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Staphylococcus aureus is a leading cause of healthcare-associated infection, and outbreaks have been associated with neonatal units and colonization of healthcare workers.To describe an outbreak of Panton-Valentine-leukocidin-producing meticillin-sensitive Staphylococcus aureus (PVL-MSSA) in a neonatal intensive care unit.Multi-disciplinary outbreak control investigation.Over a period of 16 months, seven neonates were identified as positive for PVL-MSSA. Isolates were identified in blood cultures (two patients), nasopharyngeal aspirate (one patient) and rectal screening swabs (four patients). Epidemiological and whole-genome sequencing data suggested a long-term carrier as the most likely source. Despite two rounds of mass suppression therapy of staff, using chlorhexidine initially followed by octenidine-based regimens, positive patients continued to be identified. Staff screening subsequently identified one healthcare worker colonized with the outbreak strain of PVL-MSSA who underwent enhanced screening and further suppression therapy. No further cases have been identified to date. Compliance with mass suppression therapy was95% and a post-administration staff satisfaction survey showed that the majority of staff agreed with the steps taken, with low rates of adverse reactions.S. aureus outbreaks are commonly associated with colonization of healthcare workers, and are challenging to manage within environments such as neonatal units. This study highlights the utility of whole-genome sequencing in identifying and mapping an outbreak. It is recommended that targeted staff screening should be considered early in similar outbreaks. In this setting, mass suppression therapy was not an effective strategy despite a high level of staff engagement and compliance.

Although model organisms have provided insight into the earliest stages of cardiac vascularization, we know very little about this process in humans. Here we show that spatially micropatterned human pluripotent stem cells (hPSCs) enablein vitromodeling of this process, corresponding to the first three weeks ofin vivohuman development. Using four hPSC fluorescent reporter lines, we create cardiac vascular organoids (cVOs) by identifying conditions that simultaneously give rise to spatially organized and branched vascular networks within endocardial, myocardial, and epicardial cells. Using single-cell transcriptomics, we show that the cellular composition of cVOs resembles that of a 6.5 post-conception week (PCW) human heart. We find that NOTCH and BMP pathways are upregulated in cVOs, and their inhibition disrupts vascularization. Finally, using the same vascular-inducing factors to create cVOs, we produce hepatic vascular organoids (hVOs). This suggests there is a conserved developmental program for creating vasculature within different organ systems.Graphic Abstract

How cortical circuits build representations of complex objects is poorly understood. Individual neurons must integrate broadly over space, yet simultaneously obtain sharp tuning to specific global stimulus features. Groups of neurons identifying different global features must then assemble into a population that forms a comprehensive code for these global stimulus properties. Although the logic for how single neurons summate over their spatial inputs has been well explored in anesthetized animals, how large groups of neurons compose a flexible population code of higher-order features in awake animals is not known. To address this question, we probed the integration and population coding of higher-order stimuli in the somatosensory and visual cortices of awake mice using two-photon calcium imaging across cortical layers. We developed a novel tactile stimulator that allowed the precise measurement of spatial summation even in actively whisking mice. Using this system, we found a sparse but comprehensive population code for higher-order tactile features that depends on a heterogeneous and neuron-specific logic of spatial summation beyond the receptive field. Different somatosensory cortical neurons summed specific combinations of sensory inputs supra-linearly, but integrated other inputs sub-linearly, leading to selective responses to higher-order features. Visual cortical populations employed a nearly identical scheme to generate a comprehensive population code for contextual stimuli. These results suggest that a heterogeneous logic of input-specific supra-linear summation may represent a widespread cortical mechanism for the synthesis of sparse higher-order feature codes in neural populations. This may explain how the brain exploits the thalamocortical expansion of dimensionality to encode arbitrary complex features of sensory stimuli.

How cortical circuits build representations of complex objects is poorly understood. The massive dimensional expansion from the thalamus to the primary sensory cortex may enable sparse, comprehensive representations of higher order features to facilitate object identification. To generate such a code, cortical neurons must integrate broadly over space, yet simultaneously obtain sharp tuning to specific stimulus features. The logic of cortical integration that may synthesize such a sparse, high dimensional code for complex features is not known. To address this question, we probed the integration and population coding of higher order stimuli in the somatosensory and visual cortices of awake mice using two-photon calcium imaging across cortical layers. We found that somatosensory and visual cortical neurons sum highly specific combinations of sensory inputs supra-linearly, but integrate other inputs sub-linearly, leading to selective responses to higher order features. This integrative process generates a sparse, but comprehensive code for complex stimuli from the earliest stages of cortical processing. These results from multiple sensory modalities imply that input-specific supra-linear summation may represent a widespread cortical mechanism for the synthesis of higher order feature codes. This new mechanism may explain how the brain exploits the thalamocortical expansion of dimensionality to encode arbitrary complex features of sensory stimuli.

