St Michael's Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

BACKGROUND: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. METHODS: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. FINDINGS: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. INTERPRETATION: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

BACKGROUND: Moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. METHODS: In the TOBY trial hypoxic-ischaemic encephalopathy was graded clinically according to the changes seen on amplitude integrated EEG, and infants were randomly assigned to intensive care with or without cooling by central telephone randomisation. The relation between allocation to hypothermia or normothermia and cerebral lesions was assessed by logistic regression with perinatal factors as covariates, and adjusted odds ratios (ORs) were calculated. The TOBY trial is registered, number ISRCTN 89547571. FINDINGS: 325 infants were recruited in the TOBY trial between 2002 and 2006. Images were available for analysis from 131 infants. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR 0.36, 95% CI 0.15-0.84; p=0.02), white matter (0.30, 0.12-0.77; p=0.01), and abnormal posterior limb of the internal capsule (0.38, 0.17-0.85; p=0.02). Compared with non-cooled infants, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (0.41, 0.18-0.91; p=0.03) and were more likely to have normal scans (2.81, 1.13-6.93; p=0.03). The accuracy of prediction by MRI of death or disability to 18 months of age was 0.84 (0.74-0.94) in the cooled group and 0.81 (0.71-0.91) in the non-cooled group. INTERPRETATION: Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic-ischaemic encephalopathy. The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia. FUNDING: UK Medical Research Council; UK Department of Health.

The Obstetric Anaesthetists' Association and Difficult Airway Society have developed the first national obstetric guidelines for the safe management of difficult and failed tracheal intubation during general anaesthesia. They comprise four algorithms and two tables. A master algorithm provides an overview. Algorithm 1 gives a framework on how to optimise a safe general anaesthetic technique in the obstetric patient, and emphasises: planning and multidisciplinary communication; how to prevent the rapid oxygen desaturation seen in pregnant women by advocating nasal oxygenation and mask ventilation immediately after induction; limiting intubation attempts to two; and consideration of early release of cricoid pressure if difficulties are encountered. Algorithm 2 summarises the management after declaring failed tracheal intubation with clear decision points, and encourages early insertion of a (preferably second-generation) supraglottic airway device if appropriate. Algorithm 3 covers the management of the 'can't intubate, can't oxygenate' situation and emergency front-of-neck airway access, including the necessity for timely perimortem caesarean section if maternal oxygenation cannot be achieved. Table 1 gives a structure for assessing the individual factors relevant in the decision to awaken or proceed should intubation fail, which include: urgency related to maternal or fetal factors; seniority of the anaesthetist; obesity of the patient; surgical complexity; aspiration risk; potential difficulty with provision of alternative anaesthesia; and post-induction airway device and airway patency. This decision should be considered by the team in advance of performing a general anaesthetic to make a provisional plan should failed intubation occur. The table is also intended to be used as a teaching tool to facilitate discussion and learning regarding the complex nature of decision-making when faced with a failed intubation. Table 2 gives practical considerations of how to awaken or proceed with surgery. The background paper covers recommendations on drugs, new equipment, teaching and training.

