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: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.

OBJECTIVE: To compare the management of and neonatal injury associated with shoulder dystocia before and after introduction of mandatory shoulder dystocia simulation training. METHODS: This was a retrospective, observational study comparing the management and neonatal outcome of births complicated by shoulder dystocia before (January 1996 to December 1999) and after (January 2001 to December 2004) the introduction of shoulder dystocia training at Southmead Hospital, Bristol, United Kingdom. The management of shoulder dystocia and associated neonatal injuries were compared pretraining and posttraining through a review of intrapartum and postpartum records of term, cephalic, singleton births in which difficulty with the shoulders was recorded during the two study periods. RESULTS: There were 15,908 and 13,117 eligible births pretraining and posttraining, respectively. The shoulder dystocia rates were similar: pretraining 324 (2.04%) and posttraining 262 (2.00%) (P=.813). After training was introduced, clinical management improved: McRoberts' position, pretraining 95/324 (29.3%) to 229/262 (87.4%) posttraining (P<.001); suprapubic pressure 90/324 (27.8%) to 119/262 (45.4%) (P<.001); internal rotational maneuver 22/324 (6.8%) to 29/262 (11.1%) (P=.020); delivery of posterior arm 24/324 (7.4%) to 52/262 (19.8%) (P<.001); no recognized maneuvers performed 174/324 (50.9%) to 21/262 (8.0%) (P<.001); documented excessive traction 54/324 (16.7%) to 24/262 (9.2%) (P=.010). There was a significant reduction in neonatal injury at birth after shoulder dystocia: 30/324 (9.3%) to 6/262 (2.3%) (relative risk 0.25 [confidence interval 0.11-0.57]). CONCLUSION: The introduction of shoulder dystocia training for all maternity staff was associated with improved management and neonatal outcomes of births complicated by shoulder dystocia. LEVEL OF EVIDENCE: II.

OBJECTIVE: To examine a range of demographic, social, and clinical risk factors for the development of rheumatoid arthritis (RA). METHODS: Population-based case-control study in Norfolk, England, involving adult patients, ages 18-70, with an inflammatory polyarthritis of <12 months' duration who were recruited from the Norfolk Arthritis Register. Controls, matched for sex and date of birth, were selected from the primary care register of the Norwich Health Authority. Both cases and controls completed identical self-administered questionnaires. Matched analysis of the 165 case-control sets was conducted for the whole group and for the subset in which the cases satisfied the 1987 American College of Rheumatology criteria for RA. RESULTS: The controls were of higher socioeconomic status than the cases. This was probably due to response bias. Having a body mass index > or =30 was associated with an adjusted odds ratio (OR) of 3.74 for developing RA (95% confidence interval [95% CI] 1.14-12.27). RA was also associated with a history of blood transfusion (OR 4.83, 95% CI 1.29-18.07). Even after correcting for social class, a history of having ever smoked was associated with a higher risk of developing RA (OR 1.66, 95% CI 0.95-3.06). There was no difference between cases and controls in previous exposure to childhood infections, certain surgical procedures, or reproductive history variables. CONCLUSION: RA has a number of potential environmental triggers, including smoking, obesity, and blood transfusion.

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.

OBJECTIVE: To determine the degree and causes of any excess mortality observed during the early years of inflammatory polyarthritis (IP). METHODS: Between 1990 and 1994, a total of 1,236 patients were registered with the Norfolk Arthritis Register, a primary care-based inception cohort. All patients were tracked on the National Health Service Central Register for notification of death. The vital status of each patient was determined as of December 31, 1999. Causes of death were coded according to the International Classification of Diseases, Ninth Revision. Expected death rates were calculated using annual death rates for the Norfolk population. Standardized mortality ratios (SMRs) were calculated for all IP patients and for the subgroups of patients who did and did not satisfy the American College of Rheumatology (ACR) 1987 criteria for rheumatoid arthritis (RA) at baseline, as well as for the subgroups who were and were not rheumatoid factor (RF) positive at baseline. RESULTS: By December 31, 1999, 160 patients (13%; 79 women and 81 men) had died. The median duration of followup in the entire cohort was 6.9 years. Mortality rates were not significantly increased in the entire group of patients with IP or in the subgroup who met the ACR 1987 criteria for RA at baseline. In contrast, RF-positive patients had an increased rate of death from all causes (SMR in men 1.51, in women 1.41). Cardiovascular disease was the most common cause of death. The majority of the excess mortality in the RF-positive patients could be attributed to cardiovascular causes (SMR in men 1.34, in women 2.02). CONCLUSION: Excess mortality in the early years of IP is confined to patients who are seropositive for RF. While excess cardiovascular mortality has been described in patients with established RA, this is the first report of premature death from heart disease in the early years of IP.