The 28th annual Barrels meeting was held prior to the Society for Neuroscience meeting in October 2015 at the Northwestern University School of Law in Chicago, Illinois. The meeting brought together researchers focused on the rodent sensorimotor system. The meeting focused on modern techniques to decipher cortical circuits, social interactions among rodents, and decision-making. The meeting allowed investigators to share their work via short talks, poster presentations, and a data blitz.

Understanding brain function requires technologies that can control the activity of large populations of neurons with high fidelity in space and time. We developed a multiphoton holographic approach to activate or suppress the activity of ensembles of cortical neurons with cellular resolution and sub-millisecond precision. Since existing opsins were inadequate, we engineered new soma-targeted (ST) optogenetic tools, ST-ChroME and IRES-ST-eGtACR1, optimized for multiphoton activation and suppression. Employing a three-dimensional all-optical read-write interface, we demonstrate the ability to simultaneously photostimulate up to 50 neurons distributed in three dimensions in a 550 × 550 × 100-µm3 volume of brain tissue. This approach allows the synthesis and editing of complex neural activity patterns needed to gain insight into the principles of neural codes.

Type 2B von Willebrand disease (VWD) is a rare, inherited bleeding disorder resulting from a qualitative defect in von Willebrand factor (VWF). There is very little published information on how to quantify bleeding risk and manage haemostasis in type 2B VWD patients during pregnancy. This article presents the changes in VWF parameters and details of patient management and delivery outcomes for four pregnancies in three women with two different mutations causing type 2B VWD. We report an unexpected rise in the VWF:Ag at 37 weeks gestation in two sisters with R1306W associated with significant thrombocytopenia. These patients were supported with platelet transfusions as well as intermediate purity VWF-FVIII plasma concentrates during the peri- and postpartum periods. No thrombocytopenia was observed in our third case with a mutation encoding an R1308C substitution; haemostatic support was with intermediate purity VWF-FVIII plasma concentrates alone. No adverse bleeding events occurred and in all cases a live healthy infant was delivered. One patient was readmitted post partum with bleeding symptoms due to retained placenta; no further haemostatic support was given at this time. This case series is the first to detail the progression of laboratory parameters, management and outcomes of pregnancy in patients with type 2B VWD. The cases illustrate some of the challenges posed by the increased production of a VWF variant with a gain-of-function effect. The rapid coagulation changes observed in this series illustrate the need for continual monitoring of VWF parameters and platelet count throughout pregnancy in women with type 2B VWD.

Please cite this paper as: Scotland G, McLernon D, Kurinczuk J, McNamee P, Harrild K, Lyall H, Rajkhowa M, Hamilton M, Bhattacharya S. Minimising twins in in vitro fertilisation: a modelling study assessing the costs, consequences and cost–utility of elective single versus double embryo transfer over a 20-year time horizon. BJOG 2011;118:1073–1083. Objectives To assess the cumulative costs and consequences of double embryo transfer (DET) or elective single embryo transfer (eSET) in women commencing in vitro fertilisation (IVF) treatment aged 32, 36 and 39 years. Design Microsimulation model. Setting Three assisted reproduction centres in Scotland. Sample A total of 6153 women undergoing treatment at one of three Scottish IVF clinics, between January 1997 and June 2007. Methods A microsimulation model, populated using data inputs derived from a large clinical data set and published literature, was developed to compare the costs and consequences of using eSET or DET over multiple treatment cycles. Main outcome measures Disability-free live births; twin pregnancy rate; women’s quality-adjusted life-years (QALYs); health service costs. Results Not only did DET produce a higher cumulative live birth rate compared with eSET for women of all three ages, but also a higher twin pregnancy rate. Compared with eSET, DET ranged from costing an additional £27 356 per extra live birth in women commencing treatment aged 32 years, to costing £15 539 per extra live birth in 39-year-old women. DET cost ∼£28 300 and ∼£20 300 per additional QALY in women commencing treatment aged 32 and 39 years, respectively. Conclusions Considering the high twin pregnancy rate associated with DET, coupled with uncertainty surrounding QALY gains, eSET is likely to be the preferred option for most women aged ≤36 years. The cost-effectiveness of DET improves with age, and may be considered cost-effective in some groups of older women. The decision may best be considered on a case-by-case basis for women aged 37–39 years.