Why was this consensus statement developed? Advances in clinical practice are sometimes inhibited by a multitude of different options that need to be selected. There has been significant variation in the treatment of spinal anaesthesia-induced hypotension. These guidelines are designed to provide clinicians with specific best-practice plans that will cover a wide range of drug and equipment availability. Detailed recommendations are provided for the management of hypotension in resource-rich and resource-poor environments. How does this consensus statement differ from other available guidelines? The American Society of Anesthesiologists/Society for Obstetric Anesthesia and Perinatology Task Force, and the UK National Institute for Health and Care Excellence, have made generic recommendations on this topic 1, 2. We are unaware of detailed guidelines from any organisations. We aim to offer independent, pragmatic advice that will be of benefit to clinicians and the women we treat. Hypotension is a very common consequence of the sympathetic vasomotor block caused by spinal anaesthesia for caesarean section. Maternal symptoms such as nausea, vomiting and dyspnoea frequently accompany severe hypotension, and adverse effects on the fetus, including depressed Apgar scores and umbilical acidosis, have been correlated with severity and duration of hypotension. Ephedrine, a mixed α- and β-adrenergic agonist, became the drug of choice in obstetric anaesthesia following work that found that it was the best vasopressor for preservation of uterine blood flow in a sheep model of drug-induced hypertension. However, higher doses of ephedrine, used clinically in attempts to reduce hypotension, were found not to improve neonatal acidosis, but rather the reverse 3; this is now acknowledged to be because ephedrine has a direct effect on fetal metabolism that negates any improvement in uterine blood flow produced by normalising blood pressure 4, 5. Clinical work dating from the 2000s indicated that α-adrenergic agonists are effective at reducing hypotension, and associated with less neonatal acidosis than ephedrine 6. National practice guidelines suggest the use of both ephedrine and phenylephrine for the management of hypotension; UK guidelines from 2011 state that: ‘Women who are having a caesarean section under regional anaesthesia should be offered intravenous ephedrine or phenylephrine, and volume pre-loading with crystalloid or colloid to reduce the risk of hypotension occurring during caesarean section’ 2. American guidelines from 2016 provide more detail: ‘Intravenous fluid preloading or co-loading: intravenous fluid preloading or co-loading may be used to reduce the frequency of maternal hypotension after spinal anesthesia for cesarean delivery; do not delay the initiation of spinal anesthesia in order to administer a fixed volume of intravenous fluid. Ephedrine or phenylephrine: either intravenous ephedrine or phenylephrine may be used for treating hypotension during neuraxial anesthesia; in the absence of maternal bradycardia, consider selecting phenylephrine because of improved fetal acid–base status in uncomplicated pregnancies’ 1. Surveys of clinical practice indicate that there has been a shift away from what was the almost universal use of ephedrine as the vasopressor of choice. In the UK, a 1999 survey found that 95% of respondents used ephedrine alone during caesarean section 7; in 2011, 89% of respondents used phenylephrine, and the remainder used metaraminol or ephedrine 8. A survey carried out in the USA in 2007 noted that 32% of respondents used ephedrine for vasopressor prophylaxis and treatment of hypotension, 26% and 23%, respectively, used phenylephrine, and the remainder used either agent according to maternal heart rate 9. Klöhr et al. found 15 different definitions of hypotension in 63 studies of hypotension following spinal or combined spinal-epidural anaesthesia for caesarean section, performed between 1999 and 2009 10. Definitions varied between those using an absolute blood pressure value, ranging from 80 mmHg to 100 mmHg, a decrease of 0–30% from a baseline or a combination of an absolute value and a percentage decrease. Some studies distinguished between severe hypotension and lesser (mild-moderate) degrees. All studies used the systolic arterial pressure (SAP) measured in the arm, in a variety of body positions; all but one 11 used the non-invasive oscillometric method. Baseline blood pressure readings were usually taken just before performing spinal anaesthesia, although occasionally at an earlier stage, such as on admission to the labour ward. The baseline was estimated from one, two or three replicate readings. Applying these different definitions to a cohort of women having elective caesarean section gave incidences for hypotension varying between 7.4% and 74.1% 10. The most common definitions of hypotension used in research studies were either ‘< 80% baseline’, or ‘< 100 mmHg OR < 80% baseline’ 10. A 1999 survey in the UK found that most consultant obstetric anaesthetists use a threshold of either 100 or 90 mmHg 7. The SAP is a less important variable than mean arterial pressure (MAP) as a determinant of organ perfusion; however, because methods used to measure blood pressure in routine clinical practice did not include the mean until recent decades, it is unlikely to be adopted for the definition of obstetric hypotension without considerably more supportive data. Most of the studies identified by Klohr et al. were at elective caesarean section; few included women in labour 12. Arterial pressure increases during labour; using baseline values taken in the antenatal period or at the start of labour was shown to reduce the incidence of recorded hypotension, defined as a decrease < 80% baseline value, after epidural analgesia 13. Many studies of hypotension at caesarean section did not include hypertensive women. The SAP threshold for pregnancy-induced hypertension or pre-eclampsia is > 140 mmHg 14. Nausea and vomiting are significantly more frequent during spinal anaesthesia for caesarean section than during non-obstetric surgery. The aetiology of this is multifactorial 15. Acute hypotension reduces cerebral perfusion, induces transient brainstem ischaemia and activates the vomiting centre. Transient cerebral hypoxia may occur, as studies using near-infrared spectroscopy (NIRS) show that hypotension is accompanied by a significant decrease in maternal regional cerebral blood volume, cerebral oxygen saturation and oxygenation 16. This is consistent with the observation that supplemental oxygen may relieve this nausea 17, 18. Spinal anaesthesia decreases splanchnic blood flow by approximately 20% 19, which may be accentuated by accompanying systemic hypotension. The resulting splanchnic hypoperfusion releases emetogenic factors such as serotonin from the gastro-intestinal tract. Finally, acute sympathetic blockade may cause unopposed vagal action and subsequent hyperactivity in the gastro-intestinal tract 20. Regardless of the aetiology, the use of prophylactic vasopressors significantly reduces the incidence of intra-operative nausea and vomiting during caesarean section 21. Dizziness and decreased levels of consciousness may follow severe and prolonged maternal hypotension, but are blood pressure is The effect of hypotension on fetal during caesarean section in although research that a decrease of > in uterine blood flow in and in a Clinical have from studies that with and without hypotension, or duration of hypotension. of women with hypotension significant acidosis and hypotension of more than duration was associated with a significant in umbilical and of of hypotension may be more important than A transient decrease in blood pressure did not neonatal Apgar incidence of fluid or the need for oxygen in the Hypotension for less than did not neonatal more than of maternal hypotension was associated with at of important in acid–base during spinal anaesthesia for caesarean is the choice of vasopressor used to hypotension. from studies were recent clinical suggest that phenylephrine, as an is associated with neonatal acid–base than ephedrine Ephedrine has higher than phenylephrine, with umbilical arterial of and in doses this is associated with neonatal higher and and levels 5. These of fetal sympathetic metabolism