Health economic analysis of a cluster-randomised trial (OptiBIRTH) designed to increase rates of vaginal birth after caesarean section.

OBJECTIVE: To perform a health economic analysis of an intervention designed to increase rates of vaginal birth after caesarean, compared with usual care. DESIGN: Economic analysis alongside the cluster-randomised OptiBIRTH trial (Optimising childbirth by increasing vaginal birth after caesarean section (VBAC) through enhanced women-centred care). SETTING: Fifteen maternity units in three European countries - Germany (five), Ireland (five), and Italy (five) - with relatively low VBAC rates. POPULATION: Pregnant women with a history of one previous lower-segment caesarean section; sites were randomised (3:2) to intervention or control. METHODS: A cost-utility analysis from both societal and health-services perspectives, using a decision tree. MAIN OUTCOME MEASURES: Costs and resource use per woman and infant were compared between the control and intervention group by country, from pregnancy recognition until 3 months postpartum. Based on the caesarean section rates, and maternal and neonatal morbidities and mortality, the incremental cost-utility ratios were calculated per country. RESULTS: The mean difference in costs per quality-adjusted life years (QALYs) gained from a societal perspective between the intervention and the control group, using a probabilistic sensitivity analysis, was: €263 (95% CI €258-268) and 0.008 QALYs (95% CI 0.008-0.009 QALYs) for Germany, €456 (95% CI €448-464) and 0.052 QALYs (95% CI 0.051-0.053 QALYs) for Ireland, and €1174 (95% CI €1170-1178) and 0.006 QALYs (95% CI 0.005-0.007 QALYs) for Italy. The incremental cost-utility ratios were €33,741/QALY for Germany, €8785/QALY for Ireland, and €214,318/QALY for Italy, with a 51% probability of being cost-effective for Germany, 92% for Ireland, and 15% for Italy. CONCLUSION: The OptiBIRTH intervention was likely to be cost-effective in Ireland and Germany. TWEETABLE ABSTRACT: The OptiBIRTH intervention (to increase VBAC rates) is likely to be cost-effective in Germany and Ireland.

Variation in outcome reporting in randomized controlled trials of interventions for prevention and treatment of fetal growth restriction.

OBJECTIVE: Although fetal growth restriction (FGR) is well known to be associated with adverse outcomes for the mother and offspring, effective interventions for the management of FGR are yet to be established. Trials reporting interventions for the prevention and treatment of FGR may be limited by heterogeneity in the underlying pathophysiology. The aim of this study was to conduct a systematic review of outcomes reported in randomized controlled trials (RCTs) assessing interventions for the prevention or treatment of FGR, in order to identify and categorize the variation in outcome reporting. METHODS: MEDLINE, EMBASE and The Cochrane Library were searched from inception until August 2018 for RCTs investigating therapies for the prevention and treatment of FGR. Studies were assessed systematically and data on outcomes that were reported in the included studies were extracted and categorized. The methodological quality of the included studies was assessed using the Jadad score. RESULTS: The search identified 2609 citations, of which 153 were selected for full-text review and 72 studies (68 trials) were included in the final analysis. There were 44 trials relating to the prevention of FGR and 24 trials investigating interventions for the treatment of FGR. The mean Jadad score of all studies was 3.07, and only nine of them received a score of 5. We identified 238 outcomes across the included studies. The most commonly reported were birth weight (88.2%), gestational age at birth (72.1%) and small-for-gestational age (67.6%). Few studies reported on any measure of neonatal morbidity (27.9%), while adverse effects of the interventions were reported in only 17.6% of trials. CONCLUSIONS: There is significant variation in outcome reporting across RCTs of therapies for the prevention and treatment of FGR. The clinical applicability of future research would be enhanced by the development of a core outcome set for use in future trials. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Author Correction: Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

Guinea pigs (Cavia spp.) have a long association with humans. From as early as 10,000 years ago they were a wild food source. Later, domesticated Cavia porcellus were dispersed well beyond their native range through pre-Columbian exchange networks and, more recently, widely across the globe. Here we present 46 complete mitogenomes of archaeological guinea pigs from sites in Peru, Bolivia, Colombia, the Caribbean, Belgium and the United States to elucidate their evolutionary history, origins and paths of dispersal. Our results indicate an independent centre of domestication of Cavia in the eastern Colombian Highlands. We identify a Peruvian origin for the initial introduction of domesticated guinea pigs (Cavia porcellus) beyond South America into the Caribbean. We also demonstrate that Peru was the probable source of the earliest known guinea pigs transported, as part of the exotic pet trade, to both Europe and the southeastern United States. Finally, we identify a modern reintroduction of guinea pigs to Puerto Rico, where local inhabitants use them for food. This research demonstrates that the natural and cultural history of guinea pigs is more complex than previously known and has implications for other studies regarding regional to global-scale studies of mammal domestication, translocation, and distribution.

Interaction of the NG2 chondroitin sulfate proteoglycan with type VI collagen.