INTRODUCTION The effect of primary total knee replacement on the employment status of 56 patients under 60 years of age was examined at a mean follow-up of 64 months. PATIENTS AND METHODS A total of 56 primary total knee replacements performed on patients under the age of 60 years by two surgeons between 1996 and 2003 were retrospectively assessed by postal questionnaire. Patients were selected from databases held at Holly House and Newham Hospital NHS Trust. RESULTS Overall, 97.5% of patients who were employed before their operation, returned to their previous work. However, in patients not working prior to total knee replacement none were employed after their operation. CONCLUSIONS Total knee replacement may be a valuable tool to help some patients to continue working but may not affect patients who are already unemployed.

Panton-Valentine leukocidin secreted by Staphylococcus aureus is known to cause severe skin, soft tissue and lung infections. However, until recently it has not been described as causing life-threatening musculoskeletal infection. We present four patients suffering from osteomyelitis, septic arthritis, widespread intravascular thrombosis and overwhelming sepsis from proven Panton-Valentine leukocidin-secreting Staphylococcus aureus. Aggressive, early and repeated surgical intervention is required in the treatment of these patients. The Panton-Valentine leukocidin toxin not only destroys host neutrophils, immunocompromising the patient, but also increases the risk of intravascular coagulopathy. This combination leads to widespread involvement of bone with glutinous pus which is difficult to drain, and makes the delivery of antibiotics and eradication of infection very difficult without surgical intervention.

We present a non-imaging light-field microscopy method for volume quantification of neural activity in scattering brain tissue. Individual neuron fluorescence is computed directly by independent component identification in the phase-space time domain, without deconvolution.

Objectives: To carry out an epidemiological analysis of the emerging epidemic in an Eastern European country and to compare the approach to prevention of mother-to-child transmission (MTCT) with that in Western Europe. Design: Prospective cohort study established in 1985 in Western Europe and extended to Ukraine in 2000. Methods: Data on 5967 HIV-infected pregnant women and their infants (1251 from Ukraine and 4716 from Western/Central Europe) was analysed. Factors associated with transmission were identified with logistic regression. Results: HIV-infection among pregnant women enrolled in Western European centres has shifted from being largely injecting drug use (IDU)-related to heterosexually-acquired; in Ukraine IDU also gradually declined with women increasingly identified without specific risk factors. In Ukraine in 2000-2004 most (80%) women received single dose nevirapine (sdNVP) and/or short-course zidovudine prophylaxis [MTCT rate 4.2%; 95% confidence interval (CI), 1.8-8.0 for sdNVP with short-course zidovudinel; 2% (n = 27) received antenatal HAART and 33% (n = 418) delivered by elective caesarean section (CS); in Western European centres 72% of women received HAART (MTCT rate 1.0%; 95% Cl, 0.4-1.9) and 66% delivered by elective CS during the same period. Conclusions: Our findings indicate distinct differences in the epidemics in pregnant women across Europe. The evolution of the MTCT epidemic in Ukraine does not appear to be following the same pattern as that in Western Europe in the 1980s and 1990s. Although uptake of preventive MTCT prophylaxis has been rapid in both Western Europe and Ukraine, substantial challenges remain in the more resource-constrained setting in Eastern Europe. (c) 2006 Lippincott Williams & Wilkins

Purpose To describe the presentation of cytomegalovirus retinitis (CMVR) in a series of infants. Methods Immunocompromised infants with either HIV or systemic cytomegalovirus (CMV) were examined for CMVR. Ocular involvement was recorded and monitored by digital imaging. Results Five infants were detected to have CMVR. All the infants demonstrated changes within the macula. One infant progressed from a fine granular pattern to fulminant CMVR. Conclusion Infants under a year with CMVR have a predilection for the disease to present at the macula, in contrast to the presentation in adults, which tends to involve more peripheral parts of the retina.

During active sensation, sensors scan space in order to generate a representation of the outside world. However, since spatial coding in sensory systems is typically addressed by measuring receptive fields in a fixed, sensor-based coordinate frame, the cortical representation of scanned space is poorly understood. To address this question, we probed spatial coding in the rodent whisker system using a combination of two-photon imaging and electrophysiology during active touch. We found that surround whiskers powerfully transform the cortical representation of scanned space. On the single-neuron level, surround input profoundly alters response amplitude and modulates spatial preference in the cortex. On the population level, surround input organizes the spatial preference of neurons intoa continuous map of the space swept out by the whiskers. These data demonstrate how spatial summation over a moving sensor array is critical to generating population codes of sensory space.

