/m2 vs. 25 kg/m2, adjusted odds ratio 0.75, 95% confidence interval 0.72–0.78). The posttreatment model additionally included the number of eggs from the first complete cycle (15 vs. 9 eggs, adjusted odds ratio 1.10, 95% confidence interval 1.03–1.18). According to the pretreatment model, a nulliparous woman aged 34 years with a body mass index of 23.3 kg/m2, male partner infertility, and an antimullerian hormone level of 3 ng/mL has a 61.7% chance of having a live birth over her first complete cycle of IVF (and a cumulative chance over three complete cycles of 88.8%). If a live birth is not achieved, according to the posttreatment model, her chance of having a live birth over the second complete cycle 1 year later (age 35 years, number of eggs 7) is 42.9%. The C-statistic for all models was between 0.71 and 0.73. Conclusion(s) The focus of previous IVF prediction models based on US data has been cumulative live birth excluding cycles involving frozen embryos. These novel prediction models provide clinically relevant estimates that could help clinicians and couples plan IVF treatment at different points in time.

STUDY QUESTIONAre perinatal outcomes following fresh blastocyst versus fresh cleavage stage embryo transfer (ET) different in singletons, twins, and between singleton siblings?SUMMARY ANSWERSingleton babies conceived following fresh blastocyst, versus cleavage stage, ET are less likely to be small for gestational age (SGA) or to have a congenital anomaly (a result confirmed by comparing singleton siblings), while singletons born following fresh blastocyst ET were at a higher risk of being large for gestational age (LGA) than their sibling born following fresh cleavage stage ET.WHAT IS KNOWN ALREADYBlastocyst stage transfer is now the preferred strategy in most IVF units. Previous studies have suggested that babies conceived through blastocyst transfer are at increased risk of preterm birth and LGA.STUDY DESIGN, SIZE, DURATIONA national population-based retrospective cohort study was performed using linked Human Fertilisation and Embryology Authority (HFEA) data on 130 516 IVF and ICSI livebirths occurring from 103 062 women between 2000 and 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSWe included women who had at least one singleton livebirth resulting from IVF/ICSI fresh embryo treatment, using their own eggs and partner’s sperm. A linked HFEA dataset was analysed using a multilevel framework, which accommodated repeated IVF cycles resulting in livebirths in the same woman. A population-averaged robust Poisson model was used for binary outcomes and a multinomial logistic regression model was used for categorical outcomes. Unadjusted and adjusted risk ratios (aRRs) (95% CI) were calculated.MAIN RESULTS AND THE ROLE OF CHANCEThere were 130 516 livebirths in 103 062 women, including 86 630 singletons, 43 886 twin births, and 5384 pairs of singleton siblings. In comparison with fresh cleavage stage ET, fresh blastocyst stage transfer in singletons was associated with a lower risk of low birthweight (aRR = 0.92; 95% CI 0.86, 0.99), lower risk of being SGA (0.83; 0.78, 0.89), and lower risk of congenital anomaly (0.79; 0.71, 0.89). This analysis did not show an increase in risk associated with preterm birth (1.00; 0.94, 1.06), high birthweight (0.99; 0.93, 1.06), LGA (0.99; 0.93, 1.05), and the chance of healthy singleton baby (1.00; 1.00, 1.02). Twins resulting from fresh blastocyst stage ET were at slightly higher risk of preterm birth (1.05; 1.02, 1.10) compared with twins conceived following fresh cleavage stage ET. There was insufficient evidence for an association with the other perinatal outcomes. Singleton siblings born following fresh blastocyst stage ET were at a higher risk of being LGA (1.57; 1.01, 2.46) and at lower risk of having a congenital anomaly (0.52; 0.28, 0.97) compared to their singleton siblings born following cleavage stage ET. There was some evidence of excess risk of preterm birth (1.42; 0.97, 2.23) associated with blastocyst stage transfer. However, we could not confirm an association between blastocyst stage ET and low birthweight (1.35; 0.81, 2.27), high birthweight (1.19; 0.80, 1.77), and the chance of being a healthy baby (0.97; 0.86, 1.09).LIMITATIONS, REASONS FOR CAUTIONThis was an observational study where we were unable to adjust for some key confounders, such as maternal smoking status and BMI, which may change from one pregnancy to another and are not recorded in the HFEA dataset.WIDER IMPLICATIONS OF THE FINDINGSIn the largest study of its kind, our analysis of singleton siblings, corrected for unmeasured, non-time varying maternal factors, confirms the previously reported association between blastocyst transfer and LGA babies, and shows a reduced risk of congenital anomaly following blastocyst transfer. Our sibling analysis did not confirm a decreased risk of low birthweight following blastocyst transfer. Overall, absolute risks are low and there is insufficient evidence to challenge the practice of extended culture of embryos.STUDY FUNDING/COMPETING INTEREST(S)This project is financed by an NHS Grampian Endowment Research Grant, project number 17/052. One of the authors, S.B., was the Editor in Chief of HROpen until 31 December 2022 and would have been in that role when the paper was first submitted. As an invited speaker, S.B. has received travel expenses, accommodation and honoraria from Merck, Organon, and Ferring. A.M. has received travel expenses, accommodation, and honoraria from Merck Serono, Cook Medical, Pharmasure, Gedeon Richter, and Ferring. D.J.M. is currently a HROpen Associate Editor.TRIAL REGISTRATION NUMBERN/A.

Purpose Existing research hints that people living with and beyond cancer are at an increased risk of stroke. However, there is insufficient evidence to appropriately inform guidelines for specific stroke prevention or management for cancer patients. We conducted a systematic review and meta-analysis to describe and quantify stroke incidence in people living with and beyond cancer. Methods Medline, CINAHL, and EMBASE were searched for epidemiological studies comparing stroke incidence between cancer and non-cancer patients. Reviewers independently extracted data; random-effects meta-analyses and quality assessment were performed. Results Thirty-six studies were narratively synthesised. Meta-analysis was conducted using seven studies. Methodological quality was high for most studies. Study populations were heterogeneous, and the length of follow-up and risk factors varied. There was a variation in risk between different cancer types and according to stroke type: pancreatic (HR 2.85 (95% CI 2.43–3.36), ischaemic) (HR 2.28 (95% CI 1.43–3.63), haemorrhagic); lung (HR 2.33 (95% CI 1.63–3.35), ischaemic) (HR 2.14 (95% CI 1.45–3.15), haemorrhagic); and head and neck (HR 1.54 (95% CI 1.40–1.69), haemorrhagic) cancers were associated with significantly increased incidence of stroke. Risk is highest within the first 6 months of diagnosis. Narrative synthesis indicated that several studies also showed significantly increased incidence of stroke in individuals with colorectal cancer, breast cancer, ovarian cancer, nasopharyngeal cancer, leukaemia, and myeloma, and those who have received radiotherapy for head and neck cancers and platinum-based chemotherapy may also have higher stroke incidence. Conclusions Stroke incidence is significantly increased after diagnosis of certain cancers. Implications for Cancer Survivors Cardiovascular risk should be assessed during cancer survivorship care, with attention to modifying shared cancer/cardiovascular risk factors.

Introduction With increasing caesarean section (c-section) rates, personalized communication of risk has become paramount. A reliable tool to predict complications would support evidence-based discussions around planned mode of birth. This systematic review aimed to identify, synthesize and quality appraise prognostic models of maternal complications of elective c-section. Methods MEDLINE, Embase, Web of Science, CINAHL and the Cochrane Library were searched on 27 January using terms relating to ‘c-section’, ‘prognostic models’ and complications such as ‘infection’. Any study developing and/or validating a prognostic model for a maternal complication of elective c-section in the English language after January 1995 was selected for analysis. Data were extracted using a predetermined checklist: source of data; participants; outcome to be predicted; candidate predictors; sample size; missing data; model development; model performance; model evaluation; results; and interpretation. Quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST) tool. Results In total, 7752 studies were identified; of these, 16 full papers were reviewed and three eligible studies were identified, containing three prognostic models derived from hospitals in Japan, South Africa and the UK. The models predicted risk of blood transfusion, spinal hypotension and postpartum haemorrhage. The study authors deemed their studies to be exploratory, exploratory and confirmatory, respectively. From the three studies, a total of 29 unique candidate predictors were identified, with 15 predictors in the final models. Maternal age (n = 3), previous c-section (n = 2), placenta praevia (n = 2) and pre-operative haemoglobin (n = 2) were found to be common predictors amongst the included studies. None of the studies were externally validated and all had a high risk of bias due to the analysis technique used. Conclusion Few models have been developed to predict complications of elective c-section. Existing models predicting blood transfusion, spinal hypotension and postpartum haemorrhage cannot be recommended for clinical practice. Future research should focus on identifying predictors known before surgery and validating the resulting models.

