Top 10 priorities for future infertility research: an international consensus development study.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/ COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring, and being a clinical subeditor of Human Fertility. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Not applicable.

Top 10 priorities for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Concurrent beneficial (vitamin D production) and hazardous (cutaneous DNA damage) impact of repeated low-level summer sunlight exposures.

BACKGROUND: The concurrent impact of repeated low-level summer sunlight exposures on vitamin D production and cutaneous DNA damage, potentially leading to mutagenesis and skin cancer, is unknown. OBJECTIVES: This is an experimental study (i) to determine the dual impact of repeated low-level sunlight exposures on vitamin D status and DNA damage/repair (via both skin and urinary biomarkers) in light-skinned adults; and (ii) to compare outcomes following the same exposures in brown-skinned adults. METHODS: Ten white (phototype II) and six South Asian volunteers (phototype V), aged 23-59 years, received 6 weeks' simulated summer sunlight exposures (95% ultraviolet A/5% ultraviolet B, 1·3 standard erythemal doses three times weekly) wearing summer clothing exposing ~35% body surface area. Assessments made were circulating 25-hydroxyvitamin D [25(OH)D], immunohistochemistry for cyclobutane pyrimidine dimer (CPD)-positive nuclei and urinary biomarkers of direct and oxidative (8-oxo-deoxyguanosine) DNA damage. RESULTS: Serum 25(OH)D rose from mean 36·5 ± 13·0 to 54·3 ± 10·5 nmol L-1 (14·6 ± 5·2 to 21·7 ± 4·2 ng mL-1 ) in phototype II vs. 17·2 ± 6·3 to 25·5 ± 9·5 nmol L-1 (6·9 ± 2·5 to 10·2 ± 3·8 ng mL-1 ) in phototype V (P < 0·05). Phototype II skin showed CPD-positive nuclei immediately postcourse, mean 44% (range 27-84) cleared after 24 h, contrasting with minimal DNA damage and full clearance in phototype V (P < 0·001). The findings did not differ from those following single ultraviolet radiation (UVR) exposure. Urinary CPDs remained below the detection threshold in both groups; 8-oxo-deoxyguanosine was higher in phototype II than V (P = 0·002), but was unaffected by UVR. CONCLUSIONS: Low-dose summer sunlight exposures confer vitamin D sufficiency in light-skinned people concurrently with low-level, nonaccumulating DNA damage. The same exposures produce minimal DNA damage but less vitamin D in brown-skinned people. This informs tailoring of sun-exposure policies.

A simple tool to identify elderly patients with a surgically important acute subdural haematoma.

OBJECTIVES: ASDH in the elderly is a common and increasing problem, and differs in its pathophysiology from ASDH in younger people. Admitting doctors may have difficulty identifying those elderly patients whose lesions may benefit from surgery. The objective of this study was to determine whether simple neuroradiological measurements could identify those patients, who need urgent neurosurgical referral for consideration for surgery. DESIGN: A retrospective cohort study. PARTICIPANTS: All patients aged 65 years or greater referred to Salford Royal Foundation Trust with the diagnosis of ASDH between 01/01/2008 and 31/12/2011. METHODS: The initial presenting CT brain scans were reviewed. The linear dimensions, degree of midline shift and haematoma volume (using ABC/2 method) of all scans were measured and recorded. All presenting radiology was also assessed by a consultant neurosurgeon blind to clinical and CT scan measurement data and patients were categorised as having "surgical" lesions or not. Receiver operating characteristic (ROC) curves were generated and cut point value for 100% sensitivity and specificity were tabled to assess which combination of scan parameters best predicted a "surgical" ASDH. RESULTS: 212/483 patients were considered to have a 'surgical' lesion. All 'surgical' lesions had a volume of >35ml (range 35-435), maximum thickness of ≥10mm (range 10-49) and 99% had midline shift ≥1mm (range 0-32). The best predictor of a 'surgical' lesion was a combination of maximum haematoma thickness and midline shift which offered 100% (95% CI 98.3-100) sensitivity with 83% (95% CI 77.6-87) specificity. CONCLUSION: Surgically relevant cases of ASDH in the elderly can be reliably and objectively identified by two easily performed scan measurements, haematoma thickness and midline shift. If used in routine practice, these measurements could clarify those patients who may need urgent neurosurgical referral and might avoid unnecessary transfer to neurosurgical units in this cohort.