by ephedrine the use of phenylephrine for during caesarean section in umbilical clinical in neonatal have not been these of phenylephrine ephedrine improved clinical in the is as The available studies show in the incidence of fetal acidosis either ephedrine or phenylephrine was used to blood pressure during spinal anaesthesia for caesarean both in or those with acute fetal effects on and the of resulting in In such as bradycardia, may from The clinical to α- and β-adrenergic and and fetal effects Ephedrine not has but direct which the and duration of Ephedrine increases heart rate and by has a direct with at clinical at higher than it may with a in maternal et using found the of a phenylephrine to spinal hypotension to be et al. estimated the to spinal hypotension or nausea to be However, doses of this may be associated with increases in systemic and bradycardia, and a of 100 is more common this et al. found benefit using doses of or phenylephrine to hypotension, in with doses of 100 The of phenylephrine to ephedrine for using is is a mixed α- and at doses used has both direct and it sympathetic it for to as a A recent used a of for is the by is a agonist, with with direct in higher heart than with doses of phenylephrine The for of hypotension is et al. found a of for In has for and at are more significant at higher is a mixed α- and β-adrenergic that has both direct and effects to the of and is available and fetal effects although it is a agent in a of and of this drug is that it does not The of clinical management is the of maternal blood on of the adverse effects of hypotension. However, from research studies that is an important The effect of spinal anaesthesia in a is a decrease in systemic to with a of There is a in heart rate and volume, which increases a spinal block to the sympathetic may be resulting in a of However, heart rate does not with block a of bradycardia, to is The aim of vasopressor treatment should to systemic which is best using with However, on doses of vasopressors to blood without other may to et al. used the and to measure in a of phenylephrine and ephedrine used in elective caesarean section. the decrease in systemic and hypotension more than there was between the percentage in heart rate and after the vasopressor of vasopressor that heart not is the best for the is not measured et al. found in both maternal heart rate and measured with three different of The rate both and heart rate by > This the that heart rate may indicate phenylephrine doses that are a to or hypotension and include methods to reduce and in the as as fluid the is for uterine is used to reduce with a of This of is associated with higher maternal SAP and and doses of phenylephrine than the but is in practice the is to is for may for the however, it be used during the period of before and at the before has been at that of the may be than at reducing hypotension at caesarean section but it is to during surgery. has been shown to be more effective than in hypotension, although a of that may on the and of used or to be of the lesser effect of with after spinal A between and did not show a in blood pressure found that to after spinal anaesthesia significant decrease in incidence of hypotension a found a in hypotension that an important between the studies was that crystalloid was used in the but in the crystalloid in the was performed using until a in this practice studies that it has very at reducing the incidence or severity of hypotension and is may be more effective at hypotension and vasopressor than pre-loading 63 or fluid a benefit pre-loading a recent a benefit on of vasopressor provided that a volume is under pressure during the after the spinal is more effective than crystalloid for of hypotension A of by in combination with prophylactic of phenylephrine, was associated with a significantly incidence of hypotension with a of as as less hypotension In a of colloid as effective as a of crystalloid both be to improve the provided by vasopressor have been as of hypotension, on of However, these have not been by more specific does not the frequency and severity of hypotension caesarean is associated with less hypotension than elective This is to be more to the of labour A wide variety of methods have been to the of hypotension after spinal anaesthesia These include that are not of routine and other baseline heart rate was found to be a of hypotension in studies but a of have not this > during a period in combined with > or > mmHg in SAP after from to for severe hypotension Baseline < 80% baseline < baseline Baseline > 90 for hypotension Baseline < 90 for hypotension > 100 Hypotension SAP < 100 mmHg significant hypotension hypotension as with symptoms hypotension SAP < 80 mmHg for clinically significant hypotension Baseline heart rate > Baseline methods not et al. found that was associated with a decrease in SAP than although the incidence of hypotension was not Some studies have occurring after the spinal as an of hypotension. and that provide an of hypotension, with a decrease in saturation hypotension by a et al. noted that in heart rate after the spinal were found in women who more severe hypotension a and available of hypotension is we suggest that there is a of hypotension the baseline heart rate is or there is a and recent of non-invasive blood pressure is an in heart rate after the spinal may the of hypotension. A vasopressor with is the choice to reverse the effects of spinal phenylephrine has the most use However, and decreased associated with phenylephrine have research on and which have to β-adrenergic effects in to studies to phenylephrine in the of obstetric spinal anaesthesia have found that may be a to phenylephrine however, there are the use of such a agent in a such as the labour studies of and metaraminol A survey found that there are of phenylephrine available in the UK 8. The most common is a which is a of to a of 100 are the other used usually for rather than 8. should be in for of that in order to reduce the risk of drug should consider the of or noted a of definitions of hypotension are et al. that there were in the incidence of nausea and vomiting SAP was at the baseline with < or < 80% baseline there were in neonatal umbilical blood We suggest that the aim should be to SAP of an measured baseline until of the with the of reducing the frequency and duration of of significant hypotension < 80% arterial pressure values < 80% should be usually with a vasopressor for blood pressure in practice for a period without or although this is unlikely to be in the of surgery. the other a is that the baseline blood pressure should be taken under to those after for with to studies a of in with to an baseline blood the oscillometric blood pressure et al. the to until three values of SAP were with a of < between The baseline pressure was to be the mean of those three and heart rate was as the mean of the three readings routine clinical most anaesthetists will one baseline of blood However, should be performed the value is higher than in a not to be or in a who is in it does not the from the and consider using this as the measure non-invasive blood pressure blood pressure is measured the is in one or other the non-invasive blood pressure should be on the to reduce from effects et al. performed a that included of prophylactic phenylephrine with vasopressor treatment hypotension treatment a benefit with to the incidence of hypotension both before and after as as nausea and phenylephrine in the of higher doses of phenylephrine with the risk of maternal hypertension and were A subsequent to this prophylactic variable rate and phenylephrine with This that the was more effective at spinal hypotension, nausea and with clinical Most studies have a prophylactic of vasopressor with There are prophylactic phenylephrine with prophylactic phenylephrine A by et al. found that of phenylephrine at hypotension, nausea and vomiting with a prophylactic of phenylephrine et al. having a phenylephrine with those having an prophylactic of phenylephrine, by doses the phenylephrine used in these studies be to be a of 100 is more used both to and spinal hypotension the other a phenylephrine was with from blood pressure in the this it that a prophylactic phenylephrine is to and that the start of the in reducing the incidence of hypotension. In