A survey of antibody responses to human herpesvirus 8 (HHV-8) was undertaken to examine the mode of transmission of this virus to children born to mothers with HIV. Methods. Serum samples from a cohort of 92 mother-infant pairs and a cross-sectional cohort of 100 children (median age, 4 years) were tested. In the cohort of mother-infant pairs, 14 infants were HIV-infected, 72 were not and the HIV status was unknown for 6. In the cohort of children 70 were HIV-infected and 30 were vertically exposed but uninfected. Serologic responses to two HHV-8 antigens, latency-associated nuclear antigen and the structural antigen encoded by open reading frame 65 were detected by immunofluorescent antibody test and enzyme-linked immunoassay. Results were confirmed by Western blot. Results. All HHV-8-seropositive mothers were African (17 of 92, 18.5%). Six of their infants were HHV-8-seronegative and 11 had at least 1 HHV-8-seropositive sample. One of the 11 infants tested only at birth had a lower antibody titer than the mother; the remaining 10 infants had decreasing titers up to 7 months of age and 6 became seronegative. No infants born to HHV-8-seronegative mothers had antibodies to the virus. The seroprevalence to HHV-8 was 6% in the cohort of children. All had African mothers and their median age was greater than that of the cohort (8.4 vs. 4.0 years). Five were coinfected with HIV. Conclusions. HHV-8 was not vertically transmitted by any of the HIV-coinfected mothers. Acquisition of antibody to HHV-8 occurred in older children, implying a horizontal route of transmission.

Eight patients underwent middle ray amputation with excision of the whole of the middle metacarpal and careful soft tissue repair. Excision of the base of the middle metacarpal allowed easier approximation of the index and ring rays without the tendency of these fingers to either scissor on finger flexion or to remain slightly apart. Complete removal of the middle metacarpal appears to allow the bases of the index and ring metacarpals to migrate together. The removal of the metacarpal base caused no functional problems and the technique created a good three-finger hand from both a functional and cosmetic point of view.

Children with malignancy are immunosuppressed and susceptible to serious infections with herpesviruses. The majority of children on chemotherapy for malignancy are seropositive for human herpesvirus-6 (HHV-6), and although HHV-6 has been demonstrated to be a pathogen in severely immunocompromised patients, whether this is the case for paediatric oncology patients is unknown. HHV-6 is secreted in saliva and in this study samples were examined prospectively for HHV-6 DNA in healthy children and those with malignancy. In a nested polymerase chain reaction (PCR), a 287 bp outer fragment and 163 inner fragment of HHV-6 DNA were amplified. The resulting amplimer contained a Hind III restriction site present only in "B" type HHV-6 and this was used to identify the type of HHV-6 amplified. In saliva from healthy control children, 74% (28/38) of samples were HHV-6 DNA-positive in either the supernate, pellet or both. In the patients, 58% (45/77) of all samples were HHV-6 DNA-positive. When sequential samples from twelve patients were examined the children appeared to fall into two groups: those who were frequently HHV-6 DNA-positive (60% of samples or more) and those who were rarely HHV-6 DNA-positive (33% of samples or less) (P < 0.0001). The only apparent difference between these two groups was that the less frequently HHV-6-positive group was more often febrile and unwell with neutropaenia. Hind III digestion demonstrated all the positive samples to be "B" type HHV-6. Possible explanations for this difference in HHV-6 secretion between the patient groups are discussed.

A link between deep vein thrombosis (DVT) and pulmonary tuberculosis has been described,1,2 but not with gastrointestinal tuberculosis.​tuberculosis. Figure 1 CT scan of pelvis showing thrombosis of iliac vein on right side

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.

In a 2-year period (2004 and 2005), 117 couples with infertility were referred from secondary care for IVF/ICSI treatment. This study describes the age, waiting times, diagnostic categories and outcomes for all couples referred. A total of 59% (69) of all couples referred conceived. Of these, 25% (29 couples) conceived spontaneously or as a result of simpler treatments and 34% (40 couples) conceived following IVF/ICSI treatment. The twin pregnancy rate following IVF/ICSI was 25% and the average waiting time from referral to treatment was 13–18 months. Couples with female factor infertility (excluding endometriosis) and couples with unexplained infertility experienced a higher spontaneous pregnancy rate while awaiting IVF/ICSI treatment, than those couples with male factor or combined infertility. However, couples with male factor or combined infertility achieved much higher success rates with IVF/ICSI treatment.