Interim results in clinical trials: do we need to keep all interim randomised clinical trial results confidential?

OBJECTIVES: Guidelines for the conduct of clinical trials emphasize the importance of keeping the interim results from the main endpoints confidential, in order to maintain the integrity of the trial and to safeguard patients' interests. However, is this essential in every situation? MATERIALS AND METHODS: We review the evidence for these guidelines and consider recent randomised trials that have released interim results, to assess their impact on the success of the trial. However, because the strength of opinion to keep interim results confidential is so strong, there are limited examples of such trials. RESULTS: In the QUARTZ trial (which is assessing the value of whole brain radiotherapy in patients with brain metastases from non-small cell lung cancer) the decision to release interim results was taken in response to threatened closure due to poor accrual, whereas in the GRIT trial (which compared two obstetric strategies for the delivery of growth retarded pre-term fetuses) the regular release of interim results was pre-planned. Nevertheless there are a number of common factors between these two trials. In particular, the trial treatments were already in wide use, with no reliable randomised evidence on which treatment should be used for which patients, and there was diverse clinical opinion, which meant that accrual was likely to be challenging. In a situation where a quarter to a third of trials do not accrue their required number of patients, the QUARTZ trial continues to accrue patients, and the GRIT trial successfully accrued its target of nearly 600 babies. CONCLUSIONS: This article therefore argues that there is a need to re-consider whether it is always essential to keep the interim results of randomized clinical trials confidential, and suggests some criteria that may help groups planning or running challenging trials decide whether releasing interim results would be a useful strategy.

The role of sunlight exposure in determining the vitamin D status of the U.K. white adult population.

BACKGROUND: Vitamin D is necessary for bone health and is potentially protective against a range of malignancies. Opinions are divided on whether the proposed optimal circulating 25-hydroxyvitamin D [25(OH)D] level (≥ 32 ng mL⁻¹) is an appropriate and feasible target at population level. OBJECTIVES: We examined whether personal sunlight exposure levels can provide vitamin D sufficient (≥ 20 ng mL⁻¹) and optimal status in the U.K. public. METHODS: This prospective cohort study measured circulating 25(OH)D monthly for 12 months in 125 white adults aged 20-60 years in Greater Manchester. Dietary vitamin D and personal ultraviolet radiation (UVR) exposure were assessed over 1-2 weeks in each season. The primary analysis determined the post-summer peak 25(OH)D required to maintain sufficiency in wintertime. RESULTS: Dietary vitamin D remained low in all seasons (median 3·27 µg daily, range 2·76-4·15) while personal UVR exposure levels were high in spring and summer, low in autumn and negligible in winter. Mean 25(OH)D levels were highest in September [28·4 ng mL⁻¹; 28% optimal, zero deficient (<5 ng mL⁻¹)], and lowest in February (18·3 ng mL⁻¹; 7% optimal, 5% deficient). A February 25(OH)D level of 20 ng mL⁻¹ was achieved following a mean (95% confidence interval) late summer level of 30·4 (25·6-35·2) and 34·9 (27·9-41·9) ng mL⁻¹ in women and men, respectively, with 62% of variance explained by gender and September levels. CONCLUSIONS: Late summer 25(OH)D levels approximating the optimal range are required to retain sufficiency throughout the U.K. winter. Currently the majority of the population fails to reach this post-summer level and becomes vitamin D insufficient during the winter.

Barrier agents for adhesion prevention after gynaecological surgery.

