KK Women's and Children's Hospital

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.

Langerhans cells (LCs) are the dendritic cells (DCs) of the epidermis, forming one of the first hematopoietic lines of defense against skin pathogens. In contrast to other DCs, LCs arise from hematopoietic precursors that seed the skin before birth. However, the origin of these embryonic precursors remains unclear. Using in vivo lineage tracing, we identify a first wave of yolk sac (YS)–derived primitive myeloid progenitors that seed the skin before the onset of fetal liver hematopoiesis. YS progenitors migrate to the embryo proper, including the prospective skin, where they give rise to LC precursors, and the brain rudiment, where they give rise to microglial cells. However, in contrast to microglia, which remain of YS origin throughout life, YS-derived LC precursors are largely replaced by fetal liver monocytes during late embryogenesis. Consequently, adult LCs derive predominantly from fetal liver monocyte-derived cells with a minor contribution of YS-derived cells. Altogether, we establish that adult LCs have a dual origin, bridging early embryonic and late fetal myeloid development.

Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8(+) T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141(hi) DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c(+) and CD14(+) tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141(hi) DCs were closely related to blood CD141(+) DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.

INTRODUCTION These Guidelines aim to describe appropriate assessment of fetal biometry and diagnosis of fetal growth disorders. These disorders consist mainly of fetal growth restriction (FGR), also referred to as intrauterine growth restriction (IUGR) and often associated with small‐for‐gestational age (SGA), and large‐for‐gestational age (LGA), which may lead to fetal macrosomia; both have been associated with a variety of adverse maternal and perinatal outcomes. Screening for, and adequate management of, fetal growth abnormalities are essential components of antenatal care, and fetal ultrasound plays a key role in assessment of these conditions. The fetal biometric parameters measured most commonly are biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur diaphysis length (FL). These biometric measurements can be used to estimate fetal weight (EFW) using various different formulae1. It is important to differentiate between the concept of fetal size at a given timepoint and fetal growth, the latter being a dynamic process, the assessment of which requires at least two ultrasound scans separated in time. Maternal history and symptoms, amniotic fluid assessment and Doppler velocimetry can provide additional information that may be used to identify fetuses at risk of adverse pregnancy outcome. Accurate estimation of gestational age is a prerequisite for determining whether fetal size is appropriate‐for‐gestational age (AGA). Except for pregnancies arising from assisted reproductive technology, the date of conception cannot be determined precisely. Clinically, most pregnancies are dated by the last menstrual period, though this may sometimes be uncertain or unreliable. Therefore, dating pregnancies by early ultrasound examination at 8–14 weeks, based on measurement of the fetal crown–rump length (CRL), appears to be the most reliable method to establish gestational age. Once the CRL exceeds 84 mm, HC should be used for pregnancy dating2–4. HC, with or without FL, can be used for estimation of gestational age from the mid‐trimester if a first‐trimester scan is not available and the menstrual history is unreliable. When the expected delivery date has been established by an accurate early scan, subsequent scans should not be used to recalculate the gestational age1. Serial scans can be used to determine if interval growth has been normal. In these Guidelines, we assume that the gestational age is known and has been determined as described above, the pregnancy is singleton and the fetal anatomy is normal. Details of the grades of recommendation used in these Guidelines are given in Appendix 1. Reporting of levels of evidence is not applicable to these Guidelines.

article Free AccessEnterprise resource planning: cultural fits and misfits: is ERP a universal solution? Authors: Christina Soh Nanyang Technological Univ., Singapore Nanyang Technological Univ., SingaporeView Profile , Sia Siew Kien Nanyang Technological Univ., Singapore Nanyang Technological Univ., SingaporeView Profile , Joanne Tay-Yap KK Woman's and Children's Hospital, Singapore KK Woman's and Children's Hospital, SingaporeView Profile Authors Info & Claims Communications of the ACMVolume 43Issue 401 April 2000pp 47–51https://doi.org/10.1145/332051.332070Published:01 April 2000Publication History 71citation17,190DownloadsMetricsTotal Citations71Total Downloads17,190Last 12 Months843Last 6 weeks221 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteView all FormatsPDF