Rationale & Objective There is limited evidence to guide follow-up after acute kidney injury (AKI). Knowledge gaps include which patients to prioritize, at what time point, and for mitigation of which outcomes. In this study, we sought to compare the net benefit of risk model–based clinical decisions following AKI. Study Design External validation of 2 risk models of AKI outcomes: the Grampian -Aberdeen (United Kingdom) AKI readmissions model and the Alberta (Canada) kidney disease risk model of chronic kidney disease (CKD) glomerular (G) filtration rate categories 4 and 5 (CKD G4 and G5). Process mining to delineate existing care pathways. Setting & Participants Validation was based on data from adult hospital survivors of AKI from Grampian, 2011-2013. Predictors KDIGO-based measures of AKI severity and comorbidities specified in the original models. Outcomes Death or readmission within 90 days for all hospital survivors. Progression to new CKD G4-G5 for patients surviving at least 90 days after AKI. Analytical Approach Decision curve analysis to assess the “net benefit” of use of risk models to guide clinical care compared to alternative approaches (eg, prioritizing all AKI, severe AKI, or only those without kidney recovery). Results 26,575 of 105,461 hospital survivors in Grampian (mean age, 60.9 ± 19.8 [SD] years) were included for validation of the death or readmission model, and 9,382 patients (mean age, 60.9 ± 19.8 years) for the CKD G4-G5 model. Both models discriminated well (area under the curve [AUC], 0.77 and 0.86, respectively). Decision curve analysis showed greater net benefit for follow up of all AKI than only severe AKI in most cases. Both original and refitted models provided net benefit superior to any other decision strategy. In process mining of all hospital discharges, 41% of readmissions and deaths occurred among people recovering after AKI. 1,464 of 3,776 people (39%) readmitted after AKI had received no intervening monitoring. Limitations Both original models overstated risks, indicating a need for regular updating. Conclusions Follow up after AKI has potential net benefit for preempting readmissions, death, and subsequent CKD progression. Decisions could be improved by using risk models and by focusing on AKI across a full spectrum of severity. The current lack of monitoring among many with poor outcomes indicates possible opportunities for implementation of decision support.

Purpose: This study aimed to evaluate the outcomes of juxtapapillary choroidal melanomas treated with notched ruthenium-106 plaques. Methods: Juxtapapillary choroidal melanomas (tumours within 2 disc diameters from the optic disc) treated with notched ruthenium-106 plaques (Eckert & Ziegler, BEBIG, Berlin, Germany) at the Scottish Ocular Oncology Service between 2009 and 2015 were retrospectively reviewed. The data were analysed with respect to various outcome measures including recurrence, complications, vision, and eye preservation. Results: We reviewed 40 patients with a median tumour diameter of 8.4 mm (range 5–17 mm) and a median thickness of 2.5 mm (range 1.1–6 mm). AJCC tumour category distribution was 62.5% T1, 32.5% T2, and 5% T3 tumours. The mean presenting vision was 0.3 logMAR, and the mean final vision was 0.7 logMAR, with 62.5% retaining >1.0 logMAR and 50% retaining >0.3 logMAR at the final follow-up. The median follow-up was 51 months (14–100 months). Over the maximum follow-up time, 13 tumours (32.5%) recurred. Six of these were treated with salvage proton beam therapy (PBT), 2 with transpupillary thermotherapy followed by PBT, and 5 with enucleation. The final eye retention rate was 87.5%. Complications included maculopathy (10%), retinal detachment (5%), neovascular glaucoma (2.5%), and diplopia (2.5%). The observed risk of recurrence over 5 years was 31% (95% CI: 14.1%, 47.8%), and the risk of enucleation over 5 years was 11.5% (95% CI: 0.9%, 21.8%). Conclusion: Juxtapapillary choroidal melanomas treated with notched ruthenium plaques have a high recurrence rate and frequently need salvage treatment with PBT for tumour control. This has led to a change in our practice toward offering PBT as the first-line treatment for these patients.

Background Postpartum haemorrhage (PPH) causes substantial morbidity and mortality worldwide. A reliable prognostic tool for PPH has potential to aid prevention efforts. Objective Systematically to identify and appraise prognostic modelling studies for prediction of PPH. Search strategy MEDLINE, Embase, CINAHL and the Cochrane Library were searched using a combination of terms and synonyms including 'prediction tool', 'risk score' and 'postpartum haemorrhage'. Selection criteria Any observational or experimental study developing a prognostic model for women's risk of PPH. English language publications. Data collection and analysis Predesigned data extraction form to record: data source; participant criteria; outcome; candidate predictors; actual predictors; sample size; missing data; model development; model performance; model evaluation; interpretation. Main results Of 2146 citations screened, 14 studies were eligible for inclusion. Studies addressed populations of women who experienced placenta praevia, placenta accreta spectrum, vaginal birth, caesarean birth (CS) and the general obstetric population. All studies were at high risk of bias due to low sample size, no internal validation, suboptimal or no external validation or no reporting or handling of missing data. Five studies raised applicability concerns. Three externally validated and three internally validated studies show potential for robust external validation. Conclusion Of 14 prognostic models for PPH risk, three have some potential for clinical use: in CS, in placenta accreta spectrum disorders with MRI placental Evaluation and in placenta praevia. Future research requires robust internal and external validation of existing tools and development of a model for use in the general obstetric population. Tweetable abstract Current PPH prediction tools need external validation: one for CS, one for placenta praevia and one for placenta accreta. Tools are needed for labouring women.

The treatment of unexplained infertility is a contentious topic that continues to attract a great deal of interest amongst clinicians, patients and policy makers. The inability to identify an underlying pathology makes it difficult to devise effective treatments for this condition. Couples with unexplained infertility can conceive on their own and any proposed intervention needs to offer a better chance of having a baby. Over the years, several prognostic and prediction models based on routinely collected clinical data have been developed, but these are not widely used by clinicians and patients. In this opinion paper, we propose a prognosis-based approach such that a decision to access treatment is based on the estimated chances of natural and treatment-related conception, which, in the same couple, can change over time. This approach avoids treating all couples as a homogeneous group and minimizes unnecessary treatment whilst ensuring access to those who need it early.

To study the association of donor sperm on perinatal outcomes of livebirths conceived via in vitro fertilization (IVF) when compared with partner sperm.Retrospective cohort study SETTING: National Human Fertilisation and Embryology Authority assisted reproductive technology registry PATIENTS: All live born singletons and twins conceived through IVF with or without intracytoplasmic sperm injection in the United Kingdom between 1991 and 2016 INTERVENTION(S): Donor sperm compared to partner sperm MAIN OUTCOME MEASURE(S): Perinatal outcomes were assessed. The primary outcomes were preterm and very preterm birth; low, very low, high, and very high birthweight; Secondary outcomes were congenital anomaly and health baby. These were assessed for singletons and twins separately.For singleton livebirths, compared to partner sperm, those conceived with donor sperm were at reduced odds of very preterm (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.63-0.91; adjusted OR [aOR], 0.80; 95% CI, 0.66-0.96), and preterm (OR, 0.90; 95% CI, 0.83-0.98; aOR, 0.93; 95% CI, 0.85-1.01) birth. For birthweight outcomes, donor sperm showed a reduced odds of low (OR, 0.83; 95% CI, 0.76-0.91; aOR, 0.86; 95% CI, 0.78-0.94) and an increased odds of high (OR, 1.15; 95% CI, 1.07-1.23; aOR, 1.09; 95% CI, 1.01-1.17) birthweight. There was no confirmed difference in the odds ratios of very low (OR, 0.88; 95% CI, 0.74-1.06; aOR, 0.94; 95% CI, 0.78-1.13) or very high (OR, 1.21; 95% CI, 1.04-1.40; aOR, 1.15; 95% CI, 0.98-1.34) birthweight. Liveborn twins conceived with donor sperm, compared to partner sperm, were at reduced odds of very low (OR, 0.76; 95% CI, 0.66-0.88; aOR, 0.83; 95% CI, 0.72-0.96) and low (OR, 0.87; 95% CI, 0.81-0.93; aOR, 0.91; 95% CI, 0.85-0.98) birthweight. There was a suggestion of a reduced odds of very preterm (OR, 0.81; 95% CI, 0.70-0.95; aOR, 0.86; 95% CI, 0.74-1.01) and preterm (OR, 0.93; 95% CI, 0.86-1.01; aOR, 0.96; 95% CI, 0.88-1.04) birth. There was considerable uncertainty around the ORs for high (OR, 0.73; 95% CI, 0.31-1.72; aOR, 0.72; 95% CI, 0.29-1.80) and very high (OR, 1.02; 95% CI, 0.39-2.67; aOR, 1.34; 95% CI, 0.50-3.60) birthweight.Although unmeasured confounding remains a possibility, as paternal age, body mass index, and smoking status were unavailable for analysis, women, couples, service providers can be reassured that IVF livebirths conceived with donor sperm have no greater chance of adverse outcomes when compared to partner sperm.

