A multicentre survey investigating the knowledge, behaviour, and attitudes of surgical healthcare professionals to frailty assessment in emergency surgery: DEFINE(surgery).

PURPOSE: Screening for frailty in people admitted with emergency surgical pathology can initiate timely referrals to enhanced perioperative services such as intensive care and geriatric medicine. However, there has been little research exploring surgical healthcare professionals' opinions to frailty assessment, or accuracy in identification. This study aimed to assess the knowledge, behaviour, and attitudes of healthcare professionals to frailty assessment in emergency surgical admissions. METHODS: We designed a cross-sectional multicentre study developed by a multiprofessional team of surgeons, geriatricians, and supported by patients. A semi-structured survey examined attitudes and behaviours. Knowledge was assessed by comparing respondents' accuracy in scoring twenty-two surgical case vignettes using the Clinical Frailty Scale. RESULTS: Eleven hospitals across England, Wales, and Scotland participated. Two hundred and eleven clinicians responded-20.4% junior doctors, 43.6% middle grade doctors, 24.2% senior doctors, 11.4% nurses and physician associates. Respondents strongly supported perioperative frailty assessment. Most were already assessing for frailty, although frequently not using a standardised tool. There was a strong call for more frailty education. Participants scored 2175 vignettes with 55.4% accurately meeting the gold standard; accuracy improved to 87.3% when categorised into "not frail/mildly frail/severely frail" and 94% when dichotomised to "not frail/frail". CONCLUSION: Frailty assessment is well supported by healthcare professionals working in surgery. However, standardised tools are not routinely being used, and only half of respondents could accurately identify frailty. Better education around frailty assessment is needed for healthcare professionals working in surgery to improve perioperative pathway for people living with frailty.

The National Emergency Laparotomy Audit and older people living with frailty.

The National Emergency Laparotomy Audit highlighted that older people living with frailty have poorer outcomes from emergency laparotomies. This editorial discusses some improvements in care that are needed to improve outcomes in this group of patients.

Increased care at discharge from COVID-19: The association between pre-admission frailty and increased care needs after hospital discharge; a multicentre European observational cohort study.

BACKGROUND: The COVID-19 pandemic has placed significant pressure on health and social care. Survivors of COVID-19 may be left with substantial functional deficits requiring ongoing care. We aimed to determine whether pre-admission frailty was associated with increased care needs at discharge for patients admitted to hospital with COVID-19. METHODS: Patients were included if aged over 18 years old and admitted to hospital with COVID-19 between 27 February and 10 June 2020. The Clinical Frailty Scale (CFS) was used to assess pre-admission frailty status. Admission and discharge care levels were recorded. Data were analysed using a mixed-effects logistic regression adjusted for age, sex, smoking status, comorbidities, and admission CRP as a marker of severity of disease. RESULTS: Thirteen hospitals included patients: 1671 patients were screened, and 840 were excluded including, 521 patients who died before discharge (31.1%). Of the 831 patients who were discharged, the median age was 71 years (IQR, 58-81 years) and 369 (44.4%) were women. The median length of hospital stay was 12 days (IQR 6-24). Using the CFS, 438 (47.0%) were living with frailty (≥ CFS 5), and 193 (23.2%) required an increase in the level of care provided. Multivariable analysis showed that frailty was associated with an increase in care needs compared to patients without frailty (CFS 1-3). The adjusted odds ratios (aOR) were as follows: CFS 4, 1.99 (0.97-4.11); CFS 5, 3.77 (1.94-7.32); CFS 6, 4.04 (2.09-7.82); CFS 7, 2.16 (1.12-4.20); and CFS 8, 3.19 (1.06-9.56). CONCLUSIONS: Around a quarter of patients admitted with COVID-19 had increased care needs at discharge. Pre-admission frailty was strongly associated with the need for an increased level of care at discharge. Our results have implications for service planning and public health policy as well as a person's functional outcome, suggesting that frailty screening should be utilised for predictive modelling and early individualised discharge planning.

Nosocomial COVID-19 infection: examining the risk of mortality. The COPE-Nosocomial Study (COVID in Older PEople).