BACKGROUND: Pelvic adhesion can form as a result of inflammation, endometriosis or surgical trauma. During pelvic surgery, strategies to reduce pelvic adhesion formation may include placing synthetic barrier agents such as oxidised regenerated cellulose, polytetrafluoroethylene or Fibrin sheets between the pelvic structures. OBJECTIVES: To assess the effect of physical barriers used during pelvic surgery in women of reproductive age on pregnancy rates, pelvic pain, or postoperative adhesion reformation. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched September 2007) which is based on regular searches of MEDLINE, EMBASE, CINAHL, PsycINFO and CENTRAL, plus handsearching of 20 relevant journals and conference proceedings, and searches of several key grey literature sources. In addition, companies were contacted for unpublished trials. SELECTION CRITERIA: Any randomised controlled trials (RCTs) comparing the use of physical barriers versus no treatment or other physical barriers in the prevention of adhesions in women undergoing gynaecological surgery. DATA COLLECTION AND ANALYSIS: Review authors assessed trial eligibility and quality. MAIN RESULTS: Sixteen RCTs were included. Five trials randomised patients while the remainder randomised pelvic organs. Laparoscopy (six trials) and laparotomy (10 trials) were the primary surgical techniques. Indications for surgery included myomectomy (five trials), ovarian surgery (five trials), pelvic adhesions (four trials), endometriosis (one trial), and mixed (one trial). Eleven trials assessed Interceed versus no treatment, two assessed Interceed versus Gore-Tex, one trial assessed Gore-Tex versus no treatment, and one trial assessed Seprafilm versus no treatment. A single trial assessed Fibrin sheet versus no treatment. No studies reported pregnancy or reduction in pain as outcomes. The use of Interceed was associated with reduced incidence of pelvic adhesion formation, both new formation and reformation following laparoscopic surgery or laparotomy. However, this result should be interpreted with caution. Gore-Tex was more effective than no barrier or Interceed in preventing adhesion formation. There was only limited evidence that Seprafilm was effective in preventing adhesion formation following myomectomy and no evidence to support Fibrin sheet. AUTHORS' CONCLUSIONS: The absorbable adhesion barrier Interceed reduces the incidence of adhesion formation following laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates. Gore-Tex may be superior to Interceed in preventing adhesion formation but its usefulness is limited by the need for suturing and later removal. There was no evidence of effectiveness of Seprafilm and Fibrin sheet in preventing adhesion formation.

Sparing of the thumb in Raynaud's phenomenon.

OBJECTIVES: To conduct a prospective study to determine which digits are affected (and whether the thumb is spared or not) in a cohort of patients with RP as assessed by symptoms and thermography and to determine whether the degree of thumb involvement differs between primary (PRP) and secondary Raynaud's phenomenon (SRP). METHODS: This was a cross-sectional study of 44 patients with RP. The following characteristics were recorded to allow comparisons between digits: symptoms of RP in each digit (graded on a scale of 'never', 'sometimes' and 'always' affected during an attack of RP) and thermography at 23 degrees C. A distal-dorsal difference (DDD) in temperature at 23 degrees C of -1 degree C or less was considered to be clinically relevant. RESULTS: Symptom scores in the thumb were significantly better, i.e. less severe than in each finger (P < 0.001). As only three participants had any finger better than the thumb, there was no power to compare whether the thumb was spared more in PRP compared with SRP. Mean DDD was significantly higher (i.e. better) in the thumb compared with each finger (P < 0.001). Although DDD scores were higher in PRP compared with SRP (P = 0.01), there was no evidence that the relative effect of the thumb differed between the two groups (P = 0.26). CONCLUSIONS: Our findings confirm that the thumbs are spared in RP, both primary and secondary, as demonstrated by both symptoms and thermography. The reasons for sparing of the thumb were not addressed in this study but raised questions regarding pathophysiology.

Reflective consideration of postoperative endophthalmitis as a quality marker.

