Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

Cervical cerclage, pessary, or vaginal progesterone in high-risk pregnant women with short cervix: a randomized feasibility study.

Objective: To assess feasibility for a definitive randomized controlled trial (RCT) comparing three treatments for short cervix in a population at high risk for spontaneous preterm birth (sPTB) over a 1-year period.Design: Three arm, open label feasibility randomized clinical study.Methods: Women with singleton pregnancy with risk factors for sPTB (history of sPTB or prelabor premature rupture of membranes (PPROM) <34 weeks or significant cervical surgery), and short cervix on transvaginal ultrasound scan detected between 16+0 and 24+6 weeks gestation were randomized to receive either cervical cerclage, vaginal pessary, or vaginal progesterone 200 mg nocte. Pregnancy outcomes and treatment costs were collected from hospital records, NHS Reference costs, and British National Formulary costs.Main outcome measures: Feasibility targets were defined as (i) at least 55% of eligible women randomized; (ii) maximum 5% failure to adhere to the protocol per arm; (iii) maximum 5% loss to short-term follow-up.Results: Of 417 women screened between October 2015 and 2016, 25 (6%) were eligible for trial inclusion, of whom 18 (72%) agreed to participate at the rate 0.75 participants/site/month. Adherence to protocol was 100% in pessary and cerclage arms and 80% in vaginal progesterone arm (95% CI 24-100%). No participants were lost to follow up. Cost of interventions accounted for 6% (95% CI 2-10%) of overall health care expenditure.Conclusions: A definitive clinical trial comparing treatments for prevention of sPTB in high-risk women with short cervix is feasible but will be challenging due to small numbers of eligible participants.

Women's and clinicians perspectives of presentation with reduced fetal movements: a qualitative study.

BACKGROUND: Worldwide maternal perception of fetal movements has been used for many years to evaluate fetal wellbeing. It is intuitively regarded as an expression of fetal well-being as pregnancies in which women consistently report regular fetal movements have very low morbidity and mortality. Conversely, maternal perception of reduced fetal movements is associated with adverse pregnancy outcomes. We sought to gain insight into pregnant women's and clinicians views and experiences of reduced movements. METHOD: We performed qualitative semi-structured interviews with pregnant women who experienced reduced fetal movements in their current pregnancy and health professionals who provide maternity care. Our aim was to develop a better understanding of events, facilitators and barriers to presentation with reduced fetal movements. Data analysis was conducted using framework analysis principles. RESULTS: Twenty-one women and 10 clinicians were interviewed. The themes that emerged following the final coding were influences of social network, facilitators and barriers to presentation and the desire for normality. CONCLUSIONS: This study aids understanding about why women present with reduced movements and how they reach the decision to attend hospital. This should inform professionals' views and practice, such that appreciating and addressing women's concerns may reduce anxiety and make presentation with further reduced movements more likely, which is desirable as this group is at increased risk of adverse outcome. To address problems with information about normal and abnormal fetal movements, high-quality information is needed that is accessible to women and their families.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Parents' experiences and expectations of care in pregnancy after stillbirth or neonatal death: a metasynthesis.

BACKGROUND: Pregnancy after perinatal death is characterised by elevated stress and anxiety, increasing the risk of adverse short-term and long-term outcomes. OBJECTIVES: This metasynthesis aimed to improve understanding of parents' experiences of maternity care in pregnancy after stillbirth or neonatal death. SEARCH STRATEGY: Six electronic databases were searched using predefined search terms. SELECTION CRITERIA: English language studies using qualitative methods to explore the experiences of parents in pregnancy after perinatal loss, were included subject to quality appraisal framework. DATA COLLECTION AND ANALYSIS: Searches were initiated in December 2011 and finalised in March 2013. Studies were synthesised using an interpretive approach derived from meta-ethnography. MAIN RESULTS: Fourteen studies were included in the synthesis, graded A (no or few flaws, high trustworthiness; n = 5), B (some flaws, unlikely to affect trustworthiness; n = 5) and C (some flaws, possible impact on trustworthiness; n = 4). Three main themes were identified; co-existence of emotions, helpful and unhelpful coping activities and seeking reasssurance through interactions. CONCLUSION: Parents' experiences of pregnancy are profoundly altered by previous perinatal death; conflicted emotions, extreme anxiety, isolation and a lack of trust in a good outcome are commonly reported. Emotional and psychological support improves parents' experiences of subsequent pregnancy, but the absence of an evidence base may limit consistent delivery of optimal care within current services.

Prophylactic oral betamimetics for preventing preterm labour in singleton pregnancies.