BACKGROUND: Hospital admissions for non-coronavirus disease 2019 (COVID-19) pathology have decreased significantly. It is believed that this may be due to public anxiety about acquiring COVID-19 infection in hospital and the subsequent risk of mortality. AIM: To identify patients who acquire COVID-19 in hospital (nosocomial COVID-19 infection (NC)) and their risk of mortality compared to those with community-acquired COVID-19 (CAC) infection. METHODS: The COPE-Nosocomial Study was an observational cohort study. The primary outcome was the time to all-cause mortality (estimated with an adjusted hazard ratio (aHR)), and secondary outcomes were day 7 mortality and the time-to-discharge. A mixed-effects multivariable Cox's proportional hazards model was used, adjusted for demographics and comorbidities. FINDINGS: The study included 1564 patients from 10 hospital sites throughout the UK, and one in Italy, and collected outcomes on patients admitted up to April 28th, 2020. In all, 12.5% of COVID-19 infections were acquired in hospital; 425 (27.2%) patients with COVID died. The median survival time in NC patients was 14 days compared with 10 days in CAC patients. In the primary analysis, NC infection was associated with lower mortality rate (aHR: 0.71; 95% confidence interval (CI): 0.51-0.98). Secondary outcomes found no difference in day 7 mortality (adjusted odds ratio: 0.79; 95% CI: 0.47-1.31), but NC patients required longer time in hospital during convalescence (aHR: 0.49, 95% CI: 0.37-0.66). CONCLUSION: The minority of COVID-19 cases were the result of NC transmission. No COVID-19 infection comes without risk, but patients with NC had a lower risk of mortality compared to CAC infection; however, caution should be taken when interpreting this finding.

Outcomes of ovarian stimulation in a two-day oocyte collection week with PGD cycles compared to a five-day oocyte collection week with conventional IVF/ICSI cycles.

We assessed the outcomes of ovarian stimulation in a two-day egg collection (EC) week with preimplantation genetic diagnosis (PGD) cycles (N = 307) compared to a five-day EC week with conventional in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles (N = 2,417). The mean (SD) age of women undergoing PGD was 34 (3.97) and 35 (3.85) for IVF/ICSI (P < 0.001), the number of oocytes collected was 13 (7.37) and 11 (7.02), (P < 0.001), while the mean (SD) number of fertilized oocytes was 8 (5.09) and 6 (4.58), respectively (P < 0.001). The clinical pregnancy rate per embryo transfer (ET) was 37% with PGD and 38% with IVF/ICSI (P = 0.49), while the implantation rate was 0.35 and 0.30, respectively (P = 0.05). After adjusting for age and confounding variables including the number of oocytes collected and fertilized normally, the mode of treatment (PGD or IVF/ICSI) had no effect on clinical pregnancy (P = 0.48). In conclusion, scheduling of PGD cycles to a two-day EC week did not compromise the outcomes of ovarian stimulation when compared to a five-day EC week with conventional IVF/ICSI cycles. This can allow the provision of a more patient friendly service, increase the flexibility of satellite PGD services, and facilitate cycle programming with the genetics team providing PGD.

Delayed blastocyst development does not influence the outcome of frozen-thawed transfer cycles.

OBJECTIVE: To compare the outcome of transfer of thawed blastocysts frozen on either day 5 or day 6 after in vitro fertilisation. DESIGN: Cohort observational study. SETTING: Tertiary assisted conception unit in London, UK. POPULATION: Six hundred and forty-two consecutive nondonor programmed thawed blastocyst transfer (TBT) cycles. METHODS: High-grade blastocysts were frozen on day 5 (n = 314) or day 6 (n = 328) after fertilisation using a slow-freezing protocol. Endometrial preparation was performed using estradiol valerate. Progesterone supplementation was commenced when the endometrial thickness had reached 7 mm or more. Frozen blastocysts were thawed on day 6 of progesterone supplementation and assessed immediately after thawing for survival, and after 3-4 hours for blastocoele re-expansion. Main outcome measures Thawed blastocyst survival and re-expansion rates, and pregnancy and live birth rates, per TBT. RESULTS: Thawed blastocyst survival and re-expansion rates were comparable between the day 5 and day 6 groups (87% versus 87%, P = 0.50 and 73% versus 71%, P = 0.35, respectively). The live birth rate was similar between the two groups (29% versus 28.5%, P = 0.93, respectively). After adjusting for confounding variables, the odds ratio (OR) of a live birth in cycles in which the thawed blastocysts were frozen on day 6 compared with day 5 was 1.23 [95% confidence interval (CI), 0.81-1.86, P = 0.34]. CONCLUSION: The pregnancy potential of high-grade blastocysts frozen on day 5 and day 6 after in vitro fertilisation and replaced in programmed TBT cycles is comparable.

ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening.

In 2005, the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium published a set of Guidelines for Best Practice PGD to give information, support and guidance to potential, existing and fledgling PGD programmes. Subsequent years have seen the introduction of new technologies as well as the evolution of current techniques. Additionally, in light of recent advice from ESHRE on how practice guidelines should be written/formulated, the Consortium believed it was timely to update the PGD guidelines. Rather than one document that covers all of PGD, the new guidelines are separated into four documents, including one relating to organization of the PGD centre and three relating to the methods used: DNA amplification, fluorescence in situ hybridization and biopsy/embryology. Here, we have updated the sections on organization of the PGD centre. One area that has continued to expand is Transport PGD, in which patients are treated at one IVF centre, whereas their gametes/embryos are tested elsewhere, at an independent PGD centre. Transport PGD/preimplantation genetic screening (PGS) has a unique set of challenges with respect to the nature of the sample and the rapid turn-around time required. PGS is currently controversial. Opinions of laboratory specialists and clinicians interested in PGD and PGS have been taken into account here. Current evidence suggests that PGS at cleavage stages is ineffective, but whether PGS at the blastocyst stage or on polar bodies might show improved delivery rates is still unclear. Thus, in this revision, PGS has been included. This document should assist everyone interested in PGD/PGS in developing the best laboratory and clinical practice possible.

A systematic review of the effect of oral antioxidants on male infertility.

The use of antioxidants in treatment of infertile men has been suggested, although the evidence base for this practice is unclear. A systematic review of randomized studies was conducted to evaluate the effects of oral antioxidants (vitamins C and E, zinc, selenium, folate, carnitine and carotenoids) on sperm quality and pregnancy rate in infertile men. MEDLINE, EMBASE, Cochrane Library and CINAHL were searched for relevant trials published from respective database inception dates to May 2009. Study selection, quality appraisal and data extraction were performed independently and in duplicate. Seventeen randomized trials, including a total of 1665 men, were identified, which differed in the populations studied and type, dosage and duration of antioxidants used. Only two-thirds of the studies (11/17) reported using allocation concealment and three studies (18%) used intention-to-treat analysis. Despite the methodological and clinical heterogeneity, 14 of the 17 (82%) trials showed an improvement in either sperm quality or pregnancy rate after antioxidant therapy. Ten trials examined pregnancy rate and six showed a significant improvement after antioxidant therapy. The use of oral antioxidants in infertile men could improve sperm quality and pregnancy rates. Adequately powered robust trials of individual and combinations of antioxidants are needed to guide clinical practice.

Development and successful clinical application of preimplantation genetic haplotyping for Herlitz junctional epidermolysis bullosa.

BACKGROUND: Herlitz junctional epidermolysis bullosa (HJEB) is a severe, life-threatening, autosomal recessive blistering skin disease for which no cure is currently available. Prenatal diagnosis for couples at risk is feasible through fetal skin biopsy or analysis of DNA extracted from chorionic villi, but these methods can be applied only after pregnancy has been established. An alternative approach, which involves the analysis of single cells from embryos prior to establishment of pregnancy, is preimplantation genetic diagnosis (PGD). Until now, its clinical uptake has been hindered by lengthy delays in establishing mutation-specific protocols, and by the small amount of template DNA that can be obtained from a single cell. A new method that addresses these problems, preimplantation genetic haplotyping (PGH), relies on whole genome amplification followed by haplotyping of multiple polymorphic markers using standard DNA-based polymerase chain reaction (PCR) assays. OBJECTIVES: To design and validate a generic PGH assay for HJEB and to transfer this into clinical practice. MATERIALS AND METHODS: We established a multiplex PCR-based PGH assay involving 16 markers within and flanking the LAMB3 gene (the most frequently mutated gene in HJEB). The assay was then validated in 10 families with at least one previously affected offspring. After licensing by the Human Fertilisation and Embryology Authority (HFEA), the new test was used for PGD in a couple at risk of HJEB. RESULTS: The chromosome 1 LAMB3 markers within the assay were shown to be of sufficient heterogeneity to have widespread application for preimplantation testing of HJEB. In one couple that were heterozygous carriers of nonsense mutations in LAMB3, we used the new assay to identify unaffected embryos in a series of PGD cycles. Pregnancy was established in the third PGD cycle and a healthy, unaffected child was born. DNA analysis of cord blood confirmed the predicted single-cell mutation status of wild-type LAMB3 alleles. CONCLUSIONS: PGH represents a major step forward in widening the scope and availability of preimplantation testing for serious mapped single-gene disorders. We have established a generic test that is suitable for the majority of couples at risk of HJEB.