STUDY QUESTIONWhat are the best-quality clinical prediction models in IVF (including ICSI) treatment to inform clinicians and their patients of their chance of success?SUMMARY ANSWERThe review recommends the McLernon post-treatment model for predicting the cumulative chance of live birth over and up to six complete cycles of IVF.WHAT IS KNOWN ALREADYPrediction models in IVF have not found widespread use in routine clinical practice. This could be due to their limited predictive accuracy and clinical utility. A previous systematic review of IVF prediction models, published a decade ago and which has never been updated, did not assess the methodological quality of existing models nor provided recommendations for the best-quality models for use in clinical practice.STUDY DESIGN, SIZE, DURATIONThe electronic databases OVID MEDLINE, OVID EMBASE and Cochrane library were searched systematically for primary articles published from 1978 to January 2019 using search terms on the development and/or validation (internal and external) of models in predicting pregnancy or live birth. No language or any other restrictions were applied.PARTICIPANTS/MATERIALS, SETTING, METHODSThe PRISMA flowchart was used for the inclusion of studies after screening. All studies reporting on the development and/or validation of IVF prediction models were included. Articles reporting on women who had any treatment elements involving donor eggs or sperm and surrogacy were excluded. The CHARMS checklist was used to extract and critically appraise the methodological quality of the included articles. We evaluated models’ performance by assessing their c-statistics and plots of calibration in studies and assessed correct reporting by calculating the percentage of the TRIPOD 22 checklist items met in each study.MAIN RESULTS AND THE ROLE OF CHANCEWe identified 33 publications reporting on 35 prediction models. Seventeen articles had been published since the last systematic review. The quality of models has improved over time with regard to clinical relevance, methodological rigour and utility. The percentage of TRIPOD score for all included studies ranged from 29 to 95%, and the c-statistics of all externally validated studies ranged between 0.55 and 0.77. Most of the models predicted the chance of pregnancy/live birth for a single fresh cycle. Six models aimed to predict the chance of pregnancy/live birth per individual treatment cycle, and three predicted more clinically relevant outcomes such as cumulative pregnancy/live birth. The McLernon (pre- and post-treatment) models predict the cumulative chance of live birth over multiple complete cycles of IVF per woman where a complete cycle includes all fresh and frozen embryo transfers from the same episode of ovarian stimulation. McLernon models were developed using national UK data and had the highest TRIPOD score, and the post-treatment model performed best on external validation.LIMITATIONS, REASONS FOR CAUTIONTo assess the reporting quality of all included studies, we used the TRIPOD checklist, but many of the earlier IVF prediction models were developed and validated before the formal TRIPOD reporting was published in 2015. It should also be noted that two of the authors of this systematic review are authors of the McLernon model article. However, we feel we have conducted our review and made our recommendations using a fair and transparent systematic approach.WIDER IMPLICATIONS OF THE FINDINGSThis study provides a comprehensive picture of the evolving quality of IVF prediction models. Clinicians should use the most appropriate model to suit their patients’ needs. We recommend the McLernon post-treatment model as a counselling tool to inform couples of their predicted chance of success over and up to six complete cycles. However, it requires further external validation to assess applicability in countries with different IVF practices and policies.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by the Elphinstone Scholarship Scheme and the Assisted Reproduction Unit, University of Aberdeen. Both D.J.M. and S.B. are authors of the McLernon model article and S.B. is Editor in Chief of Human Reproduction Open. They have completed and submitted the ICMJE forms for Disclosure of potential Conflicts of Interest. The other co-authors have no conflicts of interest to declare.REGISTRATION NUMBERN/A

Background and Purpose— We aimed to determine individual and combined effects of atrial fibrillation (AF) and heart failure (HF) on acute ischemic stroke outcomes: in-hospital mortality, length-of-stay, and poststroke disability; long-term mortality and stroke recurrence. Methods— Prospective cohort study of patients with acute ischemic stroke admitted to a UK center with a catchment population of ≈900 000 between 2004 and 2016. Exposure groups were patients with neither AF nor HF (reference group), those with AF but without HF, those with HF but without AF, and those with AF+HF. Logistic and Cox regressions were used to model in-hospital and long-term outcomes, respectively. Results— A total of 10 816 patients with a mean age±SD =77.9±12.1 years, 48% male were included. Only 30 (4.9%) of the patients with HF but not AF were anticoagulated at discharge. Both AF (odds ratio, 1.24 [95% CI, 1.07–1.43]), HF (odds ratio, 1.40 [1.10–1.79]), and their combination (odds ratio, 2.23 [1.83–2.72]) were associated with increased odds of in-hospital mortality. All 3 exposure groups were associated with increased length-of-stay, while only AF predicted increased disability (1.36 [1.12–1.64]). Patients were followed for a median of 5.5 and 3.7 years for mortality and recurrence, respectively. Long-term mortality was associated with AF (hazard ratio, 1.45 [95% CI, 1.33–1.59]), HF (2.07 [1.83–2.36]), and their combination (2.20 [1.96–2.46]). Recurrent stroke was associated with AF 1.50 (1.26–1.78), HF (1.33 [1.01–1.75]), and AF with HF (1.62 [1.28–2.07]). Conclusions— The AF-associated excess risk of stroke recurrence was independent of comorbid HF. HF without AF was also associated with a significant risk of recurrence. Anticoagulation for secondary stroke prevention in patients with HF without AF may require further evaluation in a clinical trial setting.

STUDY QUESTION Which couples with unexplained subfertility can expect increased chances of ongoing pregnancy with IVF compared to expectant management? SUMMARY ANSWER For couples in which the woman is under 40 years of age, IVF is associated with higher chances of conception than expectant management. WHAT IS KNOWN ALREADY The clinical indications for IVF have expanded over time from bilateral tubal blockage to include unexplained subfertility in which there is no identifiable barrier to conception. Yet, there is little evidence from randomized controlled trials that IVF is effective in these couples. STUDY DESIGN, SIZE, DURATION We compared outcomes in British couples with unexplained subfertility undergoing IVF (n = 40 921) from registry data to couples with the same type of subfertility on expectant management. Those couples on expectant management (defined as no intervention aside from the advice to have intercourse) comprised a prospective nation-wide Dutch cohort (n = 4875) and a retrospective regional cohort from Aberdeen, Scotland (n = 975). We excluded couples who had tried for PARTICIPANTS/MATERIALS, SETTING, METHODS We matched couples who received IVF and couples on expectant management based on their characteristics to control for confounding. We fitted a Cox proportional hazards model including patient characteristics, IVF treatment and their interactions to estimate the individualized chance of conception over 1 year—either following IVF or expectant management for all combinations of patient characteristics. The endpoint was conception leading to ongoing pregnancy, defined as a foetus reaching a gestational age of at least 12 weeks. MAIN RESULTS AND THE ROLE OF CHANCE The adjusted 1-year chance of conception was 47.9% (95% CI: 45.0–50.9) after IVF and 26.1% (95% CI: 24.2–28.0) after expectant management. The absolute difference in the average adjusted 1-year chances of conception was 21.8% (95%CI: 18.3–25.3) in favour of IVF. The effectiveness of IVF was influenced by female age, duration of subfertility and previous pregnancy. IVF was effective in women under 40 years, but the 1-year chance of an IVF conception declined sharply in women over 34 years. In contrast, in woman over 40 years of age, IVF was less effective, with an absolute difference in chance compared to expectant management of 10% or lower. Regardless of female age, IVF was also less effective in couples with a short period of secondary subfertility (1 year) who had chances of natural conception of 30% or above. LIMITATIONS, REASONS FOR CAUTION The 1-year chances of conception were based on three cohorts with different sampling mechanisms. Despite adjustment for the three most important prognostic patient characteristics, namely female age, duration of subfertility and primary or secondary subfertility, our estimates might not be free from residual confounding. WIDER IMPLICATIONS OF THE FINDINGS IVF should be used selectively based on judgements on gain compared to continuing expectant management for a given couple. Our results can be used by clinicians to counsel couples with unexplained subfertility, to inform their expectations and facilitate evidence-based, shared decision making. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Tenovus Scotland [grant G17.04]. Travel for RvE was supported by the Amsterdam Reproduction & Development Research Group [grant V.000296]. SB reports acting as editor-in-chief of HROpen. Other authors have no conflicts.

To determine whether perinatal outcomes following frozen vs. fresh embryo transfer (ET) differ within singletons, within sets of twins, and between siblings.Population-based retrospective cohort study.Academic Medical School PATIENT(S): 200,075 live births in 151,561 women who underwent in vitro fertilization with frozen or fresh ET between 1992 and 2017.Gestational age at birth, birthweight, congenital anomaly, and healthy baby (≥37 weeks of gestation, birthweight 2,500-4,000 g, no congenital malformations).There were 200,075 live births in 151,561 women including 132,679 singletons, 33,698 sets of twins, and 5,723 pairs of singleton siblings. In singletons, frozen ET was associated with a lower risk of very preterm birth (adjusted relative risk [aRR], 0.83; 95% confidence interval [CI], 0.73, 0.94), preterm birth (aRR, 0.93; 95% CI, 0.88, 0.97), low birthweight (2,500 g) (aRR, 0.72; 95% CI, 0.68, 0.77), small for gestational age (aRR, 0.66; 95% CI, 0.62, 0.70) and congenital anomaly (aRR, 0.85; 95% CI, 0.78, 0.94), but higher risk of high birthweight (4,000 g) (aRR, 1.64; 95% CI, 1.58, 1.72) and large for gestational age (aRR, 1.62; 95% CI, 1.55, 1.70) in comparison with fresh ET. In twins, frozen ET was associated with lower risk of very preterm birth (aRR, 0.84; 95% CI, 0.73, 0.97), and low birthweight (aRR, 0.72; 95% CI, 0.68, 0.77), but with a higher chance of a healthy baby (aRR, 1.11; 95% CI, 1.06, 1.16) compared to fresh ET. Singletons conceived following frozen ET had a lower risk of low birthweight (aRR, 0.56; 95% CI, 0.44, 0.74) and being small for gestational age (aRR, 0.54; 95% CI, 0.42, 0.68) than a singleton sibling born after a fresh ET. Frozen ET also was associated with higher risk of high birthweight (aRR, 1.85; 95% CI, 1.54, 2.24) and being large for gestational age (aRR, 1.81; 95% CI, 1.50, 2.20), and also were less likely to be preterm (aRR, 0.81; 95% CI, 0.67, 0.99).Our key finding is that singletons born following a frozen ET are less likely to be small for gestational age than a singleton sibling born following fresh ET but are more likely to be large for gestational age.