clinical vasopressor at the of a blood pressure will not be as as in research and will not be the the will be for delay in with subsequent hypotension, in with The is that the should be after the of the et al. prophylactic phenylephrine The having and to SAP > 80% with the having 100 In the and 100 higher incidences of hypertension to start an at a rate of and to variable rate are to fixed in order to the of phenylephrine a vasopressor is at a fixed rate after spinal there will be a delay in effective blood a of vasopressor after the spinal will more et al. that an phenylephrine of by an at SAP without any adverse effects work is to an for a prophylactic and that there is not a risk of hypertension and There are studies of used as a agent after the of an using an as the doses of ephedrine are to SAP < baseline combined with a heart in order to blood pressure and There is to indicate the heart rate threshold in the absence of severe hypotension; clinicians should use clinical significant with hypotension, an or may be There is to routine use of for the of hypotension not used to hypotension, has a in hypotension and after spinal research is to vasopressor use a to the of vasopressor according to maternal blood There are of that may be using The may an or a the the a fixed of vasopressor it blood pressure a threshold for the the vasopressor by is varied in with the of hypotension, for between and 100 The may the vasopressor as a or as an in to blood pressure is more with doses of using of with phenylephrine, in this include in blood pressure and higher for the and and levels for the blood pressure between the and of hypotension the use of a blood pressure may with delay and non-invasive blood pressure on the or have been including the the and These have the to blood pressure including et al. used for but a that phenylephrine or ephedrine according to heart to reduce found with phenylephrine This most recent included a that of doses blood pressure is with a This was to 80% of all SAP readings > 80% with maternal and fetal These suggest a for of vasopressor with non-invasive blood pressure to more of of these in the of to be increases during the of it has not been that ephedrine is than phenylephrine for neonatal in this ephedrine acidosis phenylephrine to be the best vasopressor choice in the of significant fetal caesarean section is for a in hypotension after spinal anaesthesia is with elective is to start a vasopressor at a rate than for elective in the of an should not delay other taken to of the The rate and severity of hypotension is after spinal and combined spinal epidural anaesthesia with combined spinal-epidural and epidural combined spinal-epidural and spinal provide with for vasopressor with severe pre-eclampsia less hypotension and have vasopressor during spinal anaesthesia, with women caesarean section These suggest that women with pre-eclampsia either have or are more to with women. There are few studies vasopressors in women with A the status of 15 women with severe pre-eclampsia having spinal anaesthesia for caesarean section for a maternal found that phenylephrine to spinal hypotension and systemic but did not significantly the volume or In a subsequent spinal anaesthesia for caesarean section in severe the maternal effects of ephedrine and phenylephrine were a colloid a of phenylephrine the spinal anaesthesia-induced in systemic heart rate and baseline more than 15 ephedrine A of ephedrine and phenylephrine for the treatment of hypotension after spinal anaesthesia in women with pre-eclampsia found in neonatal umbilical did a in women that included an of women with pre-eclampsia A recent has shown that in with severe pre-eclampsia and fetal fetal acid–base status is of the use of ephedrine phenylephrine to spinal hypotension These studies suggest that phenylephrine is the vasopressor to reverse the maternal by spinal anaesthesia in women with severe The of phenylephrine may be than in a prophylactic vasopressor may not be should be at a with the effect on blood pressure The choice of by or does not to neonatal The blood pressure for women with hypertension is of < mmHg are for SAP The aim should be to SAP to as a decrease in blood are frequently used in women with caesarean section in clinical In women with there is a during caesarean section with neuraxial with anaesthesia spinal anaesthesia is best in women with significant the and associated with spinal anaesthesia are with or fixed or neuraxial such as combined spinal-epidural or spinal anaesthesia, are There are studies the vasopressor to or hypotension after neuraxial anaesthesia in women with caesarean section. are on from and with caesarean section with neuraxial anaesthesia have been with phenylephrine by or non-invasive However, the phenylephrine should not be to all women with The of the specific and the by neuraxial anaesthesia, should the of the most vasopressor is the agent of choice in women with as it has in to ephedrine, may A decrease in systemic after neuraxial anaesthesia in the of fixed such as severe or are best or with by ephedrine may status in with phenylephrine may be in women with should be to increases in oxygen and blood the other ephedrine may be to phenylephrine in with should be may be as either are although or In the there are in of and and and may as a of antenatal with and be to of spinal to anaesthesia and should be non-invasive oscillometric blood pressure is this should be to not the or should the blood pressure as frequently as using the available at until having caesarean section need a of volume including vomiting and prolonged The of the of heart as an of in women with is now is an absolute to spinal anaesthesia for caesarean section; to in splanchnic and of blood the In this following spinal anaesthesia cause in and A of is usually for caesarean section. This may be or decreased for of but does not need to be for body is administer is an is although there are to less is to with to a for of with to a of with have been but there are be including and a and be taken to drug and with There is for the management of hypotension after spinal anaesthesia in resource-poor environments. 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Abstract Objective : To investigate the role of sleeping arrangements as risk factors for the sudden infant death syndrome after a national risk reduction campaign. Design : Two year population based case-control study. Parental interviews were conducted for each infant who died and for four controls matched for age and date of interview. Setting : Three regions in England with a total population of 17 million people. Subjects : 195 babies who died and 780 matched controls. Results : Prone and side sleeping positions both carried increased risks of death compared with supine when adjusted for maternal age, parity, gestation, birth weight, exposure to smoke, and other relevant factors in the sleeping environment (multivariate odds ratio = 9.00 (95% confidence interval 2.84 to 28.47) and 1.84 (1.02 to 3.31), respectively). The higher incidence of side rather than prone sleeping led to a higher population attributable risk (side 18.4%, prone 14.2%). More of the infants who died were found with bed covers over their heads (21.58; 6.21 to 74.99). The use of a dummy had an apparent protective effect (0.38; 0.21 to 0.70). Bed sharing for the whole night was a significant risk factor for infants whose mothers smoked (9.25; 2.31 to 34.02). No protective effect of breast feeding could be identified on multivariate analysis. Conclusions : This study confirms the importance of certain risk factors for the sudden infant death syndrome and identifies others—for example, covers over the head, side sleeping position—which may be amenable to change by educating and informing parents and health care professionals. Key messages This large case-control study is the first after the national campaign to reduce the risk of the syndrome The risk of sudden infant death is increased by prone or side sleeping position; loose bedding (particularly duvets), which can slip over the baby's head; and bed sharing by mothers who smoke The risk may be reduced by supine sleeping position; placing the baby with feet at the foot of the cot (“feet to foot”); ensuring that bedding is securely tucked in; and avoiding the use of duvets