BACKGROUND: Preterm birth occurs in up to 6% to 10% of all births and is the major complication of pregnancy associated with perinatal mortality and morbidity. Previous preterm delivery is a strong predictor for preterm labour, and the earlier the birth, the more likely it is to be repeated at the same gestation. In the acute setting, betamimetics can decrease contraction frequency or delay preterm birth by 24 to 48 hours. OBJECTIVES: To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with singleton pregnancies at high risk of preterm delivery. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (October 2007), CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE (January 1966 to December 2006), EMBASE (January 1985 to December 2006), and reference lists. SELECTION CRITERIA: Randomised controlled trials in singleton pregnancies at high risk of preterm labour comparing prophylactic oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: One trial (64 singleton pregnancies) was included. The trial compared the oral betamimetic agent isoxuprine with placebo. No difference was seen for perinatal mortality rate (relative risk (RR) 4.74, 95% confidence interval (CI) 0.50 to 45.00). There was no evidence of an effect of oral betamimetic agents in reduction of spontaneous onset of preterm labour (RR 1.07, 95% CI 0.14 to 8.09) or preterm birth, less than 37 weeks' gestation. There was no significant association between the use of oral betamimetics and side effects sufficient to stop therapy (RR 2.51, 95% CI 0.59 to 10.76). No differences were found for infant outcomes; birthweight less than 2500 grams (RR 1.74, 95% CI 0.44 to 6.87) or neonatal death (RR 4.74, 95% CI 0.50 to 45.00). This trial had adequate methodological quality; however the sample size was inappropriate to determine any significance in neonatal outcome differences between the treatment groups. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women at high risk of preterm labour with a singleton pregnancy.

Cervical leukocyte sub-populations in idiopathic preterm labour.

OBJECTIVE: To investigate cervical epithelial leukocyte sub-populations in pregnant women with a history of idiopathic preterm labour. METHODS: A prospective observational study was undertaken of 106 women with a past history of idiopathic preterm delivery following spontaneous labour. A cytobrush was used to sample the epithelium of the cervix at 12-16 weeks of gestation and again 8 weeks later. All women had investigations for cervical and vaginal infection as well as serial transvaginal ultrasonography of their cervix; the mode and gestation at delivery were recorded. Leukocyte sub-populations were examined using immunocytochemistry, and the number of leukocytes per total cell count was calculated. MAIN OUTCOME MEASURES: Cervical epithelial leukocytes populations were (1) described in pregnancy, (2) observed over increasing gestation, (3) analysed in women who developed marked cervical shortening and (4) in those whose preterm labour recurred. RESULTS: There was no significant change in cervical epithelial leukocyte populations during the second trimester of pregnancy. There was no association between cervical leukocytes and cervical shortening. Women with idiopathic preterm labour that recurred had fewer cervical macrophages at the beginning of the second trimester of pregnancy than those whose subsequent pregnancy progressed beyond 35 weeks of gestation. CONCLUSIONS: Cervical epithelial macrophages may serve to prevent recurrent preterm labour, possibly by preventing ascending infection.

Impact of laparotomy and liver resection on the peritoneal concentrations of fibroblast growth factor 2, vascular endothelial growth factor and hepatocyte growth factor.

PURPOSE: Some data have suggested that major surgery is associated with the post-operative growth of residual tumour masses but the mechanism of this is unknown. This study was designed to determine the relationship between intraperitoneal (IP) cytokine levels, and laparotomy in benign and malignant settings. METHODS: Intraperitoneal fluid specimens were obtained at the start and at the end of laparotomy in patients with benign conditions (n=10) and in others undergoing resection of hepatic metastases from colorectal cancer (n=10). Using ELISA the concentration of the angiogenic cytokines, HGF, VEGF-A, VEGF-C, VEGF-D and FGF-2 was determined. RESULTS: The data show that in 16 of 20 patients there was a significant increase (P=0.006) in the IP concentration of hepatocyte growth factor (HGF) but not in the other growth factors by the end of the operation. The mean increase in HGF concentration was 821.5 pg/ml (95% CI: 11.0-6,426.0). Neither the groups (malignant and non-malignant) nor the length of operation correlated with greater or lesser increases in HGF. CONCLUSION: The observation that the increase in HGF occurred in both the cancer and non-cancer groups suggests that it is the surgery rather than the disease that is associated with the increased cytokine concentration. As HGF is a potent endothelial, epithelial and mesenchymal mitogen the data highlight HGF as a potential target for anti-cancer treatments in the peri-operative period. However, investigators should closely monitor wound healing as this may be compromised by this new class of drugs.

A selective approach to operative cholangiography.

The value of operative cholangiography in the detection of common bile duct stones has been documented in a number of studies. This study suggests that operative cholangiography can be-used successfully on a more selective basis when used in conjunction with laboratory and operative criteria. One hundred and fifty patients who underwent routine cholecystectomy were retrospectively evaluated. Seventy-five percent had a normal cholangiogram and normal levels of bilirubin and alkaline phosphatase. The remaining 25% had abnormal cholangiograms as well as abnormal laboratory chemistry values. It was noted that if selective operative cholangiography had been performed only on those patients with indications for common bile duct exploration, no ductal stones would have been omitted. Based on these data, a selective approach to operative cholangiography is advocated.

Growth of pika in laboratory confinement.

Captive-born pikas (Ochotoma princeps) from 13 litters were maintained for up to three months in a laboratory setting. Mean litter size was 2.69 +/- 0.75, with litters of three the most frequent, and representing 68% of all litters observed. Mean individual birthweight was 11.7 g with a range of 8.8 to 16.8 g. Weights were taken every other day from birth, which yielded a growth curve equation of y = 12.18 + 1.72x. There was a strong positive linear correlation between bodyweight and time (r = 0.98, P less than 0.001), and a significant difference was noted between sexes, with females the heaviest. Subjects reached adult weight within 3 months. These data represent the first reports of growth in this species, and indicate that pikas are among the fastest growing species within the order Lagomorpha.