Type 2B von Willebrand disease (VWD) is a rare, inherited bleeding disorder resulting from a qualitative defect in von Willebrand factor (VWF). There is very little published information on how to quantify bleeding risk and manage haemostasis in type 2B VWD patients during pregnancy. This article presents the changes in VWF parameters and details of patient management and delivery outcomes for four pregnancies in three women with two different mutations causing type 2B VWD. We report an unexpected rise in the VWF:Ag at 37 weeks gestation in two sisters with R1306W associated with significant thrombocytopenia. These patients were supported with platelet transfusions as well as intermediate purity VWF-FVIII plasma concentrates during the peri- and postpartum periods. No thrombocytopenia was observed in our third case with a mutation encoding an R1308C substitution; haemostatic support was with intermediate purity VWF-FVIII plasma concentrates alone. No adverse bleeding events occurred and in all cases a live healthy infant was delivered. One patient was readmitted post partum with bleeding symptoms due to retained placenta; no further haemostatic support was given at this time. This case series is the first to detail the progression of laboratory parameters, management and outcomes of pregnancy in patients with type 2B VWD. The cases illustrate some of the challenges posed by the increased production of a VWF variant with a gain-of-function effect. The rapid coagulation changes observed in this series illustrate the need for continual monitoring of VWF parameters and platelet count throughout pregnancy in women with type 2B VWD.

To assess the cumulative costs and consequences of double embryo transfer (DET) or elective single embryo transfer (eSET) in women commencing in vitro fertilisation (IVF) treatment aged 32, 36 and 39 years.Microsimulation model.Three assisted reproduction centres in Scotland.A total of 6153 women undergoing treatment at one of three Scottish IVF clinics, between January 1997 and June 2007.A microsimulation model, populated using data inputs derived from a large clinical data set and published literature, was developed to compare the costs and consequences of using eSET or DET over multiple treatment cycles.Disability-free live births; twin pregnancy rate; women's quality-adjusted life-years (QALYs); health service costs.Not only did DET produce a higher cumulative live birth rate compared with eSET for women of all three ages, but also a higher twin pregnancy rate. Compared with eSET, DET ranged from costing an additional £ 27,356 per extra live birth in women commencing treatment aged 32 years, to costing £ 15,539 per extra live birth in 39-year-old women. DET cost ∼ £ 28,300 and ∼ £ 20,300 per additional QALY in women commencing treatment aged 32 and 39 years, respectively.Considering the high twin pregnancy rate associated with DET, coupled with uncertainty surrounding QALY gains, eSET is likely to be the preferred option for most women aged ≤ 36 years. The cost-effectiveness of DET improves with age, and may be considered cost-effective in some groups of older women. The decision may best be considered on a case-by-case basis for women aged 37-39 years.

Background First-line treatments for unexplained infertility traditionally include clomifene citrate (CC) or unstimulated intrauterine insemination (IUI). A recently published randomized controlled trial considered the effectiveness of CC and IUI in patients with unexplained infertility and found that neither treatment offered a superior live birth rate when compared with expectant management (EM). This paper reports the economic evaluation conducted alongside this trial in order to assess whether health care providers are gaining value for money in this clinical area. Methods Five hundred and eighty women across five Scottish hospitals were randomized to either EM, CC or IUI for 6 months. The primary outcome measure was live births. Resource-use data were collected during the trial and costs were calculated from a UK National Health Service (NHS) perspective. Incremental cost-effectiveness ratios were calculated, expressed as cost per live birth, in order to compare the cost-effectiveness of CC and IUI with that of EM to treat unexplained infertility. Results Live birth rates in the three randomized groups were: EM = 32/193 (17%), CC = 26/194 (13%) and IUI = 43/193 (22%). The mean (standard deviation) costs per treatment cycle were £0 for EM, £83 (£17) for CC and £98 (£31) for IUI. The mean treatment costs per patient for EM, CC and IUI were £12 (£117), £350 (£220) and £331 (£222), respectively. The cost per live birth for EM, CC and IUI was £72 (95% confidence interval £0-£206), £2611 (£1870-£4166) and £1487 (£1116-£2155), respectively. The incremental cost-effectiveness ratio for IUI versus EM was £5604 (-£12204 to £2227), with CC dominated by IUI. Conclusions Despite being more expensive, existing treatments such as empirical CC and unstimulated IUI do not offer superior live birth rates compared with EM of unexplained infertility. They are unlikely to be a cost-effective use of limited NHS resources. The study's main limitation is that it did not consider the psychological effects on couples. ISRCT Number: 71762042.

AIM: Assessment of the clinical and haematological course of autoimmune neutropenia of infancy (ANI) in a defined childhood population in the south east of Scotland. METHODS: From January 1986 to February 1991 all children presenting with persistent neutropenia were examined serologically for evidence of antigranulocyte antibodies. The clinical course of those children found to have anti-granulocyte antibodies was then closely monitored. RESULTS: During the study period five children had serologically confirmed ANI, giving an annual incidence of approximately 1/100,000 in this population. All of these cases followed the classic benign course of the condition. The presenting illnesses were mild, often with superficial skin sepsis and the initial absolute neutrophil count (ANC) ranged from 0.00-0.87 x 10(9)/l. All have remained well with no serious infections. Two children attained a normal ANC after 14 and 24 months respectively, the others currently remain neutropenic. CONCLUSIONS: Autoimmune neutropenia of infancy is a condition which rests on a serological diagnosis. It follows a chronic benign course and all children eventually attain a normal ANC. The level of antigranulocyte antibody in the serum often begins to wane prior to improvement in the ANC and can give an indication of when recovery will begin to occur.