BACKGROUND: Human papillomavirus (HPV)-6/11/16/18 vaccine reduces the risk of HPV-6/11/16/18-related cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS). Here, its impact on CIN1-3/AIS associated with nonvaccine oncogenic HPV types was evaluated. METHODS: We enrolled 17,622 women aged 16-26 years. All underwent cervicovaginal sampling and Pap testing at regular intervals for up to 4 years. HPV genotyping was performed for biopsy samples, and histological diagnoses were determined by a pathology panel. Analyses were conducted among subjects who were negative for 14 HPV types on day 1. Prespecified analyses included infection of 6 months' duration and CIN1-3/AIS due to the 2 and 5 most common HPV types in cervical cancer after HPV types 16 and 18, as well as all tested nonvaccine types. RESULTS: Vaccination reduced the incidence of HPV-31/45 infection by 40.3% (95% confidence interval [CI], 13.9% to 59.0%) and of CIN1-3/AIS by 43.6% (95% CI, 12.9% to 64.1%), respectively. The reduction in HPV-31/33/45/52/58 infection and CIN1-3/AIS was 25.0% (95% CI, 5.0% to 40.9%) and 29.2% (95% CI, 8.3% to 45.5%), respectively. Efficacy for CIN2-3/AIS associated with the 10 nonvaccine HPV types was 32.5% (95% CI, 6.0% to 51.9%). Reductions were most notable for HPV-31. CONCLUSIONS: HPV-6/11/16/18 vaccine reduced the risk of CIN2-3/AIS associated with nonvaccine types responsible for approximately 20% of cervical cancers. The clinical benefit of cross-protection is not expected to be fully additive to the efficacy already observed against HPV-6/11/16/18-related disease, because women may have >1 CIN lesion, each associated with a different HPV type. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00092521 , NCT00092534 , and NCT00092482.

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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Tracing development of the dendritic cell lineage Dendritic cells (DCs) are important components of the immune system that form from the bone marrow into two major cell lineages: plasmacytoid DCs and conventional DCs. See et al. applied single-cell RNA sequencing and cytometry by time-of-flight to characterize the developmental pathways of these cells. They identified blood DC precursors that shared surface markers with plasmacytoid DCs but that were functionally distinct. This unsuspected level of complexity in pre-DC populations reveals additional cell types and refines understanding of known cell types. Science , this issue p. eaag3009

BACKGROUND: The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were "negative to 14 HPV types" and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group). METHODS: This analysis studied 17 622 women aged 15-26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6-12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk. RESULTS: The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type. CONCLUSIONS: High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

There is a lack of high-quality evidence based on the gold standard of oral food challenges to determine food allergy prevalence. Nevertheless, studies using surrogate measures of food allergy, such as health service utilization and clinical history, together with allergen-specific immunoglobulin E (sIgE), provide compelling data that the prevalence of food allergy is increasing in both Western and developing countries. In Western countries, challenge-diagnosed food allergy has been reported to be as high as 10%, with the greatest prevalence noted among younger children. There is also growing evidence of increasing prevalence in developing countries, with rates of challenge-diagnosed food allergy in China and Africa reported to be similar to that in Western countries. An interesting observation is that children of East Asian or African descent born in a Western environment are at higher risk of food allergy compared to Caucasian children; this intriguing finding emphasizes the importance of genome-environment interactions and forecasts future increases in food allergy in Asia and Africa as economic growth continues in these regions. While cow's milk and egg allergy are two of the most common food allergies in most countries, diverse patterns of food allergy can be observed in individual geographic regions determined by each country's feeding patterns. More robust studies investigating food allergy prevalence, particularly in Asia and the developing world, are necessary to understand the extent of the food allergy problem and identify preventive strategies to cope with the potential increase in these regions.