Medical schools are increasingly called to include social responsibility in their mandates. As such, they are focusing their attention on the social determinants of health (SDOH) as key drivers in the health of the patients and communities they serve. However, underlying this emphasis on the SDOH is the assumption that teaching medical students about the SDOH will lead future physicians to take action to help achieve health equity. There is little evidence to support this belief. In many ways, the current approach to the SDOH within medical education positions them as “facts to be known” rather than as “conditions to be challenged and changed.” Educators talk about poverty but not oppression, race but not racism, sex but not sexism, and homosexuality but not homophobia. The current approach to the SDOH may constrain or even incapacitate the ability of medical education to achieve the very goals it lauds, and in fact perpetuate inequity. In this article, the authors explore how “critical consciousness” and a recentering of the SDOH around justice and inequity can be used to deepen collective understanding of power, privilege, and the inequities embedded in social relationships in order to foster an active commitment to social justice among medical trainees. Rather than calling for minor curricular modifications, the authors argue that major structural and cultural transformations within medical education need to occur to make educational institutions truly socially responsible.

BACKGROUND: Previous research has indicated that children who stutter are more likely to be bullied and to hold a lower social position than their peers who do not stutter. However, the majority of this research has used data from respondents who were in the educational system more than 20 years ago. The current policy on integration of children with severe disabilities into mainstream education and the increased awareness of bullying in schools would indicate that attitudes toward children who stutter might have changed in the intervening period. METHOD: The study uses a sociometric scale (adapted from Coie, Dodge, & Coppotelli, 1982) to assess children who stutter in classroom groups with fluent peers. The peer relationships between 16 children who stutter and their classmates (403 children in total) were examined. RESULTS: Children who stutter were rejected significantly more often than were their peers and were significantly less likely to be popular. When compared to children who do not stutter, the children who stutter were less likely to be nominated as 'leaders' and were more likely to be nominated to the 'bullied' and 'seeks help' categories. CONCLUSIONS: The changes in integration policy and the implementation of anti-bullying policies in many schools appear to have made little impact on the social status of children who stutter. The incidence of bullying and rejection reported in this study has implications for schools and clinicians.

Glucose has been reported to be beneficial to human sperm for optimal capacitation and fertilization, although it is unclear whether glucose is required for providing extra metabolic energy through glycolysis, or for generating some other metabolic product. In this study, the effects of sugars on human sperm capacitation, motility, and energy production were investigated. The glucose concentration that supported the greatest number of acrosome reactions was 5.56 mmol L(-1). Compared with incubations with no added sugar, this concentration of glucose, fructose, mannose, or galactose appeared to slightly increase the number of acrosome reactions occurring after 18 hours of capacitation, or following induction by 2 micromol A23187 + 3.6 mmol pentoxifylline L 1, but only glucose had a statistically significant effect. Glucose supported increased penetration of zona-free hamster oocytes, but its advantage was not statistically significant. The addition of 5.56 mmol glucose or fructose L(-1) to sugar-free medium immediately increased the adenosine triphosphate (ATP) concentration and motility of sperm. These parameters were then stable for 3 hours, but declined markedly after 18 hours. In the absence of a glycolysable sugar, motility began to decline in the first hour and only 2% or 3% of sperm remained motile after 18 hours. Glucose or fructose was required to support hyperactivated motility. 2-Deoxyglucose was detrimental to the ATP concentration and motility of sperm, and supported fewer spontaneous or progesterone-stimulated acrosome reactions than were observed in the absence of a sugar. We conclude that glycolytic ATP production is required for vigorous motility and hyperactivation in human sperm. Other products of glucose metabolism are not essential to support capacitation, but they may have a small, enhancing effect.

Given the multiplicity of nanoparticles (NPs), there is a requirement to develop screening strategies to evaluate their toxicity. Within the EU-funded FP7 NanoTEST project, a panel of medically relevant NPs has been used to develop alternative testing strategies of NPs used in medical diagnostics. As conventional toxicity tests cannot necessarily be directly applied to NPs in the same manner as for soluble chemicals and drugs, we determined the extent of interference of NPs with each assay process and components. In this study, we fully characterized the panel of NP suspensions used in this project (poly(lactic-co-glycolic acid)-polyethylene oxide [PLGA-PEO], TiO2, SiO2, and uncoated and oleic-acid coated Fe3O4) and showed that many NP characteristics (composition, size, coatings, and agglomeration) interfere with a range of in vitro cytotoxicity assays (WST-1, MTT, lactate dehydrogenase, neutral red, propidium iodide, (3)H-thymidine incorporation, and cell counting), pro-inflammatory response evaluation (ELISA for GM-CSF, IL-6, and IL-8), and oxidative stress detection (monoBromoBimane, dichlorofluorescein, and NO assays). Interferences were assay specific as well as NP specific. We propose how to integrate and avoid interference with testing systems as a first step of a screening strategy for biomedical NPs.