Introduction With increasing caesarean section (c-section) rates, personalised communication of risk has become paramount. A reliable tool to predict complications would support evidence-based discussion around planned mode of birth. Method MEDLINE, Embase, Web of Science, CINAHL, and the Cochrane Library were searched on 27th January with the terms relating to c-section, prognostic models, and complications such as infection. Any study developing and/or validating a prognostic model for maternal complications of c-section in the English language after January 1995 was included. Data extracted encompassed: source of data, participant criteria, outcome to be predicted, candidate predictors, actual predictors, sample size, model development, and model performance. PROBAST (Prediction model Risk Of Bias Assessment Tool) was utilised for risk of bias analysis and applicability concern in the prognostic model studies. Result 7,752 studies were identified, of which 16 were reviewed producing 3 studies where 3 prognostic models were identified which predicted risk of: blood transfusion, spinal hypotension, and postpartum haemorrhage. From the 3 studies, a total of 29 unique candidate predictors were identified and 15 predictors in the final model. Study authors deemed their studies to be exploratory, exploratory, and confirmatory respectively. None were externally validated and all had a high risk of bias due to analysis technique. Conclusion Few models have been developed to predict complications of elective c-section. Existing models predicting blood transfusion, spinal hypotension, and postpartum haemorrhage cannot be recommended for clinical practice. Future research should focus on identifying predictors known before surgery and validating resulting models. Take-home Message Systematic review of prediction models for planned C-section complications found none suitable for practice.

Study question Are perinatal outcomes different in pregnancies conceived using donor sperm compared with those with partner sperm? Summary answer The perinatal outcomes of singleton and twin pregnancies conceived with donor sperm are better when compared to those conceived with partner sperm What is known already There has been a substantial increase in the use of donor sperm in the last 15 years across the world. A recent systematic review and meta-analysis has suggested that there is an increased risk of hypertensive disorders of pregnancy and small for gestational age babies from ART treatment using donor sperm compared to partner`s sperm. This meta-analysis was limited due to poor quality of primary studies often with small sample sizes. Study design, size, duration This is a retrospective cohort study on 196,293 singleton and 46,275 twin pregnancies from the Human Fertilisation and Embryology Authority (HFEA) anonymised dataset including all live births from 1991 to 2016. Outcomes were preterm birth ( < 37 weeks); very preterm birth ( < 32 weeks); very low, low, high and very high birth weight ( < 1500g, < 2500g, >4000g and >4500g respectively); congenital anomaly and healthy baby (term live birth with appropriate weight and no congenital anomaly). Participants/materials, setting, methods All pregnancies resulting in singleton or twin livebirth were included. Any cycle involving donor oocytes, PGD, gamete intra-fallopian transfer, ectopic pregnancy, miscarriage, stillbirth, or termination was excluded. Logistic regression and generalised estimating equations were used for analysis of singletons and twins, respectively. Odds ratios (aOR) with 95% confidence intervals (CI) for donor versus partner sperm were adjusted for maternal age, previous pregnancy, cause of infertility and year for all outcomes plus gestational age for birthweight. Main results and the role of chance Baseline characteristics for donor and partner sperm pregnancies were assessed for singleton and twin livebirths separately. In both analyses there were significant differences between donor and partner sperm pregnancies in terms of maternal age, previous pregnancy status and cause of infertility. Analysis of singleton births demonstrated an increased odds (aOR, 95% CI) of having a healthy baby (1.09, 1.05 - 1.12) and reduced odds of congenital anomaly (0.34, 0.29 - 0.39), very preterm birth (0.66, 0.58-0.75), preterm birth (0.81, 0.76-0.86), low birthweight 0.89 (0.83 - 0.96) in singleton births using donor sperm compared with those using partner sperm. There was, however, an increased odds of high birthweight (1.10, 1.05 - 1.16) and very high birthweight (1.16, 1.05-1.29) with donor sperm pregnancies. Analysis of twin births conceived with donor sperm also showed higher odds of having a healthy baby (1.07, 1.01 - 1.15) and lower odds of congenital anomaly (0.52, 0.39 - 0.68) compared with partner sperm. There were no statistically significant differences between the birthweight or birth gestation outcomes for twin pregnancies. Sensitivity analysis of only cases with complete outcome data showed no significant differences when compared to the primary analysis. Limitations, reasons for caution This is a retrospective study of a single nation’s routinely collected data. We could not adjust for confounders such as smoking, BMI and pregnancy complications such as pre-eclampsia, as they are not recorded in HFEA’s dataset. Wider implications of the findings Patients and clinicians can be reassured that donor sperm pregnancies are not at higher risk of adverse perinatal outcomes. In fact, they are more likely to result in a healthy baby. Worldwide registries should consider including maternal data to enable a better assessment of outcomes. Trial registration number Not applicable

Predicting long-term stroke mortality is a clinically important and unmet need. We aimed to develop and internally validate a 10-year ischaemic stroke mortality prediction score. In this UK cohort study, 10,366 patients with first-ever ischaemic stroke between January 2003 and December 2016 were followed up for a median (interquartile range) of 5.47 (2.96–9.15) years. A Cox proportional-hazards model was used to predict 10-year post-admission mortality. The predictors associated with 10-year mortality included age, sex, Oxfordshire Community Stroke Project classification, estimated glomerular filtration rate (eGFR), pre-stroke modified Rankin Score, admission haemoglobin, sodium, white blood cell count and comorbidities (atrial fibrillation, coronary heart disease, heart failure, cancer, hypertension, chronic obstructive pulmonary disease, liver disease and peripheral vascular disease). The model was internally validated using bootstrap resampling to assess optimism in discrimination and calibration. A nomogram was created to facilitate application of the score at the point of care. Mean age (SD) was 78.5 ± 10.9 years, 52% female. Most strokes were partial anterior circulation syndromes (38%). 10-year mortality predictors were: total anterior circulation stroke (hazard ratio, 95% confidence intervals) (2.87, 2.62–3.14), eGFR

Childhood obesity has become a serious global healthcare challenge. No UK data currently define its anaesthetic and perioperative implications. We aimed to determine obesity prevalence amongst UK children undergoing general anaesthesia and the incidence of predefined adverse perioperative events, and to compare perioperative obesity rates with National Child Measurement Programme (NCMP) data.During a site-selected consecutive 7-day study period, all children (2-16 yr) undergoing general anaesthesia were included. Anonymised hospital, surgical, and procedural details; demographic data; and adverse perioperative events were collected prospectively by Paediatric Anaesthesia Trainee Research Network (PATRN) collaborators.For this study, 102 UK hospitals participated and 4232 cases were included in the final analysis; 76% of hospitals did not routinely calculate BMI. In addition, 3030 (71.6%; 95% confidence interval [CI]: 70.2-73.0%) children of healthy weight were compared with 537 (12.7%; 11.7-13.7%) children who were overweight and 478 (11.3%; 10.3-12.2%) children with obesity. Children with obesity (n=71; 14.9%) more commonly underwent (adeno)tonsillectomy than children of healthy weight (n=282; 9.3%; P0.001; odds ratio [OR] 2.15; 95% CI: 1.58-2.92). Fewer children with obesity (n=365; 77% vs n=2552; 85%) were anaesthetised by consultant anaesthetists (OR 0.62; 95% CI: 0.48-0.79). Mask ventilation was difficult for 3.7% of children with obesity vs 0.6% of children of healthy weight (difference 3.0%; 95% CI: 1.3-4.7%; P0.001). Comparison with NCMP data demonstrated an over-representation of obesity amongst the paediatric surgical population.This large multicentre cohort study suggests a concerning prevalence of children with obesity presenting for anaesthesia. These results should be used to inform optimal provision of care for this population and support perioperative healthcare initiatives to address the burden of childhood obesity.ClinicalTrials.gov Identifier: NCT03994419.

Background and Aims There is limited evidence to inform which people should receive follow up after AKI and for what reasons. Here we report the external validation (geographical and temporal) and potential clinical utility of two complementary models for predicting different post-discharge outcomes after AKI. We used decision curve analysis, a technique that enables visualisation of the trade-off (net benefit) between identifying true positives and avoiding false positives across a range of potential risk thresholds for a risk model. Based on decision curve analysis we compared model guided approaches to follow up after AKI with alternative strategies of standardised follow up – e.g. follow up of all people with AKI, severe AKI, or a discharge eGFR Method The Alberta AKI risk model predicts the risk of stage G4 CKD at one year after AKI among those with a baseline GFR>=45 and at least 90 days survival (2004-2014, n=9973). A trial is now underway using this tool at a 10% threshold to identify high risk people who may benefit from specialist nephrology follow up. The Aberdeen AKI risk model provides complementary predictions of early mortality or unplanned readmissions within 90 days of discharge (2003, n=16453), aimed at supporting non-specialists in discharge planning, with a threshold of 20-40% considered clinically appropriate in the study. For the Alberta model we externally validated using Grampian residents with hospital AKI in 2011-2013 (n=9382). For the Aberdeen model we externally validated using all people admitted to hospital in Grampian in 2012 (n=26575). Analysis code was shared between the sites to maximise reproducibility. Results Both models discriminated well in the external validation cohorts (AUC 0.855 for CKD G4, and AUC 0.774 for death and readmissions model), but as both models overpredicted risks, recalibration was performed. For both models, decision curve analysis showed that prioritisation of patients based on the presence or severity of AKI would be inferior to a model guided approach. For predicting CKD G4 progression at one year, a strategy guided by discharge eGFR Conclusion In conclusion, prioritising AKI follow up is complex and standardised recommendations for all people may be an inefficient and inadequate way of guiding clinical follow-up. Guidelines for AKI follow up should consider suggesting an individualised approach both with respect to purpose and prioritisation.