One hundred and thirty-seven very low birthweight (VLBW) children were compared at 12 years with a sample of matched peers on a number of psychiatric symptoms including Attention Deficit/Hyperactivity Disorder, depression, anxiety, and antisocial behaviour using the Child and Adolescent Psychiatric Assessment parent interview and various parent and child questionnaires. The main psychiatric risk was Attention Deficit Hyperactivity (ADH) disorders, with 31/136 (23%) VLBW children meeting clinical criteria, compared to 9/148 (6%) of peers. VLBW children were also more likely to have generalised anxiety and more symptoms of depression. More than one quarter of VLBW children (38/136; 28%) showed a psychiatric disorder of some type compared to 9% (14/148) of peers. VLBW children are at increased risk of psychiatric symptoms especially ADHD. This outcome is discussed in relation to neurological, demographic, and cumulative impairment factors.

BACKGROUND: The debriefing process during simulation-based education has been poorly studied despite its educational importance. Videotape feedback is an adjunct that may enhance the impact of the debriefing and in turn maximize learning. The purpose of this study was to investigate the value of the debriefing process during simulation and to compare the educational efficacy of two types of feedback, oral feedback and videotape-assisted oral feedback, against control (no debriefing). METHODS: Forty-two anesthesia residents were enrolled in the study. After completing a pretest scenario, participants were randomly assigned to receive no debriefing, oral feedback, or videotape-assisted oral feedback. The debriefing focused on nontechnical skills performance guided by crisis resource management principles. Participants were then required to manage a posttest scenario. The videotapes of all performances were later reviewed by two blinded independent assessors who rated participants' nontechnical skills using a validated scoring system. RESULTS: Participants' nontechnical skills did not improve in the control group, whereas the provision of oral feedback, either assisted or not assisted with videotape review, resulted in significant improvement (P < 0.005). There was no difference in improvement between oral and video-assisted oral feedback groups. CONCLUSIONS: Exposure to a simulated crisis without constructive debriefing by instructors offers little benefit to trainees. The addition of video review did not offer any advantage over oral feedback alone. Valuable simulation training can therefore be achieved even when video technology is not available.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