PURPOSE: To study the incidence of acute postoperative presumed infectious endophthalmitis (PIE) in a UK district general hospital over a 10-year period. Consideration of such departmental healthcare-associated infection frequency rates as part of reflective and comparative quality practice in the light of local concerns. METHODS: Hospital-based retrospective case series: 12 831 cataract extraction operations from 01/01/1995 to 31/12/2004 were studied. All cases of PIE within 6 weeks of cataract surgery were ascertained and investigated in a standardised format. PIE incidence rate per 1000 cataract surgical procedures was contrasted with the existing literature. RESULTS: Seven isolated PIE cases occurred following phacoemulsification. None followed extra-capsular extractions. The PIE rate was 0.55 [95% CI; 0.22 to 1.12] cases per 1000 cataract extractions, or one PIE case within 6 weeks of surgery in every 1833 [95% CI; 893 to 4545] cataract operations undertaken. Five cases were culture positive. Details of PIE cases are presented. CONCLUSION: PIE incidence rates in our department are slightly lower than reported case series in similar settings. Whether this is due to a variety of preventive measures deployed locally and/or methods of case ascertainment in published studies is problematic and is discussed. Departmental benchmarking data is important in relation to rare, but critical, patient safety incidents. Collection and monitoring of endophthalmitis outcomes is of merit and may inform patient choice. Surgical site infection surveillance systems of relevance are discussed. Implications for making healthcare safer, including reflective practice are, discussed in relation to cataract care.

Ten year follow up of ulcerative colitis patients with and without low grade dysplasia.

BACKGROUND AND AIMS: Low grade dysplasia (LGD) is believed to predispose to colorectal cancer (CRC), and proctocolectomy has been advocated when this is identified. Between 1978 and 1990, 160 patients with longstanding extensive ulcerative colitis (UC) were recruited for annual colonoscopic surveillance and 40 developed LGD at some stage. We report the outcome of this cohort 10 years after the original study ended. METHODS: Retrospective cohort study and histopathological review of the original diagnoses of LGD. The outcome of 158/160 (98.8%) patients was established in 2000. RESULTS: Of the 128 patients still alive and with an intact colon at the end of 1990, two were not traceable, 29 had LGD, and 97 had no dysplasia (controls). After 10 years, high grade dysplasia (HGD) or CRC developed in 3/29 LGD (10%) and in 4/97 controls (4.0%). Kaplan-Meier analysis from 1991 to death or colectomy did not show a statistically significant difference between the two groups (log rank test p=0.63). Histopathological review demonstrated the unreliability of LGD diagnosis. Agreement between pathologists was uniformly poor: kappa <0.4 for all comparisons. CONCLUSION: LGD diagnosis is not sufficiently reliable to justify prophylactic colectomy. Conservative management of established LGD cases should not be ruled out.

Barrier agents for preventing adhesions after surgery for subfertility.

BACKGROUND: Pelvic adhesions can be the result of inflamation, endometriosis or surgical trauma. Prevention of postoperative adhesions (either new or reoccurance) has been postulated by using barriers to prevent two surfaces being in contact. When pelvic surgery is being undertaken strategies to reduce pelvic adhesions occurring may be undertaken and these include barrier agents which are placed between the pelvic structures. Two synthetic barriers with differential characteristics are commercially available: oxidised regenerated cellulose (Interceed) and polytetrafluoroethylene (PTFC) (GoreTex). OBJECTIVES: The objective of this review was to assess the effect of mechanical barriers (materials interposed between pelvic structures to prevent adherence of serosal surfaces) used during pelvic surgery in women of reproductive age on pregnancy rates, pelvic pain, or postoperative adhesion reformation. SEARCH STRATEGY: The Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled clinical trials was undertaken. In addition, companies were contacted for unpublished trials. SELECTION CRITERIA: Randomised controlled trials or controlled clinical trials of barriers versus no treatment or other barriers in women undergoing fertility preserving pelvic surgery. DATA COLLECTION AND ANALYSIS: Reviewers assessed eligibility and trial quality. MAIN RESULTS: 15 randomised controlled trials were included. Five trials randomised patients while the remainder randomised pelvic organs. Laparoscopy was the primary surgical technique in six trials while the remaining trials were laparotomy. Indications for surgery included myomectomy (five trials), ovarian surgery (four trials), pelvic adhesions (six trials), endometriosis (two trials) and mixed (one trial). Thirteen trials assessed Interceed versus no treatment, two assessed Interceed versus Gore-Tex, one trial assessed Gore-Tex versus no treatment, and one trial assessed Seprafilm versus no treatment. No study reported pregnancy or reduction in pain as an outcome. The use of Interceed in women was associated with reduced incidence of pelvic adhesion formation, both new formation and re-formation following laparoscopic surgery and after laparotomy. Gore-Tex was more effective than no barrier or Interceed in preventing adhesion formation. There was limited evidence that Seprafilm was effective in preventing adhesion formation in women following myomectomy. REVIEWER'S CONCLUSIONS: The absorbable adhesion barrier Interceed reduces the incidence of adhesion formation, both new formation and re-formation, at laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates. Gore-Tex may be superior to Interceed in preventing adhesion formation but its usefulness is limited by the need for suturing and later removal. There was no evidence of effectiveness of Seprafilm in preventing adhesion formation.

Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family.

Members of the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors have been identified in a wide variety of organisms, ranging from invertebrates to mammals. Bone morphogenetic proteins (BMPs) constitute a subgroup of proteins belonging to the TGF-beta superfamily. BMPs were initially identified by their ability to induce endochondral bone formation at ectopic sites, suggesting a critical role for this family in development and regeneration of the skeleton. They are also expressed at a variety of nonskeletal sites during development, suggesting possible extraskeletal roles for these proteins. We cloned a novel member of the BMP family that is expressed at high levels in the placenta and the prostate and that we have designated as prostate-derived factor (PDF). Based on cDNA sequence analysis, the predicted PDF protein contains two cysteines in addition to the seven conserved cysteines that are the hallmark of the members of the TGF-beta superfamily. In addition, Northern blot hybridization to poly(A)+ RNA showed low levels of expression in the kidney and pancreas. We further characterized the expression of this member of the BMP family by in situ hybridization and immunohistochemistry. These results show high expression in the terminal villae of the placenta. The expression of the protein as visualized by immunohistochemistry shows an expression pattern identical to that of the message in the terminal villae of the placenta. In day 18 rat embryos, protein expression was also seen in the skin and in the cartilaginous tissue of developing skeleton. Orchidectomy and dihydrotestosterone treatment of rats revealed that PDF expression is regulated by androgens in the prostate. In addition, subcutaneous implantation of recombinant PDF induced cartilage formation and the early stages of endochondral bone formation. These data indicate that PDF has a functional relationship to the BMPs.

Case-control study of breast cancer in south east England: nutritional factors.

OBJECTIVES: To explore dietary risk factors, in particular fat intake, for breast cancer, using an approach to reduce recall bias of subjects and so provide a more reliable estimate of dietary intake than previous similar studies. DESIGN: A case-control study of women aged 50-65 years attending the breast assessment clinics of the breast screening programme in Southampton and Portsmouth, southern England. Data were analysed for all women requiring further clinical procedures; all women recalled to have an early rescreen; and a random sample of women found to be normal and referred for a routine rescreening appointment (standard recall). MEASUREMENTS: An interview obtained information on various lifestyle characteristics including smoking and alcohol intake, weight, waist, and hip measurements were also taken at the clinic. Women were given a detailed questionnaire on food intake to complete at home and return by post. RESULTS: 1577 women were included in the study: 220 with breast cancer (cases); 179 with benign breast disease; 353 early rescreen and 825 given a standard recall appointment. There were few differences in nutritional intake between the four groups. Logistic regression analyses were carried out comparing the dietary intake of cases with that of each control group adjusting for important demographic and reproductive factors. Results for the case and standard recall comparison are presented. The only non-calorific nutrient to reach significance was iron, which was negatively associated with risk (p = 0.03). For fat intake, the odds decreased with increasing polyunsaturated fat (p = 0.15), showed no trend with monounsaturated fat (p = 0.37) and increased (p = 0.10) with increasing saturated fat. No pattern was clear for the other calorie providing nutrients. CONCLUSIONS: In line with recent cohort studies, this study has shown no evidence to support the hypothesis that dietary fat is an important contributor to breast cancer rates. Biases should have been reduced by studying subjects from the screening programme who were at an early stage of disease.

Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique.

Since 1989, we have used a relatively straightforward technique for giving total body irradiation (TBI), using anterior and posterior parallel opposed fields with the arms and fists acting as compensators. The dosimetry, toxicity and outcome of 48 patients (26 adults, 22 children) treated with TBI using this technique have been audited. A dose of 14.4 Gy in eight fractions over 4 days was prescribed to all patients with an unrelated donor and 12 Gy in six fractions over 3 days to those with a sibling donor. From May 1994, all children received 14.4 Gy because of a recommendation from the United Kingdom Children's Cancer Study Group. The range of lung dosimetry was -6% to +7% when the dose was specified to the lung maximum. The trunk doses were all within +/-10% of the prescribed dose. Doses to other regions of the body were less homogeneous but clinically acceptable in that the minimum doses were never less than -10% of the prescribed dose. Mucositis was the most common side effect; its treatment with opioids was more frequent after 14.4 Gy than after 12 Gy (P=0.0004) and in adults than in children (P=0.01). No cataracts have yet been seen in these patients. The radiation was not found to be a proven cause of clinical pneumonitis, although there was one death due to interstitial pneumonitis, which was likely to have been caused by cytomegalovirus infection in which radiation pneumonitis could not be excluded. There were no other suspected TBI-related deaths. In conclusion, this straightforward technique achieved acceptable dosimetry and was well tolerated.

The effect of rhGH in vitro on donor-specific hyporesponsiveness in pediatric transplantation.

Recombinant human growth hormone (rhGH) improves growth in children after renal transplantation, but may be associated with augmented immune responses. To understand the effect of rhGH in transplantation, we evaluated the role of rhGH in a mixed leukocyte culture (MLC) in vitro. We demonstrated that PBMC isolated from normal adult volunteers cultured in an MLC in the presence of rhGH develop an augmented proliferative (25-400%) and cytotoxic (50-600%) response. Using in situ hybridization (ISH), we demonstrated that the frequency of cells expressing mRNA for IFNgamma increased in the presence of rhGH (100-800%). In vitro responses of PBMC from adults in an MLC may only loosely reflect responses in vivo during pediatric transplantation. After transplantation, adults develop decreased responses to donor-specific antigens in an MLC (donor-specific hyporesponsiveness - DSH). We evaluated the donor-specific responses of 20 pediatric patients who had each received a renal allograft from one parent. Pediatric patients developed DSH similarly to adults; however, no correlation was seen between the amount of DSH and graft function. We also evaluated the expression/production of IFNgamma and IL4 in response to donor-specific alloantigens. Patients exhibit marked DSH of IFNgamma expression and production. However, IL4 production was seen in 8 out of 10 patients with normal renal function, but only 1 out of 7 patients with biopsy proven chronic rejection. Finally, we evaluated the effect of rhGH in vitro on DSH. Only 3 out of 20 patients developed augmented donor-specific responses in the presence of rhGH in vitro. rhGH augments proliferation, cytotoxicity and IFNgamma expression during an MLC. After renal transplantation, rhGH augments donor-specific responses during an MLC in some pediatric patients.

Non-prescribed drug use during methadone treatment by clinic- and community-based patients.

We investigated the efficacy of methadone maintenance treatment in clinic-based (n = 10) and community-based (n = 10) patients by studying the relationships between dose, plasma concentrations of methadone and non-prescribed drug-use using logistic regression. We found that clinic-based patients had significantly reduced odds of having a urine sample test positive for illicit drugs when compared to community-based patients (OR = 0.20; 95% confidence interval 0.10-0.38: p < 0.001). There was no relationship between either methadone dose or plasma methadone concentration and testing positive for non-prescribed drugs (including cocaine, cannabis, amphetamine, ecstasy, benzodiazepines). We looked specifically at the misuse of opiate drugs. Location was again important and clinic-based patients had significantly reduced odds of having a urine sample test positive for opiate drugs (OR = 0.36, 95% confidence interval 0.18-0.71: p approximately 0.004). Opiate drug use in our patients was also significantly related to plasma methadone concentration, increasing noticeably when the drug concentration < 0.48 nmol/L (p approximately 0.04). We found no relationship between methadone dose and odds of having a positive urine drug test in either clinic- or community-based patients.