Background and purpose: Urinary tract infection (UTI) is one of the most common complications following stroke and has prognostic significance. UTI rates have been shown to vary between hospitals, but it is unclear whether this is due to case-mix differences or heterogeneities in care among hospitals. Methods: A prospective multi-center cohort study of acute stroke patients admitted to eight National Health Service (NHS) acute hospital trusts within the Anglia Stroke & Heart Clinical Network between 2009 and 2011 was conducted. We modeled the association between hospital (as a fixed-effect) and inpatient UTI using a multivariable logistic regression model, adjusting for established patient-level risk factors. We graphically and descriptively analyzed heterogeneities in hospital-level characteristics. Results: We included 2,241 stroke admissions in our analysis; 171 (7.6%) acquired UTI as an inpatient. UTI rates varied significantly between the eight hospitals, ranging from 3 to 11%. The hospital that had the lowest odds of UTI [odds ratio (OR) = 0.50 (95% confidence interval (CI) 0.22-.11)] in adjusted analysis, had the highest number of junior doctors and occupational therapists per five beds of all hospitals. The hospital with the highest adjusted UTI rate [OR=2.69 (1.56-4.64)] was tertiary, the largest and had the highest volume of stroke patients, lowest number of stroke unit beds per 100 admissions, and the highest number of hospital beds per CT scanner. Conclusions: There is hospital-level variation in post-stroke UTI. Our results suggest the potential influence of service characteristics independently of patient-level factors which may be amenable to be addressed to improve the ultimate stroke outcome.

BACKGROUND Registry data from the Human Fertilisation and Embryology Authority (HFEA) show an increase of 40% in IUI and 377% in IVF cases using donor sperm between 2006 and 2016. OBJECTIVE AND RATIONALE The objective of this study was to establish whether pregnancies conceived using donor sperm are at higher risk of obstetric and perinatal complications than those conceived with partner sperm. As more treatments are being carried out using donor sperm, attention is being given to obstetric and perinatal outcomes, as events in utero and at delivery have implications for long-term health. There is a need to know if there is any difference in the outcomes of pregnancies between those conceived using donor versus partner sperm in order to adequately inform and counsel couples. SEARCH METHODS We performed a systematic review and meta-analysis of the outcomes of pregnancies conceived using donor sperm compared with partner sperm. Searches were performed in the OVID MEDLINE, OVID Embase, CENTRAL and CINAHL databases, including all studies published before 11 February 2019. The search strategy involved search terms for pregnancy, infant, donor sperm, heterologous artificial insemination, donor gametes, pregnancy outcomes and perinatal outcomes. Studies were included if they assessed pregnancies conceived by any method using, or infants born from, donor sperm compared with partner sperm and described early pregnancy, obstetric or perinatal outcomes. The Downs and Black tool was used for quality and bias assessment of studies. OUTCOMES Of 3391 studies identified from the search, 37 studies were included in the review and 36 were included in the meta-analysis. For pregnancies conceived with donor sperm, versus partner sperm, there was an increase in the relative risk (RR) (95% CI) of combined hypertensive disorders of pregnancy: 1.44 (1.17–1.78), pre-eclampsia: 1.49 (1.05–2.09) and small for gestational age (SGA): 1.42 (1.17–1.79) but a reduced risk of ectopic pregnancy: 0.69 (0.48–0.98). There was no difference in the overall RR (95% CI) of miscarriage: 0.94 (0.80–1.11), gestational diabetes: 1.49 (0.62–3.59), pregnancy-induced hypertension (PIH): 1.24 (0.87–1.76), placental abruption: 0.65 (0.04–10.37), placenta praevia: 1.19 (0.64–2.21), preterm birth: 0.98 (0.88–1.08), low birth weight: 0.97 (0.82–1.15), high birthweight: 1.28 (0.94–1.73): large for gestational age (LGA): 1.01 (0.84–1.22), stillbirth: 1.23 (0.97–1.57), neonatal death: 0.79 (0.36–1.73) and congenital anomaly: 1.15 (0.86–1.53). WIDER IMPLICATIONS The majority of our findings are reassuring, except for the mild increased risk of hypertensive disorders of pregnancy and SGA in pregnancies resulting from donor sperm. However, the evidence for this is limited and should be interpreted with caution because the evidence was based on observational studies which varied in their quality and risk of bias. Further high-quality population-based studies reporting obstetric outcomes in detail are required to confirm these findings.

STUDY QUESTION Is there a difference in the odds of a live birth following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF? SUMMARY ANSWER After adjusting for indication bias, there was not enough evidence to suggest a difference in the odds of live birth following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF. WHAT IS KNOWN ALREADY Replacement of blastocyst-stage embryos has become the dominant practice in IVF but there is uncertainty about whether this technique offers an improved chance of cumulative live birth over all fresh and frozen-thawed embryo transfer attempts associated with a single oocyte retrieval. STUDY DESIGN, SIZE, DURATION National population-based retrospective cohort study of 100 610 couples who began their first IVF/ICSI treatment at a licenced UK clinic between 1 January 1999 and 30 July 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS Data from the Human Fertilisation and Embryology Authority (HFEA) register on IVF/ICSI treatments using autologous gametes between 1999 and 2010 were analysed. The primary outcome was the live birth rate over the first complete cycle of IVF. Cumulative live birth rates (CLBR) were compared for couples who underwent blastocyst and cleavage transfer, and the adjusted odds of live birth over the first complete cycle were estimated for each group using binary logistic regression. This analysis was repeated within groups of female age, oocytes collected and primary versus secondary infertility. Inverse probability of treatment weighting was used to account for the imbalance in couple characteristics between treatment groups. MAIN RESULTS AND THE ROLE OF CHANCE In total, 94 294 (93.7%) couples had a cleavage-stage embryo transfer while 6316 (6.3%) received blastocysts. Over the first complete cycle of IVF/ICSI (incorporating all fresh and frozen-thawed embryo transfers associated with the first oocyte retrieval), the CLBR was increased in those who underwent blastocyst transfer (56.5%) compared to cleavage-stage embryo transfer (34.8%). However, after accounting for the imbalance between exposures, blastocyst transfer did not significantly influence the odds of live birth over the first complete cycle (adjusted odds ratio: 1.03 (0.96, 1.10)). LIMITATIONS, REASONS FOR CAUTION Limitations of our study include the retrospective nature of the HFEA dataset and availability of linked data up until 2010. We were unable to adjust for some confounders, such as smoking status, BMI and embryo quality, as these data are not collected at national level by the HFEA. Similarly, there may be unknown couple, treatment or clinic variables that may influence our results. We were unable to assess the intended stage of embryo transfer for women who did not have an embryo replaced, and therefore excluded them from our study. Perinatal outcomes were not included in our analyses and would be a useful basis for future study. WIDER IMPLICATIONS OF THE FINDINGS Our findings show that blastocyst-stage embryo transfer may offer an improved chance of live birth in both the first fresh and the first complete cycle of IVF/ICSI compared to cleavage-stage transfer, even in couples with typically poorer prognoses. Where possible, offering blastocyst transfer to a wider range of couples may increase cumulative success rates. STUDY FUNDING/COMPETING INTEREST(S) N.J.C. received a Wolfson Foundation Intercalated Degree Research Fellowship funded by the Wolfson Foundation, through the Royal College of Physicians. This work was supported by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06) held by D.J.M. The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office or the Wolfson Foundation. The funders did not have any role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. None of the authors has any conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A

Background and Purpose- We aimed to determine individual and combined effects of atrial fibrillation (AF) and heart failure (HF) on acute ischemic stroke outcomes: in-hospital mortality, length-of-stay, and poststroke disability; long-term mortality and stroke recurrence. Methods- Prospective cohort study of patients with acute ischemic stroke admitted to a UK center with a catchment population of ≈900 000 between 2004 and 2016. Exposure groups were patients with neither AF nor HF (reference group), those with AF but without HF, those with HF but without AF, and those with AF+HF. Logistic and Cox regressions were used to model in-hospital and long-term outcomes, respectively. Results- A total of 10 816 patients with a mean age±SD =77.9±12.1 years, 48% male were included. Only 30 (4.9%) of the patients with HF but not AF were anticoagulated at discharge. Both AF (odds ratio, 1.24 [95% CI, 1.07-1.43]), HF (odds ratio, 1.40 [1.10-1.79]), and their combination (odds ratio, 2.23 [1.83-2.72]) were associated with increased odds of in-hospital mortality. All 3 exposure groups were associated with increased length-of-stay, while only AF predicted increased disability (1.36 [1.12-1.64]). Patients were followed for a median of 5.5 and 3.7 years for mortality and recurrence, respectively. Long-term mortality was associated with AF (hazard ratio, 1.45 [95% CI, 1.33-1.59]), HF (2.07 [1.83-2.36]), and their combination (2.20 [1.96-2.46]). Recurrent stroke was associated with AF 1.50 (1.26-1.78), HF (1.33 [1.01-1.75]), and AF with HF (1.62 [1.28-2.07]). Conclusions- The AF-associated excess risk of stroke recurrence was independent of comorbid HF. HF without AF was also associated with a significant risk of recurrence. Anticoagulation for secondary stroke prevention in patients with HF without AF may require further evaluation in a clinical trial setting.