OBJECTIVE: To test the hypothesis that free fetal DNA (ffDNA) circulating in maternal plasma originates mainly from the placenta we studied ffDNA levels in anembryonic pregnancies. METHODS: Maternal blood samples were collected from 15 normal first-trimester pregnancies in which fetal sex was subsequently determined and nine patients with a diagnosis of anembryonic gestation (AG). The Y chromosome DYS14 gene was quantified by real-time quantitative PCR (RT-PCR) for the determination of fetal sex in both plasma and chorionic tissue samples. Fetal sex in chorionic tissue samples was also determined using quantitative fluorescence PCR (QF-PCR). RESULTS: The correct sex result was obtained from maternal plasma in all. Four AG pregnancies were female (DYS14 negative) results. In five of the AG cases, the chorionic tissue was found to be male (by both QF-PCR and RT-PCR which agreed) and positive male signal was found in maternal plasma by RT-PCR. There was no statistical difference between median free fetal DNA concentration in plasma between the AG male cases (148.3 GE/mL) and controls (145.8 GE/mL). CONCLUSION: Since ffDNA levels are normal in pregnancies without a fetus, the data support the hypothesis that the trophoblastic cells are the major source ffDNA in maternal plasma.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 mL. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative.The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and improvements in dysmenorrhoea (pain or cramps during menstruation). Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months after commencing treatment. OBJECTIVES: To determine the effectiveness, acceptability and safety of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH METHODS: All randomised controlled trials of progesterone or progestogen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, the specialised register of MDSG, MEDLINE (1966 to January 2015), EMBASE (1980 to January 2015), CINAHL (inception to December 2014) and PsycINFO (inception to January 2015). Additional searches were undertaken for grey literature and for unpublished trials in trial registers. Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Potential trials were independently assessed by at least two review authors. The review authors extracted the data independently and data were pooled where appropriate. Risk ratios (RRs) were estimated from the data for dichotomous outcomes and mean differences (MD) for continuous outcomes. The primary outcomes were reduction in menstrual blood loss and satisfaction; in addition, rate of adverse effects, changes in quality of life, failure of treatment and withdrawal from treatment were also assessed. MAIN RESULTS: We included 21 RCTs (2082 women). The included trials mostly assessed the levonorgestrel-releasing intrauterine device (LNG IUS) (no conclusions could be reached from one small study assessing Progestasert which was discontinued in 2001) and so conclusions are based only on LNG IUS. Comparisons were made with placebo, oral medical treatment, endometrial destruction techniques and hysterectomy. Ratings for the overall quality of the evidence for each comparison ranged from very low to high. Limitations in the evidence included inadequate reporting of study methods and inconsistency.Seven studies compared the LNG IUS with oral medical therapy: either norethisterone acetate (NET) administered over most of the menstrual cycle, medroxyprogesterone acetate (MPA) (administered for 10 days), the oral contraceptive pill, mefenamic acid or usual medical treatment where participants could choose the oral treatment that was most suitable. The LNG IUS was more effective at reducing HMB as measured by the alkaline haematin method (MD 66.91 mL, 95% CI 42.61 to 91.20; two studies, 170 women; I(2) = 81%, low quality evidence) or by Pictorial Bleeding Assessment Chart (PBAC) scores (MD 55.05, 95% CI 27.83 to 82.28; three studies, 335 women; I(2) = 79%, low quality evidence), improving quality of life and a greater number of women continued with their treatment at two years when compared with oral treatment. Although substantial heterogeneity was identified for the bleeding outcomes, the direction of effect consistently favoured the LNG IUS. There was insufficient evidence to reach conclusions on satisfaction. Minor adverse effects (such as pelvic pain, breast tenderness and ovarian cysts) were more common with the LNG IUS.Ten studies compared the LNG IUS with endometrial destruction techniques: three with transcervical resection, one with rollerball ablation and six with thermal balloon ablation. Evidence was inconsistent and very low quality with respect to reduction in bleeding outcomes and satisfaction was comparable between treatments (low and moderate quality evidence). Improvements in quality of life were experienced with both types of treatment. Minor adverse events were more common with the LNG IUS overall, but it appeared more cost effective compared to thermal ablation within a two-year time frame in one study.Three studies compared the LNG IUS with hysterectomy. The LNG IUS was not as successful at reducing HMB as hysterectomy (high quality evidence). The women in these studies reported improved quality of life, regardless of treatment. In spite of the high rate of surgical treatment in those having LNG IUS within 10 years, the LNG IUS was more cost effective than hysterectomy. AUTHORS' CONCLUSIONS: The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than oral medication as a treatment for heavy menstrual bleeding (HMB). It is associated with a greater reduction in HMB, improved quality of life and appears to be more acceptable long term but is associated with more minor adverse effects than oral therapy.When compared to endometrial ablation, it is not clear whether the LNG IUS offers any benefits with regard to reduced HMB and satisfaction rates and quality of life measures were similar. Some minor adverse effects were more common with the LNG IUS but it appeared to be more cost effective than endometrial ablation techniques.The LNG IUS was less effective than hysterectomy in reducing HMB. Both treatments improved quality of life but the LNG IUS appeared more cost effective than hysterectomy for up to 10 years after treatment.