The NG2 chondroitin sulfate proteoglycan is a membrane-associated molecule of approximately 500 kD with a core glycoprotein of 300 kD. Both the complete proteoglycan and a smaller quantity of the 300-kD core are immunoprecipitable with polyclonal and monoclonal antibodies against purified NG2. From some cell lines, the antibodies coprecipitate NG2 and type VI collagen, the latter appearing on SDS-PAGE as components of 140 and 250 kD under reducing conditions. The immunoprecipitation of type VI collagen does not seem to be due to recognition of the collagen by the antibodies, but rather to binding of the collagen to NG2. Studies on the NG2-type VI collagen complex suggest that binding between the two molecules is mediated by protein-protein interactions rather than by ionic interactions involving the glycosaminoglycans. Immunofluorescence double labeling in frozen sections of embryonic rat shows that NG2 and type VI collagen are colocalized in structures such as the intervertebral discs and arteries of the spinal column. In vitro the two molecules are highly colocalized on the surface of several cell lines. Treatment of these cells resulting in a change in the distribution of NG2 on the cell surface also causes a parallel change in type VI collagen distribution. Our results suggest that cell surface NG2 may mediate cellular interactions with the extracellular matrix by binding to type VI collagen.

Analysis of obsidian from moho cay, belize: new evidence on classic maya trade routes.

Trace element analysis of obsidian artifacts from Moho Cay, Belize, reveals that the obsidian derives primarily from the El Chayal outcrop in highland Guatemala and not from the Ixtepeque source. This is contrary to the widely accepted obsidian trade route model for Classic Maya civilization and suggests that Classic Maya obsidian trade was a more complex economic phenomenon than has been recognized.

Deficit of spinal cord glycine/strychnine receptors in inherited myoclonus of Poll Hereford calves.

Inherited myoclonus of Poll Hereford calves is characterized by hyperesthesia and myoclonic jerks of the skeletal musculature, which occur spontaneously and in response to sensory stimuli. The disease shows autosomal recessive inheritance, and significant proportions of the Poll Hereford herds in many countries are thought to be carriers of the mutant gene. Studies revealed a specific and marked (90 to 95 percent) deficit in [3H]strychnine binding sites in spinal cord membranes from myoclonic animals compared to controls, reflecting a loss of, or defect in, glycine/strychnine receptors. Spinal cord synaptosomes prepared from affected animals showed a significantly increased ability to accumulate [3H]glycine, indicating an increased capacity of the high-affinity neuronal uptake system for glycine. In contrast, stimulus-induced glycine release and spinal cord glycine concentrations were unaltered.

MRI changes in psoriatic dactylitis--extent of pathology, relationship to tenderness and correlation with clinical indices.

OBJECTIVES: To quantify the extent of inflammation in psoriatic dactylitis and to examine the relationship between clinical and magnetic resonance imaging (MRI) data in both tender and non-tender dactylitis. METHODS: Seventeen patients with psoriatic dactylitis underwent clinical assessment for 6 months after change of treatment, usually to methotrexate. Measures of dactylitis included the Leeds Dactylitis Index, the assessment tool used in the Infliximab in Psoriatic Arthritis Clinical Trial (IMPACT), a simple count of tender dactlylitic digits and a count of all dactylitic digits, both tender and non-tender. MRI scans of the affected hand or foot were performed before and after treatment using a 1.5T Siemen's scanner pre- and post-contrast. RESULTS: All patients improved clinically, as did their respective dactylitis scores and MRI images. The findings on MRI in both dactylitic and non-dactylitic digits were profound and widespread. The difference between tender and non-tender dactylitis was quantitative rather than qualitative. Synovitis and soft-tissue oedema were the most frequent abnormalities being present in 69% of tender dactylitic digits but bone oedema and flexor tenosynovitis were also frequently seen. Soft-tissue oedema was circumferential and enhancing and not limited to association with the flexor or extensor tendons. None of the clinical indices of dactylitis showed a close relationship to the extent of MRI abnormalities. CONCLUSIONS: MRI images demonstrate widespread abnormalities in digits of people with psoriatic arthritis. Tender dactylitic digits have more abnormalities than other digits but the relationship between clinical and MRI scores is not strong.

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BACKGROUND: Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS: Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS: Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS: The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

BACKGROUND: In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT). METHODS: This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time. RESULTS: Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. CONCLUSIONS: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

Expression of the F84.1 glycoprotein in the spinal cord and cranial nerves of the developing rat.

The monoclonal antibody designated as F84.1 was used for an immunohistochemical study of the developing rat nervous system. The most prominent neural components recognized by F84.1 are motor and sensory components of the spinal cord and cranial nerves. F84.1 is first detected in the dorsal root ganglia of embryonic day 11 spinal cord. The expression in the dorsal roots persists in the adult. In contrast, a more transient expression of F84.1 is found in the spinal motor system. F84.1 labels primary neurons of cranial nerves V, VIII, IX and X. F84.1 is also expressed by the non-neuronal cells of the notochord and the floor plate. Immunoprecipitation experiments from several types of cells in culture show that the F84.1 antigen is a cell-surface glycoprotein with a molecular weight of 90-105 kDa. An analysis of the amino terminal sequence demonstrates that the F84.1 antigen is similar to the chick cell adhesion molecule SC1/DM-GRASP, a member of the immunoglobulin superfamily. The pattern of expression of F84.1 in the rat differs in several aspects from that of the chick molecules, leaving a possibility that F84.1 may be a variant of SC1/DM-GRASP.