Objectives: To determine the risk factor profiles associated with post-acute ischaemic stroke (AIS) myocardial infarction (MI) over long-term follow-up. Methods: This observational study includes prospectively identified AIS patients (n=9840) admitted to a UK regional centre between January 2003-December 2016 (median follow-up: 4.72 years). Predictors of post-stroke MI during follow up were examined using logistic and Cox regression models for in-hospital and post-discharge events, respectively. MI incidence was determined using a competing risk non-parametric estimator. The influence of post-stroke MI on mortality was examined using Cox regressions. Results: Mean age (SD) of study participants was 77.3(12.2) years (48% males). Factors associated with in-hospital MI (OR(95%CI)) were increasing blood glucose (1.80(1.17-2.77) per 10mmol/L), total leukocyte count (1.25(1.01-1.54) per 10x109/L), and CRP (1.05(1.02-1.08) per 10mg/L increase). Age (HR(95%CI) =1.03(1.01-1.06)), coronary heart disease (1.59(1.01-2.50)), chronic kidney disease (2.58(1.44-4.63)), and cancers (1.76(1.08-2.89)) were associated with incident MI between discharge and one year follow-up. Age ((1.02(1.00-1.03)), diabetes (1.96(1.38-2.65)), congestive heart failure (2.07(1.44-2.99), coronary heart disease (1.81(1.31-2.50)), hypertension (1.86(1.24-2.79)), and peripheral vascular disease (2.25(1.40-3.63)) were associated with incident MI between 1-5 years after discharge. Diabetes (2.01(1.09-3.72)), hypertension (3.69(1.44-9.45)), and peripheral vascular disease (2.46(1.02-5.98)) were associated with incident MI between 5-10 years after discharge. Cumulative MI incidence over 10 years was 5.4%. MI during all follow-up periods (discharge-1 year, 1-5 years, 5-10 years) was associated with increased risk of death (respective HR(95%CI)=3.26(2.51-4.15), 1.96(1.58-2.42) and 1.92(1.26-2.93)). Conclusions: In conclusion, prognosis is poor in post-stroke MI. We highlight a range of potential areas to focus preventative efforts.

Our paper presents two clinical prediction models that estimate the chance of having a baby over multiple complete cycles of in vitro fertilisation (IVF)—that is, cumulative live birth.1 The pretreatment model predicts the chance of cumulative live birth before treatment starts, and the post-treatment model predicts the chance of cumulative live birth just after the first embryo transfer. Through a collaboration with researchers from the University of Utrecht, who have externally validated these models, we have decided to revise the method used to assess the discriminatory ability of our models in the original study. In time to event models, such as ours, discrimination indicates the proportion of all pairs of women who can be ordered such that the woman with the lower predicted chance of live birth is the one who either did not have a live birth or had more complete cycles of IVF to have a live …

Infertility is defined as failure to conceive after 1 year of unprotected intercourse. This dichotomization into fertile versus infertile, based on lack of conception over 12-month period, is fundamentally flawed. Time to conception is strongly influenced by factors such as female age and whilst a minority of couples have absolute infertility (sterility), many are able to conceive without intervention but may take longer to do so, reflecting the degree of subfertility. This natural variability in time to conception means that subfertility reflects a prognosis rather than a diagnosis. Current clinical prediction models in fertility only provide individualized estimates of the probability of either treatment-independent pregnancy or treatment-dependent pregnancy, but do not take account of both. Together, prognostic factors which are able to predict natural pregnancy and predictive factors of response to treatment would be required to estimate the absolute increase in pregnancy chances with treatment. This stratified medicine approach would be appropriate for facilitating personalized decision-making concerning whether or not to treat subfertile patients. Published models are thus far of little value for decisions regarding when to initiate treatment in patients who undergo a period of, ultimately unsuccessful, expectant management. We submit that a dynamic prediction approach, which estimates the change in subfertility prognosis over the course of follow-up, would be ideally suited to inform when the commencement of treatment would be most beneficial in those undergoing expectant management. Further research needs to be undertaken to identify treatment predictive factors and to identify or create databases to allow these approaches to be explored. In the interim, the most feasible approach is to use a combination of previously published clinical prediction models.

Concern about calcium supplements, and mainly minor side effects (e.g. constipation) impacting on compliance, means that assessing dietary calcium intake is important. There is no suitable biomarker. Compared to food diaries, a short questionnaire was an efficient way of confirming that patients had adequate calcium intakes (>700 or >1,000 mg) Calcium is usually given alongside treatments for osteoporosis, but recent concerns about potential side effects have led to questioning whether supplements are always necessary. It is difficult to assess calcium intake in a clinical setting and be certain that the patient is getting enough calcium. The aim of this study was to determine whether a short questionnaire for estimating dietary calcium intakes in a clinical setting was fit for purpose. We assessed dietary calcium intakes using a short questionnaire (CaQ) in patients attending an osteoporosis clinic (n = 117) and compared them with calcium intakes obtained from a 7-day food diary (n = 72) and a food frequency questionnaire (FFQ) (n = 33). Mean (SD) daily calcium intakes from the CaQ were 836 (348) mg; from the diaries, 949 (384) mg; and from the FFQ, 1,141 (387) mg. The positive predictive value (PPV) was >80 % for calcium cut-offs > 700 mg and 70 % for cut-offs > 1,000 mg. The calcium intakes for the false positives results were not far below the cut-off. For 1,200 mg, the PPV was 67 % or less. The CaQ is an adequate tool for assessing whether a patient has daily calcium intakes above 700 or 1,000 mg; if below these cut-offs, it is possible that the patient still has enough calcium in the diet, which could be clarified by questioning the patient further. As there were few patients with calcium intakes above 1,200 mg a day, the CaQ cannot be recommended as a tool for confirming higher dietary calcium intakes.

Background Reducing readmissions is an international priority in healthcare. Acute kidney injury (AKI) is common, serious and also a global concern. This analysis evaluates AKI as a candidate risk factor for unplanned readmissions and determines the reasons for readmissions. Methods GLOMMS-II is a large population cohort from one health authority in Scotland, combining hospital episode data and complete serial biochemistry results through data-linkage. 16453 people (2623 with AKI and 13830 without AKI) from GLOMMS-II who survived an index hospital admission in 2003 were used to identify the causes of and predict readmissions. The main outcome was “unplanned readmission or death” within 90 days of discharge. In a secondary analysis, the outcome was limited to readmissions with acute pulmonary oedema. 26 candidate predictors during the index admission included AKI (defined and staged 1–3 using an automated e-alert algorithm), prior AKI episodes, baseline kidney function, index admission circumstances and comorbidities. Prediction models were developed and assessed using multivariable logistic regression (stepwise variable selection), C statistics, bootstrap validation and decision curve analysis. Results Three thousand sixty-five (18.6%) patients had the main outcome (2702 readmitted, 363 died without readmission). The outcome was strongly predicted by AKI. Multivariable odds ratios for AKI stage 3; 2 and 1 (vs no AKI) were 2.80 (2.22–3.53); 2.23 (1.85–2.68) and 1.50 (1.33–1.70). Acute pulmonary oedema was the reason for readmission in 26.6% with AKI and eGFR

Objective: Sex hormone binding globulin (SHBG) is a marker of insulin resistance. Given established links between BMI and socioeconomic disadvantage, we investigated how SHBG varies by index of multiple deprivation (IMD). Research Design and Methods: Using laboratory data from a Midlands UK population of mixed ethnicity, we examined the relation between blood concentrations of SHBG and IMD in 1160 women aged between 17 and 71 years. Women with a serum SHBG >250 nmol/L were excluded. Results: Mean age was 28.7 (95% confidence interval (CI) 28.2-29.1) years. 48.2% of women were of Caucasian origin, 15.5% of Southern Asian ethnicity and 2.6% were of African or other origin (33.7% were of unknown origin). SHBG increased with age (Spearman’s ρ=0.195; p

A randomised controlled trial of substance misuse indicated that many patients who use methadone have respiratory symptoms and/or are prescribed respiratory medications. There is little research in this area. To determine the prevalence of respiratory disease and prescriptions among drug misusers. This historical cohort study of drug misusers and matched controls analysed routinely collected primary care data. The prevalence of common chronic respiratory diseases, class and number of respiratory medications were examined. The cohort of 18,570 patients (9,285 per group) was mostly male (64%, n=11,890) and aged 31–59 years (76%, n=14,060). After adjusting for age, gender, deprivation and smoking status, the results showed that more drug misusers than controls had a diagnosis of asthma or chronic obstructive pulmonary disease (17.1% vs. 10.9%; adjusted odds ratio (OR) 1.61, 95% confidence interval (CI) 1.46 to 1.77, and 2.4% vs. 0.8%; OR 1.86, 95% CI 1.42 to 2.44, respectively) and were prescribed more chronic respiratory medications: short-acting β2-agonists (16.4% vs. 7.9%; OR 2.00, 95% CI 1.80 to 2.22), long-acting β2-agonists (1% vs. 0.4%; OR 1.93, 95% CI 1.29 to 2.89), and inhaled corticosteroids (10.6% vs. 7.6%; OR 1.49, 95% CI 1.33 to 1.67). All differences were statistically significant (p

Please cite this paper as: Scotland G, McLernon D, Kurinczuk J, McNamee P, Harrild K, Lyall H, Rajkhowa M, Hamilton M, Bhattacharya S. Minimising twins in in vitro fertilisation: a modelling study assessing the costs, consequences and cost–utility of elective single versus double embryo transfer over a 20-year time horizon. BJOG 2011;118:1073–1083. Objectives To assess the cumulative costs and consequences of double embryo transfer (DET) or elective single embryo transfer (eSET) in women commencing in vitro fertilisation (IVF) treatment aged 32, 36 and 39 years. Design Microsimulation model. Setting Three assisted reproduction centres in Scotland. Sample A total of 6153 women undergoing treatment at one of three Scottish IVF clinics, between January 1997 and June 2007. Methods A microsimulation model, populated using data inputs derived from a large clinical data set and published literature, was developed to compare the costs and consequences of using eSET or DET over multiple treatment cycles. Main outcome measures Disability-free live births; twin pregnancy rate; women’s quality-adjusted life-years (QALYs); health service costs. Results Not only did DET produce a higher cumulative live birth rate compared with eSET for women of all three ages, but also a higher twin pregnancy rate. Compared with eSET, DET ranged from costing an additional £27 356 per extra live birth in women commencing treatment aged 32 years, to costing £15 539 per extra live birth in 39-year-old women. DET cost ∼£28 300 and ∼£20 300 per additional QALY in women commencing treatment aged 32 and 39 years, respectively. Conclusions Considering the high twin pregnancy rate associated with DET, coupled with uncertainty surrounding QALY gains, eSET is likely to be the preferred option for most women aged ≤36 years. The cost-effectiveness of DET improves with age, and may be considered cost-effective in some groups of older women. The decision may best be considered on a case-by-case basis for women aged 37–39 years.