BACKGROUND: Critical incident reporting and observational studies have identified nontechnical skills that are vital to successful anesthesia crisis management. Examples of such skills include task management, team working, situation awareness, and decision making. These skills are not necessarily acquired through clinical experience and may need to be specifically taught. This study uses a high-fidelity patient simulator to assess the effect of repeated exposure to simulated anesthesia crises on the nontechnical skills of anesthesia residents. METHODS: After institutional research board approval and informed consent, 20 anesthesia residents were recruited. Each resident was randomized to participate as the primary anesthesiologist in the management of three different simulated anesthesia crises using a high-fidelity patient simulator. After each session, videotaped footage was used to facilitate debriefing of their nontechnical skills. The videotapes were later reviewed by two expert blinded independent assessors who rated each resident's nontechnical skills by using a previously validated and reliable marking system. RESULTS: : A significant improvement in the nontechnical skills of residents was demonstrated from their first to second session and from their first to third session (both P < 0.005). However from their second to third session, no significant improvement was observed. Interrater reliability between assessors was modest (single rater intraclass correlation = 0.53). CONCLUSION: A single exposure to anesthesia crises using a high-fidelity patient simulator can improve the nontechnical skills of anesthesia residents. However, an additional simulation session may confer little or no additional benefit.

OBJECTIVE: Therapeutic hypothermia (HT) is the standard treatment for newborns after perinatal asphyxia. Preclinical studies report that HT is more effective when started early. METHODS: Eighty cooled newborns were analyzed and grouped according to when cooling was started after birth: early (≤180 min) or late (>181 min). For survivors we analyzed whether starting cooling early was associated with a better psychomotor or mental developmental index (PDI or MDI, Bayley Scales of Infant Development II) than late cooling. RESULTS: Forty-three newborns started cooling early and 37 started late. There was no significant difference in the severity markers of perinatal asphyxia between the groups; however, nonsurvivors (n = 15) suffered more severe asphyxia and had significantly lower centiles for weight (BWC; p = 0.009). Of the 65 infants that survived, 35 were cooled early and 30 were cooled late. There was no difference in time to start cooling between those who survived and those who did not. For survivors, median PDI (IQR) was significantly higher when cooled early [90 (77-99)] compared to being cooled later [78 (70-90); p = 0.033]. There was no increase in cardiovascular adverse effects in those cooled early. There was no significant difference in MDI between early and late cooling [93 (77-103) vs. 89 (76-106), p = 0.594]. CONCLUSION: Starting cooling before 3 h of age in surviving asphyxiated newborns is safe and significantly improves motor outcome. Cooling should be initiated as soon as possible after birth in eligible infants.

The authors of the World Health Organization Semen Analysis Manual are to be congratulated on producing a new edition; it is an essential tool to disseminate good practice in andrology. However, the tests described have poor prognostic power to predict a man's fertility and show little about the underlying causes of sub-fertility. This commentary urges a revival of research into the diagnosis of male fertility. It suggests that fertility should be regarded as a continuum and that the artificial binary division between fertile and infertile should be abandoned. Models to predict a sub-fertile couple's chance of conception in a year should be developed on the basis of prospective data. These models would allow for sophisticated decision making about management. The future lies in the identification of tests to detect underlying pathologies open to specific treatment. Leads such as oxidative stress, defects in the intracellular regulation and the developing field of proteomics should be explored.

OBJECTIVE: To determine the expected duration of symptoms of common respiratory tract infections in children in primary and emergency care. DESIGN: Systematic review of existing literature to determine durations of symptoms of earache, sore throat, cough (including acute cough, bronchiolitis, and croup), and common cold in children. DATA SOURCES: PubMed, DARE, and CINAHL (all to July 2012). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials or observational studies of children with acute respiratory tract infections in primary care or emergency settings in high income countries who received either a control treatment or a placebo or over-the-counter treatment. Study quality was assessed with the Cochrane risk of bias framework for randomised controlled trials, and the critical appraisal skills programme framework for observational studies. MAIN OUTCOME MEASURES: Individual study data and, when possible, pooled daily mean proportions and 95% confidence intervals for symptom duration. Symptom duration (in days) at which each symptom had resolved in 50% and 90% of children. RESULTS: Of 22,182 identified references, 23 trials and 25 observational studies met inclusion criteria. Study populations varied in age and duration of symptoms before study onset. In 90% of children, earache was resolved by seven to eight days, sore throat between two and seven days, croup by two days, bronchiolitis by 21 days, acute cough by 25 days, common cold by 15 days, and non-specific respiratory tract infections symptoms by 16 days. CONCLUSIONS: The durations of earache and common colds are considerably longer than current guidance given to parents in the United Kingdom and the United States; for other symptoms such as sore throat, acute cough, bronchiolitis, and croup the current guidance is consistent with our findings. Updating current guidelines with new evidence will help support parents and clinicians in evidence based decision making for children with respiratory tract infections.