From January, 1982, to July, 1990, 51 children with recurrent infections were investigated for immunodeficiency in this department by testing neutrophil function, lymphocyte subsets and serum immunoglobulin and complement concentrations. The prevalence of immune dysfunction within the group was 39% (20 of 51). A previously described clinical scoring system, which aims to identify children with a history of recurrent infection who merit investigation for immunodeficiency was also applied to all 51 children. The scoring system identified only 55% (11 of 20) of those with laboratory-proved immunodeficiency and had a false negative rate of 45% (9 of 20). This latter group included 2 children with severe combined immunodeficiency and 1 with hypogammaglobulinemia, diagnoses that one cannot afford to miss. The system was not sufficiently sensitive to be of use in deciding which child to test for immunodeficiency.

In 1974, an Edinburgh family was described in which five infants from three generations had a consistently abnormal facial appearance, retarded motor and mental development, and failure to thrive. All died in the first months of life. The eponym "Typus Edinburgensis" was used to label these infants.1 Although at that time no chromosomal abnormality was detected, it was predicted that the advancement of cytogenetic technology might eventually reveal an associated chromosomal abnormality. High-resolution chromosome analysis has now identified a familial reciprocal and apparently balanced translocation between chromosomes 1 and 2 in three members of this family, following detection of an unbalanced karyotype in a neonate with an abnormal phenotype similar to that previously described.

SummarySeven women delivered at the Simpson Memorial Maternity Pavilion between September 1987 and May 1989 were found to be suffering from the familial disorder, myotonic dystrophy. They experienced many of the classical obstetric and anaesthetic complications of the disease including hydramnios, preterm labour and post-anaesthetic apnoea. Three of the seven patients gave a history of previous neonatal death yet in only one of these three (and in two of the remaining four women) was the diagnosis of myotonic dystrophy made before the delivery reported here. We believe that the condition is underdiagnosed by obstetricians.

BACKGROUND: Plasma HIV-1 RNA levels are high in vertically infected infants. Information in older children is limited, particularly in those who have not received antiretroviral therapy. OBJECTIVES: To describe the relationships between HIV-1 RNA, age and CD4 cell count in untreated vertically infected children. DESIGN: HIV-1 RNA was measured in 70 children [median age, 3.5 years (range, 0.4-11.9 years); median CD4 cell count, 881 x 10(6)/l (interquartile range, 576-1347 x 10(6) cells/l)] enrolled in a randomized placebo-controlled trial comparing immediate with deferred zidovudine in asymptomatic or mildly symptomatic vertically infected children (PENTA-1 trial). Short-term variability was assessed by comparing HIV-1 RNA at -2 and 0 weeks (prior to randomization). The relationship between age and HIV-1 RNA, and CD4 cell count was analysed using data from all children prior to randomization and sequential samples from 35 remaining on placebo for up to 105 weeks, by fitting mixed linear models. RESULTS: The within-individual SD in viral load was 0.26 log10 copies/ml. The median plasma HIV-1 RNA at enrollment was 4.61 log10 (range, 2.3-6.56 log10 copies/ml), significantly higher in children aged < or = 2 years (median, 5.23 log10 copies/ml) than in those aged > 2 years (4.51 log10 copies/ml; P < 0.0001). Mean HIV-1 RNA fell by 0.38 log10 copies/ml per year up to 2 years of age, by 0.21 log10 copies/ml per year from 2 to 4 years of age, and by 0.03 log10 copies/ml per year from 4 to 6 years of age reaching a nadir of 4.25 log10 copies/ml at 6 years. Mean log10 CD4 cell count declined steadily with age and was not significantly correlated with HIV-1 RNA, although there was some evidence that the rate of log10 CD4 cell decline was negatively correlated with the initial rate of HIV-1 RNA decline. No mutations associated with resistance to zidovudine were observed. CONCLUSIONS: Age is a key factor in the interpretation of both viral load and CD4 cell count in vertically infected children