Purpose To describe the characteristics of patient reporters to the UK's Yellow Card Scheme (YCS) and the suspect drugs reported, and to determine patient views and experiences of making a Yellow Card report. Methods A questionnaire was developed for distribution by the Medicines and Healthcare products Regulatory Agency (MHRA) to all patients reporting through the YCS between March 2008 and January 2009. Associations between reporting method (online, postal and telephone) and questionnaire responses were examined using Pearson's Chi-squared test. Results Evaluable questionnaires were returned by 1362 out of 2008 reporters (68%). Respondents' median (IQR) age was 56.5 (43.0, 67.0) years, 910 (66.8%) were female, 1274 (93.5%) were white and 923 (67.8%) had at least a further education qualification. The most frequent reporting method was postal (59.8%), followed by online (32.8%) and telephone (6.3%). Online reporters were younger with a higher education level than those using other reporting methods. Most respondents, 1274 (93.6%), thought that the report was fairly or very easy to complete, although many identified the need for improvements to the system. One third (n = 448; 32.9%) expected feedback from the MHRA and 828 (60.8%) would have liked feedback. Almost all respondents (n = 1302; 95.6%) would report again. Conclusions The majority of patients found the current methods of reporting suspected ADRs easy to use and would recommend them to others. Different methods of reporting were used by different demographic subgroups of reporters. Improvements to the system, including the provision of feedback to reporters, could be made. Copyright © 2011 John Wiley & Sons, Ltd.

In the UK, spontaneous reporting of suspected adverse drug reactions (ADRs) by healthcare professionals has been in operation since 1964 through the Yellow Card Scheme (YCS). From 2005, patients themselves have been able to submit Yellow Card reports.To compare patient characteristics, suspected drugs and suspected ADRs reported by patients with those reported by healthcare professionals using the YCS.Retrospective observational study in the UK.Participants were patients reported to the Medicines and Healthcare products Regulatory Agency (MHRA), either by themselves, a representative or a healthcare professional, as having one or more suspected ADRs between October 2005 and September 2007. The main outcome measures were ADRs and time taken to report.In total, 26 129 Yellow Card reports from patients and healthcare professionals were received from the MHRA for the 2-year study period (19.8% patient and 80.2% healthcare professional). More Yellow Card reports were made for female than male patients (p0.001). Patients reported a significantly higher number of suspected ADRs per report than healthcare professionals (median [interquartile range {IQR}] of 3 [2-5] vs 2 [1-3], respectively; p0.001). A higher proportion of patient reports (16.1%) contained more than one suspect drug than healthcare professional reports (9%; p0.001). Healthcare professional reports had a higher proportion of ADRs that caused hospitalization (18.8% vs 12.9%), were life threatening (11.1% vs 6.2%) or caused death (2.6% vs 0.7%) than patient reports (all p0.001). Patient reporters took a significantly longer time to report their reaction than healthcare professionals (median [IQR] of 104 [27-463] vs 28 [13-75] days respectively; p0.001). Direct comparisons of the seriousness of the ADRs were not possible because of important differences between patient and healthcare professional versions of the Yellow Cards.This is the first substantial, published study in the UK to compare Yellow Card reports from patients and healthcare professionals. Whilst patients report more suspected ADRs to more suspect drugs than healthcare professionals, healthcare professionals tend to report more serious reactions that result in hospitalization, are life threatening or cause death. Further research is required to investigate the extent to which the extra information from patient reporters contributes to signal identification when assessing drug safety.

The McGrath Series 5 videolaryngoscope might reduce the incidence of unexpected difficult tracheal intubation. If it also performs as well as a standard laryngoscope during uncomplicated intubations, there would be an argument for the McGrath to become the laryngoscope of choice in higher risk settings, such as rapid sequence induction by inexperienced anaesthetists. Therefore, we compared the McGrath and the Macintosh laryngoscopes during routine tracheal intubation performed by inexperienced anaesthetists.Single-blind randomized controlled trial with 120 adult patients allocated to intubation by first-year anaesthetic trainees, using a McGrath or Macintosh laryngoscope. The primary outcome was time to intubation. Secondary outcomes were quality of view at laryngoscopy and evidence of differential learning between using the two laryngoscopes. A Cox proportional hazards model was used to determine the effect of the laryngoscopes on time to intubation.Duration of intubation was significantly longer (P0.001) in the McGrath group [median (IQR); 47.0 (39.0-60.0) vs 29.5 (23.0-36.8) s]. There were no significant differences in other outcomes, including grade of laryngoscopy view, visual confirmation of tube placement, number of laryngoscopies, or complications (oesophageal intubation, hypoxaemia, and airway trauma). There was no differential learning effect.There were no advantages to using the McGrath laryngoscope for uncomplicated tracheal intubation and duration of intubation was longer, so it should not be used as a first-line laryngoscope instrument by inexperienced anaesthetists.

Background: patients who present with abnormal liver function tests (LFTs) in primary care and no obvious symptoms can be difficult to manage. Objective: the objective is to follow-up a cohort of liver function tested patients to determine their outcome. Methods: this population-based retrospective cohort study was conducted in Tayside, Scotland, from 1989 to 2003. Subjects were patients with no clinically obvious liver disease at initial liver function testing in primary care. Main outcomes were diagnosed liver disease and mortality. Record linkage of databases ascertained risk factors and outcomes. Measures of performance were calculated and Weibull regression analysis from initial LFT date was performed on all outcomes by level of abnormality. Results: in total, 95 977 patients had 364 194 incident initial LFTs, with median follow-up 3.7 years. A total of 21.7% had at least one abnormal LFT and 1108 (1.15%) developed liver disease. Elevated transaminase was strongly associated with diagnosed liver disease, hazard ratio (HR) = 4.23 (95% confidence interval 3.55, 5.04) for mild levels and HR = 12.67 (95% CI 9.74, 16.47) for severe levels versus normal. For gamma-glutamyl transferase, these hazards were 2.54 (95% CI 2.17, 2.96) and 13.44 (95% CI 10.71, 16.87), respectively. Low albumin was strongly associated with all-cause mortality, HR = 2.65 (95% CI 2.47, 2.85) for mild levels and HR = 4.99 (95% CI 4.26, 5.84) for severe levels. Sensitivity for predicting events over 5 years was low and specificity high. Conclusions: all LFTs were predictive markers for liver disease as well as general ill health, although sensitivity was poor. Most patients with abnormal LFTs had no later formal diagnosis of liver disease within the study period. The time taken to develop liver disease in these patients provides opportunity to intervene

Objectives. Health-state utilities are essential for cost-utility analysis. Few estimates exist for liver disease in the literature. The authors' aim was to conduct a systematic review of health-state utilities in liver disease, to look at the variation of study designs used, and to pool utilities for some liver disease states. Methods. A search of MED-LINE, EMBASE, and CINAHL from 1966 to September 2006 was conducted including key words related to liver disease and utility measuring tools. Articles were included if health-state utility tools or expert opinion were used. Variance-weighted mean utility estimates were pooled using metaregression adjusting for disease state and utility assessment method. Results. Thirty studies measured utilities of liver diseases/disease states. Half of these estimated utilities for hepatitis viruses: hepatitis A (n = 1), hepatitis B (n = 4), and hepatitis C (n = 10). Others included liver transplant (n= 6) and chronic liver disease (n= 5) populations. Twelve utility methods were used throughout. The EQ-5D (n = 10) was most popular method, followed by visual analogue scale (n = 9), time tradeoff (n = 6), and standard gamble (n = 4). Respondents were patients (n= 16), an expert panel (n = 10), non— liver diseases adults ( n= 2), patient and expert (n = 1), and patient and healthy adult (n = 1). Type of perspective included community (n= 21), patient (n= 4), and both (n = 5). The pooled mean estimates in hepatitis C with moderate disease, compensated cirrhosis, decompensated cirrhosis, and post— liver transplant using the EQ-5D were 0.75, 0.75, 0.67, and 0.71, respectively. The change in these utilities using different methods were - 0.07 (visual analogue scale), - 0.01 (health utilities index version 3), + 0.04 (standard gamble), + 0.08 (health utilities index version 2), + 0.12 (time tradeoff), and + 0.15 (standard gamble— transformed visual analogue scale). Conclusions. The authors have created a valuable liver disease— based utility resource from which researchers and policy makers can easily view all available utility estimates from the literature. They have also estimated health-state utilities for major states of hepatitis C.