Sperm capacitation can be increased by the addition of reactive oxygen species (ROS) and decreased by antioxidants. Broadly consistent results have been achieved with a wide variety of methods and across different species. Exposure to ROS increases protein tyrosine phosphorylation consequent on an increase in cAMP and activation of tyrosine kinase and inhibition of tyrosine phosphatase. The measurement of ROS production by sperm is complicated by contamination of suspensions by leukocytes, laying many studies open to doubt. In human sperm the observation that extracellular NADPH could support superoxide production detected with the chemiluminescent probe lucigenin and had physiological effects similar to hydrogen peroxide led to the suggestion that they contained NADPH oxidase activity to generate ROS to support capacitation. However, the realization that lucigenin can signal superoxide artefactually, combined with failure to detect superoxide production using spin trapping techniques or to detect NADPH oxidase components in mature sperm, and confirmation of old reports that NADPH solution contains substantial amounts of hydrogen peroxide due to autoxidation, have undermined this hypothesis. Although the presence of significant NADPH oxidase activity in mature human sperm now seems less likely, other observations continue to suggest that they can make ROS in some way. There is stronger evidence that animal sperm can make ROS although these may be mainly of mitochondrial origin.

It is doubtful that diffusion can deliver sufficient ATP from the mitochondria to sustain activity at the distal end of the sperm flagellum. Glycolytic enzymes bound to the fibrous sheath could provide energy along the flagellum at the point it is required. An obligatory role for glycolysis is supported by the lack of progressive motility in sperm from mice where the gene for sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHs) had been 'knocked out'. Here, I review some evidence against this idea. First, pure diffusion from the mitochondrion is likely to be adequate in species with smaller sperm, and it is possible that rapid ATP delivery required in larger sperm could be achieved by an adenylate kinase shuttle. Second, experience with alpha-chlorohydrin demonstrates that sperm can remain motile with normal ATP concentrations despite inhibition of GAPDHs; adverse effects only occur if glucose is added and high levels of glycolytic intermediates accumulate. These observations undermine the GAPDHs knockout mouse as evidence for an essential role of local glycolysis. Third, sperm from many species can remain motile for long periods in sugar-free media and excepting dog sperm, evidence that gluconeogenesis is a possible explanation, is weak. In most species, it is unlikely that local glycolysis is the only way that ATP can be supplied to the distal flagellum.

OBJECTIVE: To evaluate the effectiveness of endometrial resection as a surgical treatment for menorrhagia. DESIGN: Randomised controlled trial. SETTING: Gynaecology department at a teaching hospital. SUBJECTS: Two hundred women needing surgical treatment for menorrhagia between January 1990 and May 1991. After withdrawal of four women 97 underwent hysterectomy and 99 underwent endometrial resection. MAIN OUTCOME MEASURES: Patient satisfaction 4 months after surgery; post-operative complications; length of hospital stay; duration of time before return to work, normal daily activities and sexual intercourse; change in premenstrual symptoms. RESULTS: The difference in patient satisfaction between endometrial resection (84 out of 99) and abdominal hysterectomy (89 out of 95) just reached statistical significance in favour of abdominal hysterectomy at 4 months after surgery (difference = 9%, 95% confidence intervals (CI) 1.1%-17.5%). Post-operative morbidity, length of hospital stay and time taken to return to work, normal daily activities and sexual intercourse were significantly less in the endometrial resection group. However, the premenstrual symptoms of dysmenorrhoea, bloating and breast tenderness were less frequent after hysterectomy. CONCLUSION: In the short term, endometrial resection was almost as satisfactory as abdominal hysterectomy for the surgical treatment of menorrhagia, and was associated with less morbidity. However, even at 4 months after surgery, there was a failure rate of at least 10% in those in whom endometrial resection appeared complete. Longer term comparative studies are necessary before the widespread introduction of endometrial resection as an alternative to abdominal hysterectomy for the surgical treatment of menorrhagia.

Darkening of parts of the Greenland ice sheet surface during the summer months leads to reduced albedo and increased melting. Here we show that heavily pigmented, actively photosynthesising microalgae and cyanobacteria are present on the bare ice. We demonstrate the widespread abundance of green algae in the Zygnematophyceae on the ice sheet surface in Southwest Greenland. Photophysiological measurements (variable chlorophyll fluorescence) indicate that the ice algae likely use screening mechanisms to downregulate photosynthesis when exposed to high intensities of visible and ultraviolet radiation, rather than non-photochemical quenching or cell movement. Using imaging microspectrophotometry, we demonstrate that intact cells and filaments absorb light with characteristic spectral profiles across ultraviolet and visible wavelengths, whereas inorganic dust particles typical for these areas display little absorption. Our results indicate that the phototrophic community growing directly on the bare ice, through their photophysiology, most likely have an important role in changing albedo, and subsequently may impact melt rates on the ice sheet.