Viral infections are known to adversely affect pregnancy, but scant attention has been given to human papilloma virus (HPV) infection. We aimed to determine the molecular and histopathological features of placental HPV infection, in association with pregnancy complications including fetal growth restriction, pre-maturity, pre-eclampsia, and diabetes. Three hundred and thirty-nine placentae were selected based on the presence or absence of pregnancy complications. Five independent methods were used to identify HPV in the placenta, namely, immunohistochemistry for L1 viral capsid, in situ hybridization to high-risk HPV DNA, PCR, western blotting, and transmission electron microscopy. Pregnancy complications and uterine cervical smear screening results were correlated with placental HPV histopathology. In this study, which was deliberately biased towards complications, HPV was found in the decidua of 75% of placentae (253/339) and was statistically associated with histological acute chorioamnionitis (P o0.05). In 14% (35/253) of the HPV positive cases, HPV L1 immunoreactivity also occurred in the villous trophoblast where it was associated with a lymphohistiocytic villitis (HPV-LHV), and was exclusively of high-risk HPV type. HPV-LHV significantly associated with fetal growth restriction, preterm delivery, and pre-eclampsia (all P o0.05). All cases of pre-eclampsia (20/20) in our cohort had high-risk placental HPV. A further 55 cases (22%, 55/253) of HPV positive placentae had minimal villous trophoblast HPV L1 immunoreactivity, but a sclerosing pauci-immune villitis, statistically associated with diabetes (49.1%, 27/55, Po 0.05). For women with placental HPV, 33% (69/207) had an HPV-related positive smear result before pregnancy compared with (9.4% 8/85) of women with HPV-negative placentae (P = 0.0001). Our findings support further investigations to determine if vaccination of women and men will improve pregnancy outcomes. Modern Pathology (2015Pathology ( ) 28, 1369Pathology ( -1382 doi:10.1038/modpathol.2015 published online 21 August 2015 In the immune and hormonal modulated milieu of pregnancy, viruses are well known to infect the placenta, developing fetus, and neonate. The most common and important neoplastic driver of the lower uterine tract, human papillomavirus (HPV), 1 has been detected in the uterine cervix of 15-25% of pregnant women 2-6 and a cervical HPV infection during pregnancy has been associated with a higher incidence of spontaneous abortions, 7-9 premature rupture of the membranes, 10 spontaneous preterm labor, 11,12 pre-eclampsia, 13 and placental 'villitis' not otherwise specified. 12 HPV DNA has been detected in the placenta and amniotic fluid. 7,11,[14][15][16][17]11,16,18,and 31 have been shown to replicate in trophoblast cell lines, [18][19][20] where HPV infection decreased trophoblast number and trophoblast-endometrial cell adhesion in vitro. 19,20 We investigated for the presence of HPV in the placenta and carried out a histopathological and molecular cross-sectional study of 339 ...

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BRIrisH MEDICAL JOURNAL 10 PEBRUARY 1973 321 Depth of coma and the presence of abnormal plantar reflexes in the acute stage of poisoning were considered by Zahle (1948) to correlate with the development of neuropsychiatric sequelae, while Bokonjic (1963) determined that the duration of coma, the advancing age of the patient, and the development of cardiovascular failure indicated a poor prognosis for both survival and the recovery of mental functions. In the current study the level of consciousness on admission correlated with the development of gross neuropsychiatric sequelae, but the correlation with reflex abnormalities failed to reach a significant level; prolonged periods of delirium associated with poisoning and advancing age were not of prognostic significance, and only one patient had been in cardiac failure on admission. A relapsing course had occurred in one patient developing a dementing process. Oxygen therapy had been reserved for the more severely affected patients, so that the consequence of failing to administer oxygen could not be established, and the carboxyhaemoglobin levels had been estimated on too few patients to allow any conclusions. Subjective complaints and objective evidence of memory impairment were also related to the level of consciousness on admission.The frequency of acute CO poisoning in Great Britain is sharply declining (Office of Health Economics, 1972), but the high mortality rate and the considerable morbidity in the survivors call for continuing efforts to prevent acute poisoning and to treat promptly those exposed. The lowering of the CO content of town gas has reduced the frequency of accidental and suicidal exposure (Gremy et al., 1968;Hassall and Trethowan, 1972), but inadequate ventilation and flueing of appliances burning natural gas can produce high levels of CO with fatal consequences (Ministry of Technology, 1970). Firemen may be exposed to black smoke, and the possibility that patients sustaining burns from fires in enclosed spaces may be suffering severe CO poisoning should always be considered (Pollard, 1970). The internal combustion engine is likely to continue as a source of exposure.Our findings suggest that the hazards of CO poisoning are not always appreciated by casualty officers, and as it becomes less common the dangers of unfamiliarity are increased. In our view every patient exposed to CO should receive prompt and efficient oxygenation including hyperbaric therapy where available, and the early reduction of cerebral oedema with hypertonic solutions or steroids may be of value. The importance of providing follow-up facilities in the anticipation of a relapsing course or the delayed development of neuropsychiatric and cardiac sequelae has been established.We wish to thank Mrs. P. Walker for her invaluable work in the tracing of patients, and all of our colleagues who helped in this tracing and made their clinical records available to us.

We are glad to see that a chairman of a Local Research Ethics Committee (LREC) acknowledges that, in a certain number of cases, there may be valid criticisms of the workings of LRECs. To answer the specific points raised by your correspondent: we also do not understand why the major cause of delay was difficulty in obtaining the necessary forms for completion. Repeated requests were often required before they were sent. Our suspicion was that t h s was merely administrative incompetence. The reason the gestation period of our trial was so long (1985 to 1989) was the difficulty in obtaining financial support. Whereas trials of new drugs or equipment are usually funded by the commercial company that may benefit, it is much more difficult to finance evaluation of routine clinical interventions, especially if it might result from a retreat from established practice rather than an "advance". We should all be concerned about this "negative research bias". However, delays that start after the commencement of the research grant are a particular problem for researchers. They delay the actual start of the clinical investigations and therefore limit the time for data collection, whilst the grant money steadily runs out. Yet multiple ethics committee applications are very time consuming to make, and therefore cannot readily be submitted before a funded person is available to give their whole attention to it. The point about the local coordinator was that multiple applications to LRECs of necessity entail dealing with many people of varying administrative capabilities and often with limited time. A centralised approval process, possibly a National Research Ethics Committee, would save on t h s sort of delay. The fact that only four points were raised more than once indicated to us that the comments on the research proposal were mostly inconsistent. The majority of the points raised were trivial and arose because of ignorance and not because of well founded concern about study design or ethics. We would whole heartedly agree with the view that all research should be reviewed by a committee of well informed and critical people not directly involved with the research project, and that the research should be of the highest ethical and methodological quality. Our complaint is about the lack of urgency with which research proposals are considered, leading to wasting of scarce research grants. We feel that committees should distinguish between local "kite-flying " and major national or multicentre initiatives, and prioritise accordingly. We also found the varying quality of such committees disturbing. We suspect this reflects the lack of priority given by active researchers to working on such committees; they are nowadays too busy obtaining their own funding to be willing to participate. In the absence of active, well informed researchers on many committees, it is hardly surprising that many display a relative lack of insight into the needs of research. Until such work is recognised by the Higher Education Funding Councils and by T...

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