First use of preimplantation genotyping in prevention of recurrent diandric complete hydatidiform mole.

Complete hydatidiform moles have a diploid chromosome constitution, generally with only paternal genetic material present (diandry). Diandric complete moles are thought to arise either by fertilization of an anucleate oocyte by two spermatozoa or, more commonly, doubling of a single sperm genotype. Molar pregnancies are usually sporadic, and may be accompanied by malignant transformation; however, recurrence is associated with increased risk of further affected pregnancies and of persistent trophoblastic neoplasia or choriocarcinoma. This study presents the first use of preimplantation genotyping to ensure biparental inheritance in a woman presenting with recurrent diandric complete hydatidiform mole. Following an IVF cycle, a single cell from each of 11 embryos was tested by whole genome amplification and genotyping at 16 different simple tandem repeat loci. All embryos showed normal biparental inheritance; one blastocyst was transferred, resulting in the delivery of healthy monozygotic twin girls.

Creation of a registry for human embryonic stem cells carrying an inherited defect: joint collaboration between ESHRE and hESCreg.

Human embryonic stem cells (hESCs), derived from human blastocysts, hold a great promise for regenerative medicine, drug development and basic research in developmental biology. Moreover, hESC lines that carry a clinically relevant inherited defect, monogenic or chromosomal, present an important tool for research into the pathophysiology of these diseases. The hESC registry (hESCreg) was started up in 2007 in order to register all stem cell lines derived in Europe (www.hescreg.eu). Because of the special nature of the hESC lines that carry an inherited disease, they are of particular interest to researchers outside the assisted reproductive technologies or stem cell fields, for instance, those involved in regenerative medicine and in medical and human genetics. To reach these researchers, and to better disseminate the information on the cell lines, a concerted action of the hESCreg together with ESHRE's Special Interest Groups in Reproductive Genetics and Stem Cells was initiated. This mini-review is a first report that will be followed by yearly reports of new lines, not unlike the reports from the Preimplantation Genetic Diagnosis Consortium or the European IVF Monitoring.

Preimplantation genetic diagnosis as a source of human embryonic stem cells for disease research and drug discovery.

Embryos surplus to therapeutic requirements following preimplantation genetic diagnosis can be used to derive human embryonic stem cell (hESC) lines carrying mutations significant to human disease. These cells provide a powerful in vitro tool for modelling disease progression in a number of cell types as well as having the potential to revolutionise drug discovery. Robust and reproducible directed differentiation protocols are needed to maximise the potential of these cells. In this review, we explore the current use of hESC and induced pluripotent stem cells in disease-specific research and discuss the use of stem cell technology in drug discovery and toxicity testing.

Selective single blastocyst transfer reduces the multiple pregnancy rate and increases pregnancy rates: a pre- and postintervention study.

OBJECTIVE: To examine the clinical pregnancy rate (CPR) and multiple pregnancy rate (MPR) in a large in vitro fertilisation (IVF) programme before and after the introduction of single blastocyst transfer (SBT) strategy in a selected group of women. DESIGN: A 3-year pre- and postintervention study. SETTING: A tertiary reproductive medicine and assisted conception unit in a London teaching hospital. POPULATION: Two thousand four hundred and fifty-one fresh IVF cycles performed between July 2004 and June 2007 at the Assisted Conception Unit at Guy's and St Thomas' Hospital NHS Foundation Trust were included in the study. METHODS: In January 2006, we implemented a multidisciplinary intervention involving the introduction of a selective day 5 SBT service together with an educational programme on the risks of multiple pregnancy and potential advantages of blastocyst transfer aimed at couples at high risk of multiple pregnancy. MAIN OUTCOME MEASURES: The CPR per cycle started and MPR per clinical pregnancy achieved. RESULTS: A statistically significant increase in the CPR from 27% (324/1198) to 32% (395/1253) (risk difference [RD] 5%, risk ratio [RR] 1.17, 95% CI 1.03-1.32, P= 0.015) and reduction in the MPR per clinical pregnancy from 32% (103/272) to 17% (69/395) (RD 15%, RR 0.46, 95% CI 0.35-0.60, P < 0.001) were observed after introduction of the SBT service. CONCLUSION: Selective SBT in women with good prognosis can reduce the MPR after IVF while maintaining the overall success rate of the IVF programme.