10.1093/ije/dyt125

As congenital hearing impairment has a worldwide incidence of 4 to 5 per 1000 babies and is thus one of the most common congenital problems seen today, universal newborn screening has a crucial role to play in its early detection and intervention. It provides the opportunity for better outcomes and normal language development. Prior to embarking on a screening programme, the newborn population and the current health care system should be analysed to select the best method of coverage. The screening tool and protocol, communication of results, as well as the follow-up measures should be clearly determined and tested. The multidisciplinary team required should be provided with the necessary information. Parents need to be educated about the importance of early hearing screening. Data management and surveillance should be established in a systematic manner. The costs of the programme should be carefully anticipated and funding sources determined. Finally, support for the programme should be sought from governmental or public health bodies, to ensure the success of the programme. Legislation can be considered if necessary.

INTRODUCTION: Healthcare workers (HCWs) were at the frontline during the battle against Severe Acute Respiratory Syndrome (SARS). Understanding their fears and anxieties may hold lessons for handling future outbreaks, including acts of bioterrorism. METHOD: We measured risk perception and impact on personal and work life of 15,025 HCWs from 9 major healthcare institutions during the SARS epidemic in Singapore using a self-administered questionnaire and Impact of Events Scale and analyzed the results with bivariate and multivariate statistics. RESULTS: From 10,511 valid questionnaires (70% response), we found that although the majority (76%) perceived a great personal risk of falling ill with SARS, they (69.5%) also accepted the risk as part of their job. Clinical staff (doctors and nurses), staff in daily contact with SARS patients, and staff from SARS-affected institutions expressed significantly higher levels of anxiety. More than half reported increased work stress (56%) and work load (53%). Many experienced social stigmatization (49%) and ostracism by family members (31%), but most (77%) felt appreciated by society. Most felt that the personal protective measures implemented were effective (96%) and that the institutional policies and protocols were clear (93%) and timely (90%). CONCLUSION: During epidemics, healthcare institutions have a duty to protect HCWs and help them cope with their personal fears and the very stressful work situation. Singapore's experience shows that simple protective measures based on sound epidemiological principles, when implemented in a timely manner, go a long way to reassure HCWs.

For over a decade the term "Big data" has been used to describe the rapid increase in volume, variety and velocity of information available, not just in medical research but in almost every aspect of our lives. As scientists, we now have the capacity to rapidly generate, store and analyse data that, only a few years ago, would have taken many years to compile. However, "Big data" no longer means what it once did. The term has expanded and now refers not to just large data volume, but to our increasing ability to analyse and interpret those data. Tautologies such as "data analytics" and "data science" have emerged to describe approaches to the volume of available information as it grows ever larger. New methods dedicated to improving data collection, storage, cleaning, processing and interpretation continue to be developed, although not always by, or for, medical researchers. Exploiting new tools to extract meaning from large volume information has the potential to drive real change in clinical practice, from personalized therapy and intelligent drug design to population screening and electronic health record mining. As ever, where new technology promises "Big Advances," significant challenges remain. Here we discuss both the opportunities and challenges posed to biomedical research by our increasing ability to tackle large datasets. Important challenges include the need for standardization of data content, format, and clinical definitions, a heightened need for collaborative networks with sharing of both data and expertise and, perhaps most importantly, a need to reconsider how and when analytic methodology is taught to medical researchers. We also set "Big data" analytics in context: recent advances may appear to promise a revolution, sweeping away conventional approaches to medical science. However, their real promise lies in their synergy with, not replacement of, classical hypothesis-driven methods. The generation of novel, data-driven hypotheses based on interpretable models will always require stringent validation and experimental testing. Thus, hypothesis-generating research founded on large datasets adds to, rather than replaces, traditional hypothesis driven science. Each can benefit from the other and it is through using both that we can improve clinical practice.