Background: The agents used for conscious sedation are well known to have potentially serious complications. It is recommended that patients receiving them should be objectively monitored until it is deemed safe. An audit of our departmental practices led us to conduct a national questionnaire to determine how we compared with other units in the UK. Methods: All 211 UK emergency departments (EDs) seeing >40 000 patients/year were contacted and asked to take part in a telephone questionnaire. Interviewees were asked questions regarding which agents were used within their department, the types and duration of monitoring, whether or not patients were fasted, what consent was recorded, the number of staff present and who they were, and what follow-up arrangements were used. Results: 183 departments (87%) completed the questionnaire. Opiates (77%) and benzodiazepines (97%) were the most commonly used agents. Heart rate/blood pressure monitoring (95%), ECG (86%) and pulse oximetry (97%) were used in the majority of cases. Other monitoring modalities, particularly neurological, were either used or documented infrequently. 112 departments (61%) monitored their patients for a set time (4–360 min; mean 97 min). The remainder were monitored until the patient scored a certain Glasgow Coma Score or was subjectively deemed fit. Only 24 departments (13%) ensured that their patients were fasted. 62 departments (34%) did not formally record either written or verbal consent. 80 departments (44%) had 2 members of staff present; the remainder had a minimum of 3. All departments had at least 1 ED doctor and nurse. 174 departments (95%) used fracture clinic follow-up. For conscious sedation, 51 departments (28%) had set proformas and 54 departments (30%) had set policies. Conclusion: Certain practices were applied in most departments but none were universal, with most being subject to wide variation. The local results reflected this, suggesting that a variation may exist both within and between individual units.

Objective To compare the effectiveness of clomifene citrate and unstimulated intrauterine insemination with expectant management for the treatment of unexplained infertility. Design Three arm parallel group, pragmatic randomised controlled trial. Setting Four teaching hospitals and a district general hospital in Scotland. Participants Couples with infertility for over two years, confirmed ovulation, patent fallopian tubes, and motile sperm. Intervention Expectant management, oral clomifene citrate, and unstimulated intrauterine insemination. Main outcome measures The primary outcome was live birth. Secondary outcome measures included clinical pregnancy, multiple pregnancy, miscarriage, and acceptability. Results 580 women were randomised to expectant management (n=193), oral clomifene citrate (n=194), or unstimulated intrauterine insemination (n=193) for six months. The three randomised groups were comparable in terms of age, body mass index, duration of infertility, sperm concentration, and motility. Live birth rates were 32/193 (17%), 26/192 (14%), and 43/191 (23%), respectively. Compared with expectant management, the odds ratio for a live birth was 0.79 (95% confidence interval 0.45 to 1.38) after clomifene citrate and 1.46 (0.88 to 2.43) after unstimulated intrauterine insemination. More women randomised to clomifene citrate (159/170, 94%) and unstimulated intrauterine insemination (155/162, 96%) found the process of treatment acceptable than those randomised to expectant management (123/153, 80%) (P=0.001 and P

Patients with mild haemophilia A may have a discrepancy in the factor VIII (FVIII) level when measured with a one-stage assay (FVIII:C1) compared with a two-stage assay (FVIII:C2). This discrepancy usually results in the one-stage level being higher than the two-stage level. A F8 mutation resulting in a Tyr346-->Cys substitution within the a1 interdomain region has been described which results in the converse assay discrepancy. We report four individuals (three families) who have this mutation. Mean FVIII:C1 level was 25 IU dL(-1) compared with a mean FVIII:C2 level of 63 IU dL(-1). These individuals had presented opportunistically and did not have a clinically significant bleeding disorder. The bleeding phenotype correlated with the two-stage assay result rather than the one-stage result. FVIII replacement therapy does not appear to be required for these individuals.

Prior to the introduction of interventions reducing mother-to-child transmission of HIV-1 natural history data reports vertical transmission rates in the order of 25%. The risk of transmission from mother-to-child has been associated with advanced maternal HIV disease, maternal plasma HIV viral load and CD4 lymphocyte count, mode of delivery, length of rupture of membranes, prematurity and breast feeding. During the last 10–15 years the introduction of prelabour cesarean section, formula feeding and antiretroviral therapy has reduced transmission to less than 1% for pregnant women in the UK who are aware of their HIV status. Attention is now turning to the minimization of possible drug side effects for both mother and infant as women are increasingly conceiving on combination antiretroviral therapy. The evolution of current UK guidelines on the prevention of mother-to-child transmission of HIV-1 are discussed.