BACKGROUND: In light of increasing rates and severity of sepsis worldwide, this study aimed to estimate the incidence of, and describe the causative organisms, sources of infection, and risk factors for, severe maternal sepsis in the UK. METHODS AND FINDINGS: A prospective case-control study included 365 confirmed cases of severe maternal sepsis and 757 controls from all UK obstetrician-led maternity units from June 1, 2011, to May 31, 2012. Incidence of severe sepsis was 4.7 (95% CI 4.2-5.2) per 10,000 maternities; 71 (19.5%) women developed septic shock; and five (1.4%) women died. Genital tract infection (31.0%) and the organism Escherichia coli (21.1%) were most common. Women had significantly increased adjusted odds ratios (aORs) of severe sepsis if they were black or other ethnic minority (aOR = 1.82; 95% CI 1.82-2.51), were primiparous (aOR = 1.60; 95% CI 1.17-2.20), had a pre-existing medical problem (aOR = 1.40; 95% CI 1.01-1.94), had febrile illness or were taking antibiotics in the 2 wk prior to presentation (aOR = 12.07; 95% CI 8.11-17.97), or had an operative vaginal delivery (aOR = 2.49; 95% CI 1.32-4.70), pre-labour cesarean (aOR = 3.83; 95% CI 2.24-6.56), or cesarean after labour onset (aOR = 8.06; 95% CI 4.65-13.97). Median time between delivery and sepsis was 3 d (interquartile range = 1-7 d). Multiple pregnancy (aOR = 5.75; 95% CI 1.54-21.45) and infection with group A streptococcus (aOR = 4.84; 2.17-10.78) were associated with progression to septic shock; for 16 (50%) women with a group A streptococcal infection there was <2 h-and for 24 (75%) women, <9 h-between the first sign of systemic inflammatory response syndrome and a diagnosis of severe sepsis. A limitation of this study was the proportion of women with sepsis without an identified organism or infection source (16.4%). CONCLUSIONS: For each maternal sepsis death, approximately 50 women have life-threatening morbidity from sepsis. Follow-up to ensure infection is eradicated is important. The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign guideline of early administration of high-dose intravenous antibiotics within 1 h of admission to hospital for anyone with suspected sepsis. Signs of severe sepsis in peripartum women, particularly with confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency. Please see later in the article for the Editors' Summary.

In many growth models, economic growth arises from people creating ideas, and the long-run growth rate is the product of two terms: the effective number of researchers and their research productivity.We present a wide range of evidence from various industries, products, and firms showing that research effort is rising substantially while research productivity is declining sharply.A good example is Moore's Law.The number of researchers required today to achieve the famous doubling every two years of the density of computer chips is more than 18 times larger than the number required in the early 1970s.Across a broad range of case studies at various levels of (dis)aggregation, we find that ideas-and in particular the exponential growth they imply -are getting harder and harder to find.Exponential growth results from the large increases in research effort that offset its declining productivity.

Nasotracheal intubation offers the head and neck surgeon more scope for surgical manoeuvre in operations of the mouth, pharynx, larynx and also the neck. Concern over the complications of using this route of intubation and lack of training may be limiting its use. A thorough knowledge of the anatomy, benefits of using nasal vasoconstrictors and attention to technique are prerequisites to maintaining the skill. This article reviews each of these topics and aims to encourage the appropriate use of nasotracheal intubation in current practice.

BACKGROUND: The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. METHODS: We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. FINDINGS: 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5). INTERPRETATION: Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

Randomised clinical trials show that two injections of corticosteroid into the mother before preterm delivery reduce respiratory distress syndrome, neonatal mortality, and intraventricular haemorrhage. However, repeated courses of antenatal steroid are not backed by such evidence of safety and efficacy. Animal studies have shown that maternal corticosteroid delays myelination and reduces the growth of all fetal brain areas particularly the hippocampus. Corticosteroids may reduce or enhance hypoxic-ischaemic injury to the developing brain depending on timing and dosage. Clinical trials of maternally administered corticosteroid show no evidence of increased disability on follow up but numbers are small. Postnatal trials of dexamethasone when brain maturity is still preterm show a significant increase in later disability in the dexamethasone treated groups. There is evidence from randomised trials, retrospective data, experiments on pregnant mice, and the chemical make up of the preparations that betamethasone may be safer and more protective of the immature brain than dexamethasone. Single course corticosteroid treatment before preterm delivery must still be recommended as a life saving and cost effective intervention, but clinicians may wish to change from using dexamethasone to betamethasone. In view of the animal and postnatal data, clinicians should be cautious with repeated courses of antenatal corticosteroids and repetition may be unnecessary for lung maturity.

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia. Considerable progress has been made in elucidating the molecular genetics and genotype–phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. We discuss the genetics, and clinical, psychophysical, electrophysiological and retinal imaging characteristics of cone and cone-rod dystrophies, focusing particularly on four of the most common disease-associated genes: GUCA1A , PRPH2 , ABCA4 and RPGR . Additionally, we briefly review the current management of these disorders and the prospects for novel therapies.

RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death.

The author discusses issues confronted by aging women, particularly those related to ageism and body image, emphasizing society's role in influencing women's perceptions of their bodies. Although body image issues cause anxiety throughout most women's lives, women entering middle age become more conscious of this concern. Problems related to a woman's realization that she no longer conforms to society's standards of youth and beauty include low self‐esteem, depression, and anxiety.