Coronavirus disease 2019 (COVID-19) is spreading rapidly around the world with devastating consequences on patients, health care workers, health systems, and economies. As it reaches low- and middle-income countries, its effects could be even more dire, because it will be difficult for them to respond aggressively to the pandemic. There is a great shortage of all health care providers, who will be at risk due to a lack of personal protection equipment. Social distancing will be almost impossible. The necessary resources to treat patients will be in short supply. The end result could be a catastrophic loss of life. A global effort will be required to support faltering economies and health care systems.

The neurovascular unit is a complex, interdependent system composed of neurons and neural supporting cells, such as astrocytes, as well as cells that comprise the vascular system including endothelial cells, pericytes, and smooth muscle cells. Each cell type in the neurovascular unit plays an essential role, either in transmitting and processing neural signals or in maintaining the appropriate microenvironmental conditions for healthy neural function. In vitro neurovascular models can be useful for understanding the different roles and functions of the cells composing the neurovascular unit, as well as for assessing the effects on neural function of therapeutic compounds after crossing the endothelial barrier. Here, we report a novel three-dimensional neurovascular microfluidic model consisting of primary rat astrocytes and neurons together with human cerebral microvascular endothelial cells. These three cell types in our neurovascular chip (NVC) show distinct cell type-specific morphological characteristics and functional properties. In particular, morphological and functional analysis of neurons enables quantitative assessment of neuronal responses, while human cerebral endothelial cells form monolayers with size-selective permeability similar to existing in vitro blood-brain barrier (BBB) models.

Endothelial progenitor cell (EPC) nomenclature remains ambiguous and there is a general lack of concordance in the stem cell field with many distinct cell subtypes continually grouped under the term "EPC." It would be highly advantageous to agree on standards to confirm an endothelial progenitor phenotype and this should include detailed immunophenotyping, potency assays, and clear separation from hematopoietic angiogenic cells which are not endothelial progenitors. In this review, we seek to discourage the indiscriminate use of "EPCs," and instead propose precise terminology based on defining cellular phenotype and function. Endothelial colony forming cells and myeloid angiogenic cells are examples of two distinct and well-defined cell types that have been considered EPCs because they both promote vascular repair, albeit by completely different mechanisms of action. It is acknowledged that scientific nomenclature should be a dynamic process driven by technological and conceptual advances; ergo the ongoing "EPC" nomenclature ought not to be permanent and should become more precise in the light of strong scientific evidence. This is especially important as these cells become recognized for their role in vascular repair in health and disease and, in some cases, progress toward use in cell therapy. Stem Cells Translational Medicine 2017;6:1316-1320.

In the past decade, advances in liquid chromatography-mass spectrometry (LC-MS) have revolutionized untargeted metabolomics analyses. By mining metabolomes more deeply, researchers are now primed to uncover key metabolites and their associations with diseases. The employment of untargeted metabolomics has led to new biomarker discoveries and a better mechanistic understanding of diseases with applications in precision medicine. However, many major pertinent challenges remain. First, compound identification has been poor, and left an overwhelming number of unidentified peaks. Second, partial, incomplete metabolomes persist due to factors such as limitations in mass spectrometry data acquisition speeds, wide-range of metabolites concentrations, and cellular/tissue/temporal-specific expression changes that confound our understanding of metabolite perturbations. Third, to contextualize metabolites in pathways and biology is difficult because many metabolites partake in multiple pathways, have yet to be described species specificity, or possess unannotated or more-complex functions that are not easily characterized through metabolomics analyses. From a translational perspective, information related to novel metabolite biomarkers, metabolic pathways, and drug targets might be sparser than they should be. Thankfully, significant progress has been made and novel solutions are emerging, achieved through sustained academic and industrial community efforts in terms of hardware, computational, and experimental approaches. Given the rapidly growing utility of metabolomics, this review will offer new perspectives, increase awareness of the major challenges in LC-MS metabolomics that will significantly benefit the metabolomics community and also the broader the biomedical community metabolomics aspire to serve.