Objectives Highly active antiretroviral therapy (HAART) has extended survival of HIV-infected children into adulthood, raising concerns about long-term metabolic changes in childhood. Methods A longitudinal study of metabolite levels in paediatric HIV-infected patients before and after starting HAART (January 2000 to June 2003). The effects of HAART on nonfasting blood levels of total (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, cholesterol ratio and lactate were analysed using mixed-effects regression. Results A total of 146 children attended 1208 appointments (median 6.7/child). Of these, 99 (68%) were African. At baseline, 75 (51%) were on HAART and had higher TC (4.19 vs 3.49 mmol/L, P

Introduction Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dualnucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1. Methods In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptomfree (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat. Findings Children had a median CD4 percentage of 22% (IQR 15–29) and a mean HIV-1 RNA concentration of 5·0 log copies/mL (SD 0·8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1·71, 2·19, and 2·63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0·02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events—six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir. Interpretation Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.

Summary We describe an elderly patient with generalized atherosclerosis who presented with recurrent iron-deficiency anaemia. He underwent right hemicolectomy which revealed ischaemic colonic ulceration caused by cholesterol embolism. Surgery appeared to be curative. Cholesterol embolism should be considered as a possible cause of unexplained gastrointestinal blood loss in the elderly.

Objectives To ascertain current practices in the diagnosis and management of HIV and pregnancy in the North Thames Region. Methods Postal survey using a self-completed questionnaire sent to the head of all of the Region's 34 units involved in the care of HIV. The survey asked questions on current policy around HIV and pregnancy in the HIV units and associated antenatal clinics and was linked to a case-note survey of pregnant, HIV-positive women in the last 2 years. Results Over 50% of the responding antenatal units recommended the HIV test by March 1999. Most HIV units were offering a range of antiretroviral regimens in pregnancy, although a minority (33%) did not offer triple therapy. Elective Caesarean section was the recommended mode of delivery for most women (90%) irrespective of drug therapy or viral load. Most infants were being tested for HIV infection by a combination of PCR, viral culture and antibody testing to 18 months of age. All the infants (19) followed to 6 months of age in the case-note survey were PCR negative. Reporting rates to the National Survey of HIV in Pregnancy were high (87%) but poor for the Drug Exposure Register (33%). Conclusions Management of HIV and pregnancy in the North Thames units showed a large amount of consistency with regard to testing policies and management. However, there were a few units that did not offer therapy appropriate for advanced disease despite the recommendations of national bodies and a few units still did not recommend HIV testing to all women.

Editor,—Since 1992 Department of Health guidelines have recommended that HIV screening be offered to all pregnant women in areas of high seroprevalence1 but implementation and uptake has been poor. In 1998 an intercollegiate working party recommended that HIV testing be integrated with antenatal screening for other infections and that the test should be offered and recommended to all pregnant women in high seroprevalence areas.2 In 1999 the Department of Health extended these recommendations to all regions aiming to reduce neonatal HIV infection by 80% by 2002.3 We present the case of an infant with symptomatic HIV infection, whose mother's antenatal HIV test was negative and discuss the implications. A …

Very limited information is available on the normal size of the anterior fontanelle but this measurement may be of value in the early diagnosis for example of bone diseases, and of hypothyroidism. The purpose of this study was to provide a reference range applicable to the first two years of life, using a larger sample population than previous studies. Measurements were made of the anterior-posterior and transverse dimensions in 334 full term infants between birth and the age of 24 months. Despite the wide variation, both in size and age of closure, it proved possible to define a reference range and also, for the first time, to present a centile chart.

The prevention of mother to child transmission of HIV-1 by zidovudine monotherapy is well known, but increasingly combination anti-retroviral therapy is prescribed during pregnancy. In this prospective study, 19 pregnant women with human immunodeficiency virus-1 (HIV-1) infection who elected to take anti-retroviral therapy during the second and third trimesters were treated with zidovudine or zidovudine plus lamivudine. Fourteen women treated with zidovudine monotherapy had a mean 0.3 log(10) reduction in viral load and a mean 52 x 10(6)/L (17%) increase in CD4+ lymphocytes at delivery compared with pre-treatment samples. Genotypic mutations associated with decreased susceptibility to zidovudine were detected in 2 of 10 women at delivery. Five women with more advanced HIV-1 infection were treated with zidovudine plus lamivudine and a mean 1.5 log(10) reduction in viral load together with a mean 30 x 10(6)/L (33%) increase in CD4+ lymphocytes was observed in this group. However, four of five women in the dual therapy arm had the M184V mutation in the reverse transcriptase gene associated with decreased susceptibility to lamivudine at delivery. We conclude that zidovudine plus lamivudine reduced HIV-1 plasma viraemia to low levels in pregnant women with advanced HIV-1 disease but the rapid development of genotypic resistance to lamivudine indicates that additional therapy is required both for the long-term benefit of the mothers and to prevent the development of resistant virus that may be transmitted to the infant.