Objective To develop a prediction model to estimate the chances of a live birth over multiple complete cycles of in vitro fertilisation (IVF) based on a couple’s specific characteristics and treatment information.\ud \ud Design Population based cohort study.\ud \ud Setting All licensed IVF clinics in the UK. National data from the Human Fertilisation and Embryology Authority register.\ud \ud Participants All 253 417 women who started IVF (including intracytoplasmic sperm injection) treatment in the UK from 1999 to 2008 using their own eggs and partner’s sperm.\ud \ud Main outcome measure Two clinical prediction models were developed to estimate the individualised cumulative chance of a first live birth over a maximum of six complete cycles of IVF—one model using information available before starting treatment and the other based on additional information collected during the first IVF attempt. A complete cycle is defined as all fresh and frozen-thawed embryo transfers arising from one episode of ovarian stimulation.\ud \ud Results\ud After exclusions, 113 873 women with 184 269 complete cycles were included, of whom 33 154 (29.1%) had a live birth after their first complete cycle and 48 925 (43.0%) after six complete cycles. Key pretreatment predictors of live birth were the woman’s age (31 v 37 years; adjusted odds ratio 1.66, 95% confidence interval 1.62 to 1.71) and duration of infertility (3 v 6 years; 1.09, 1.08 to 1.10). Post-treatment predictors included number of eggs collected (13 v 5 eggs; 1.29, 1.27 to 1.32), cryopreservation of embryos (1.91, 1.86 to 1.96), the woman’s age (1.53, 1.49 to 1.58), and stage of embryos transferred (eg, double blastocyst v double cleavage; 1.79, 1.67 to 1.91). Pretreatment, a 30 year old woman with two years of unexplained primary infertility has a 46% chance of having a live birth from the first complete cycle of IVF and a 79% chance over three complete cycles. If she then has five eggs collected in her first complete cycle followed by a single cleavage stage embryo transfer (with no embryos left for freezing) her chances change to 28% and 56%, respectively.\ud \ud Conclusions This study provides an individualised estimate of a couple’s cumulative chances of having a baby over a complete package of IVF both before treatment and after the first fresh embryo transfer. This novel resource may help couples plan their treatment and prepare emotionally and financially for their IVF journey.

Objectives: To determine the operating characteristics of prostate-specific antigen (PSA) testing and prostate cancer diagnosis rates in men who have had an initial PSA test in Tayside. Setting: A retrospective cohort study in Tayside, Scotland from 1992 to 2001. Methods: In total, 20,623 men were PSA tested during the period 1992–2001. After exclusions, 19,660 were studied. Sensitivity and specificity were calculated for various PSA cut-off values by age group using logistic regression weighted for verification bias (biopsy). Cox regression analysis was performed using six test pattern cohorts. Results: The annual rate of PSA testing increased from 5.1 per 1000 man years in 1992 to 21.3 per 1000 man years in 2001. The average number of PSA tests per patient increased from 1.11 in 1992 to 2.57 in 2001. Prostate cancer diagnosis and death rates remained constant from 1995 onward. The PSA test had generally inadequate sensitivity and specificity values, so a unique cut-off could not be found for the two older age groups which could be used as a recommendation for biopsy. The commonly used 4 ng/mL cut-off was reasonably sensitive and specific only for the under 60 age group with values of 92.4% and 90.7%, respectively. For prostate cancer diagnosis, the hazard ratios (HR) were reported relative to those with a series of all normal tests. For those with an initially normal PSA test who had at least one abnormal retest result the HR for diagnosis was 10.43 (95% confidence interval [CI] 6.17–17.63). For those with initially abnormal tests with normal retests HR = 1.63 (95% CI 0.65–4.07). Conclusions: There are no optimal PSA cut-off values for older age groups with which to make a confident referral for biopsy. The increase in PSA testing and the questionable cut-off values of the test calls for the development of an alternative screening strategy.

AIMS This paper describes the process of validating the Readiness for Interprofessional Learning Scale (RIPLS) for use with postgraduate health care professionals. CONTEXT The RIPLS questionnaire has proved useful in the undergraduate context, enabling tutors to assess the readiness of students to engage in interprofessional learning (IPL). With the drive in the National Health Service (NHS) to deliver health care in interprofessional teams, it seems logical to ask whether postgraduate education should, or could, be delivered successfully in interprofessional contexts. As a preliminary to undertaking an extended IPL project, the researchers tested the validity of the RIPLS tool in the postgraduate health care context. METHOD A modified version of the RIPLS questionnaire was administered to all general practitioners, nurses, pharmacists and allied health professionals in the Dundee Local Health Care Cooperative (LHCC) (n = 799). A total of 546 staff responded (68%). RESULTS Three factors, comprising 23 statements, emerged from the statistical analysis of the survey data, namely, teamwork and collaboration, sense of professional identity and patient-centredness. The internal consistency measure was 0.76. Analysis of variance suggested some key differences between the different professions in respect of the factors. CONCLUSIONS The RIPLS questionnaire was validated for use in the postgraduate context, thus providing researchers with a tool for assessing health professionals' attitudes towards interprofessional learning at practice level, community health partnership level or at a national level of education and training. Significant differences between professional groups should be taken into account in designing any interprofessional learning programme.

Digital self-tracking is rising, including tracking of menstrual cycles by women using fertility tracking apps (FTAs). However, little is known about users’ experiences of FTAs and their relationships with them. The aim of this study was to explore women’s uses of and relationships with FTAs. This exploratory study employed a mixed methods approach, involving the collection and analysis of an online survey and follow-up interviews. Qualitative analysis of survey and interview data informed hypothesis development. Online surveys yielded 241 responses and 11 follow-up interviews were conducted. Just over a third of women surveyed had experience of using FTAs (89/241) and follow-up interviews were conducted with a proportion of respondents (11/241). Four main motivations to use FTAs were identified: (a) to observe cycle (72%); (b) to conceive (34%); (c) to inform fertility treatment (12%); and (d) as contraception (4%). Analysis of the free-text survey questions and interviews using grounded theory methodology highlighted four themes underpinning women’s relationships with FTAs: (a) medical grounding; (b) health trackers versus non-trackers; (c) design; and (d) social and ethical aspects. Participants who used other health apps were more likely to use FTAs ( p = 0.001). Respondents who used contraception were less likely to use FTAs compared with respondents who did not use contraception ( p = 0.002). FTA usage also decreases ( p = 0.001) as age increases. There was no association between FTA usage and menstrual status ( p = 0.259). This research emphasises the differing motivations for FTA use. Future research should further explore the diverse relationships between different subgroups of women and FTAs.

© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. STUDY QUESTION: What is the impact of different age and BMI groups on total investigation and treatment costs in women attending a secondary/tertiary care fertility clinic? summary answer: Women in their early to mid-30s and women with normal BMI had higher cumulative investigation and treatment costs, but also higher probability of live birth. WHAT IS KNOWN ALREADY: Female age and BMI have been used as criteriafor rationing publically funded fertility treatments. Populationbased data on the costs of investigating and treating infertility are lacking. study design, size an d duration: A retrospective cohort study of 2463 women was conducted in a single secondary/tertiary care fertility clinic in Aberdeen, Scotland from 1998 to 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included all women living in a defined geographical area referred from primary care to a specialized fertility clinic over an 11-year period. Women were followed up for 5 years or until live birth if this occurred sooner. Mean discounted cumulative National Health Service costs (expressed in 2010/2011 GBP) offertility investigations, treatments (including all types of assisted reproduction), and pregnancy (including delivery episode) and neonatal admissions were calculated and summarized by age ( 35.00kg/m). Further multivariate modelling was carried out to estimate the impact of age and BMI on investigation and treatment costs and live birth outcome, adjusting for covariates predictive of the treatment pathway and live birth. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 2463 women referred, 1258 (51.1%) had a live birth within 5 years, with 694 (55.1%) of these being natural conceptions. The live birth rate was highest among women in the youngest age group (64.3%), and lowest in those aged.40 years (13.4%). Overall live birth rates were generally lower in women with BMI.30 kg/m.The total costs of investigations were generally highest among women younger than 30 years (£491 in those with normal BMI),whilsttreatmentcoststendedtobehigherin31-35 year olds (£1,840 in those with normal BMI). Multivariate modelling predicted a cost increase associated with treatment which was highest among women in the lowest BMI group (across all ages), and also highest among women aged 31-35 years. The increase in the predicted probability of live birth with exposure to treatment was consistent across age and BMI categories (∼ 10%), except in the oldest age group where a slightly smaller increase in the probability of live birth was observed. The ratio of increased costs to the increased probability of live birth in women who were treated increased markedly in women over the age of 40 years, but tended to fall as BMI increased within all age groups. limitations and reason for caution: Our results, based on retrospective observational data from a single centre, have limited generalizability and are not free from clinician and clinic selection bias which can influence the choice of treatments as well as their costs. WIDER IMPLICATIONS OF THE FINDINGS: Spontaneous live birth rates were particularly high in younger women with unexplained infertility, suggesting that expectant management is a reasonable option in this group. The policy of not over-investigating older women and offering early treatment where appropriate still incurred the highest costs per additional live birth associated with treatment, owing to the lower probability of treatment success. The increased additional cost for each live birth associated with treatment for women with decreasing BMI across all age groups, suggests that it may be possible to identify a more targeted approach to treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was partly funded by an NHS endowment grant (Grant Number 12/48) and D.J.M. by a Chief Scientist Office Postdoctoral Fellowship (Ref PDF/12/06). There are no conflicts of interest to declare.

This work was supported by the UK National Health Service Research & Development Programme Health Technology Assessment Programme (project number 03/38/02) and also by the Backett Weir Russell Career Development Fellowship, University of Aberdeen. OBJECTIVE: To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. DESIGN: Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. SETTING: Primary care, Tayside, Scotland. PARTICIPANTS: Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosis of a liver condition within 2 years. RESULTS: From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20-30% for high-risk patients. CONCLUSIONS: This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk. Publisher PDF