Risk factor analysis of data from assessment clinics in the UK breast screening programme: a case-control study in Portsmouth and Southampton.

STUDY OBJECTIVES: The aim was to quantify the influence of demographic and reproductive factors on breast cancer. The subjects' path through the screening clinic, the inherent differences between the control groups, and the possible biases when using screening programmes were also considered. DESIGN: A case-control study using both personal contact and postal questionnaires to gather demographic and reproductive information. SETTING: Women attending two breast screening recall clinics in Portsmouth and Southampton over the period 1990-92. PARTICIPANTS: Altogether 1813 subjects between the ages of 50 and 65 years. The subjects' disease status was ascertained using a mammography and classified into four categories: 253 breast cancer (cases); 207 benign breast disease (BD); 410 requiring early rescreen (ER); and 943 for standard recall (SR). The BD, ER, and SR groups were used as separate controls. MAIN RESULTS: Of the factors considered here, the only two that showed a consistently significant effect on the risk of breast cancer were age and body mass index (BMI). Odds ratios were calculated for five yearly age groups and four groups of BMI using the youngest and lightest group as the baseline, respectively. There seemed to be an increase in the risk of breast cancer for increasing age for each comparison made (for cases v SR:OR (95% CI) = 1.60 (1.10, 2.34), 2.54 (1.76, 3.68)). All subjects above the lowest quartile of BMI experienced increased risk, although a trend was not clear (for cases v SR: OR (95% CI) = 1.66 (1.03, 2.66), 1.37 (0.86, 2.20), 1.98 (1.24, 3.15)). CONCLUSIONS: Various other potential risk factors were found to be inconsistently significant depending on choice of control group. This may help in understanding the differences between the three control groups used.

Clinical and surgical factors influencing corneal graft survival, visual acuity, and astigmatism. Corneal Transplant Follow-up Study Collaborators.

PURPOSE: To quantify clinical and operative factors that influence corneal graft outcome. METHODS: A multifactorial analysis was done on 2242 corneal grafts registered by the United Kingdom Transplant Service from July 1987 to June 1991. RESULTS: There was an increased risk of graft failure in patients with preoperative diffuse and other noncentral stromal edema, less-common eye diseases, small trephine size, difference in donor and recipient sizes greater than 0.25 mm, and use of mixed continuous and interrupted sutures. Visual acuity 3 months after surgery was poorer in patients who had glaucoma and low visual acuity preoperatively, small trephine size, and combined vitreous surgery. Use of interrupted sutures resulted in higher astigmatism at 3 months. CONCLUSIONS: After allowing for the effects of recipient factors, surgical factors significantly affected corneal graft outcome. No factors that showed significant benefits for graft survival also adversely affected visual performance. Details of medical history, clinical condition, and surgical method failed to predict more than a small proportion of observed variability in visual performance of functioning grafts.

An audit of the management of malignant hypercalcaemia.

A protocol was designed to help junior doctors to manage patients with malignant hypercalcaemia (MH). Seventy-five patients received 30 mg, 60 mg or 90 mg doses of pamidronate, depending on their initial serum calcium level. Fifty-four (72%) patients achieved normocalcaemia (NC) within 5 days after a single infusion of pamidronate. A further ten (13%) patients reached NC after a second dose, and 11 (15%) remained hypercalcaemic until death. NC was maintained for a median duration of 24 days. Patients received, on average, 30 mg less pamidronate than that given in the manufacturer's dosing schedule. The protocol was considered effective, economical and practical in the routine management of MH.