Validity of the in vitro fertilisation league tables: influence of patients' characteristics.

We tested the hypothesis that restricting comparison of the live birth rate following in vitro fertilisation (IVF) treatment in those couples having their first IVF cycle in whom the female is under 35 years of age and has a normal follicle-stimulating hormone level would improve the validity of comparing IVF clinics' success rates. We analysed all cycles performed over a 2-year period in patients who fulfilled these criteria and divided the study population according to the referring primary care trusts: group A (n = 90) were referred from Lambeth, Southwark and Lewisham and group B (n = 134) were referred from Brent and Harrow. There was no significant difference between the two groups with regard to their IVF cycle characteristics. The two groups differed in their ethnicity, cause of infertility, prevalence of uterine fibroids and smoking and alcohol consumption habits. Group A had a significantly lower live birth rate (OR = 0.45, 95% CI 0.21-0.95, P = 0.02) compared with group B. This study confirms the impact of the non-IVF-related patient characteristics on treatment outcome and the poor validity of comparing IVF clinics' success rates based on the sparse data published by national IVF registries.

Assisted hatching is more effective when embryo quality was optimal in previous failed IVF/ICSI cycles.

Assisted hatching (AH) was developed as a possible solution to repeated implantation failure. The aim of this analysis was to examine the relationship between the morphology of embryos in a previous cycle on outcome in a subsequent cycle with AH. A total of 175 AH cycles performed after previous failed ART without hatching were divided into group A with optimal and group B with suboptimal embryos transferred previously. The groups were similar in terms of demographic and cycle characteristics. In group A, there was a significant improvement (p<0.001) in implantation (28.8 vs 5.1%), clinical pregnancy (41.9 vs 12.1%) and live birth rate (38.5 vs 8.6%) compared with group B. The data suggest that the prognosis for treatment is better if AH is performed after failure despite optimal embryos compared with failure associated with suboptimal embryos and embryo quality is the most significant factor affecting outcome.

Three hundred and thirty cycles of preimplantation genetic diagnosis for serious genetic disease: clinical considerations affecting outcome.

OBJECTIVE: To report on our experience with preimplantation genetic diagnosis (PGD) cycles performed for serious genetic disease in relation to the clinical factors affecting outcome. DESIGN: Retrospective review of data from a single centre. SETTING: Tertiary referral PGD centre in a London teaching hospital. METHODS: The PGD cycles included 172 cycles for chromosome rearrangements, 96 cycles for single-gene disorders and 62 cycles for X-linked disorders. In vitro fertilisation was the preferred method in chromosome rearrangement and X-linked cases, while intra cytoplasmic sperm injection was used in all single-gene disorders. Appropriate in situ hybridisation fluorescence probes were used in chromosome rearrangement and X-linked cases and polymerase chain reaction was used in single-gene disorders. All pregnancies were followed till delivery. MAIN OUTCOME MEASURE: Live birth rate per PGD cycle started. RESULTS: Eighty-six percent of cycles started (283) reached oocyte retrieval and 3743 eggs were collected, of which 2086 fertilised normally (55.7%). Two hundred and fifty cycles (76%) had embryos sutiable for biopsy on day 3 of in vitro culture, 1714 embryos were biopsied, and in 205 cycles (62%), there was at least one unaffected embryo available for transfer, resulting in 90 pregnancies, 68 clinical pregnancies and 58 live birth. The live birth rate was 18% per cycle started, 21% per egg retrieval and 28% per embryo transfer which significantly affected the live birth outcome. Woman age, number of eggs collected and achieving cryopreservation of surplus embryos had no statistically significant effect on treatment outcome. CONCLUSIONS: The live birth outcome of PGD cycles for serious genetic disorder is modest and is affected by the number of embryos genetically suitable for transfer.