A granulocyte test for detection of cattle heterozygous for mannosidosis.

alpha-Mannosidase and beta-N-acetylglucosaminidase activities were found to differ between lymphocytes and granulocytes isolated from bovine blood. Activities of both enzymes in granulocyte preparations were found to be related to the eosinophil content of the preparations. A procedure is described that allows definition of the mannosidosis genotype of adult cattle by giving consideration to the influence of eosinophil content of granulocyte preparations upon the activity of alpha-mannosidase relative to that of beta-N-acetylglucosaminidase.

Interference in estimation of serum copper concentration resulting from use of silicone-coated tubes for collection of blood.

Prolonged contact between silicone-treated stoppers in evacuated tubes and serum was found to interfere in estimation of serum copper concentration using atomic absorption spectrophotometry.

Isoenzymes of alkaline phosphatase in serum of lambs and ewes.

Electrophoresis in polyacrylamide gels was used to identify isoenzymes of serum alkaline phosphatase in sheep. Skeletal isoenzyme predominated in the serum of lambs and liver, skeletal and intestinal isoenzymes were found in the serum of adult ewes. In r ewes (R-r-i blood group system) intestinal isoenzyme activity was 67 per cent of total serum activity; in R ewes intestinal activity was only 36 per cent of total activity. Relative activities of the three isoenzymes differed greatly within individual ewes and between individual ewes during pregnancy and lactation.

Isoenzymes of alkaline phosphatase in serum of newly born lambs.

In the serum of lambs at birth most of the circulating alkaline phosphatase, identified by electrophoretic analysis, was of skeletal origin. Suckling was associated with a rapid increase in activity of intestinal alkaline phosphatase isoenzymes in serum. There was a coincidental increase in level of circulating gamma globulin. Activity of the intestinal isoenzymes in serum began to fall between 15 and 21 h after birth and this fall preceded a fall in serum gamma globulin concentration. The electrophoretic characteristics of the intestinal isoenzymes in serum changed as activity of these isoenzymes increased and then decreased.

Lysosomal hydrolase activity in leucocytes from cattle, sheep, goats, horses and pigs.

Activities of lysosomal hydrolases were measured in the leucocytes of cattle, sheep, goats, horses and pigs. There was high activity of arylsulphatase in leucocytes from cattle, high activities of alpha-fucosidase and beta-glucuronidase in leucocytes from horses and high activity of acid phosphatase in granulocytes from pigs. Within species, arylsulphatase and beta-galactosidase activities were higher in granulocytes than in mononuclear cells, but beta-glucuronidase, phosphodiesterase and alpha-galactosidase activities were higher in mononuclear cells than in granulocytes. Eosinophils of cattle, sheep, goats and horses contained at least 10 times the activity of alpha-mannosidase and arylsulphatase found in neutrophils. For most of the other enzymes studied, there were differences in cattle and goats but not in sheep, horses or pigs between their specific activities in neutrophils and eosinophils.

Modified granulocyte test for determination of mannosidosis genotype of cattle.

Recovery of alpha-mannosidase, beta-N-acetylglucosaminidase and arylsulphatase activity from granulocytes is increased by inclusion of 154 mM sodium chloride, in place of 1 mM zinc chloride, in aqueous Triton X-100 used to extract the cells. Calculation of the ratio of alpha-mannosidase to beta-N-acetylglucosaminidase and to arylsulphatase permits diagnosis of the mannosidosis genotype without recourse to examination of smears of the granulocyte preparations.

Serum alkaline phosphatase activity in relation to liveweight of lambs.

Groups of lambs were fed four levels of a diet based upon oaten grain. Two groups gained weight rapidly, one less rapidly and the other lost liveweight over a 32-day period. Serum alkaline phosphatase activity was found to be closely correlated to liveweight, in a positive linear manner, in those lambs gaining weight rapidly. This relationship was similar in lambs of R or r blood group. Supplementation of the diet with limestone and or sodium chloride did not influence the relationship. This relationship is considered to reflect the influence of the dietary treatments upon the rate of skeletal metabolism.

An interaction between diet and blood group upon serum alkaline phosphatase activity in lambs.

Serum alkaline phosphatase activity was studied in groups of lambs fed diets containing different amounts of wheat grain and lucerne hay with different levels of supplementation with formaldehyde treated casein-sunflower seed. Total serum alkaline phosphatase activity increased more in groups fed 100 per cent wheat or 67 per cent wheat 33 per cent lucerne than in those fed 33 per cent wheat 67 per cent lucerne or 100 per cent lucerne. Supplementation of the diets with the casein-sunflower seed preparation resulted in an increase in the heat resistant proportion of serum alkaline phosphatase activity. This effect was more apparent in lambs of the r blood group (R-r-i blood group system) than in R lambs. These finds are discussed in relation to the relative heat resistance of tissue isoenzymes of alkaline phosphatase.

Definition of the mutation responsible for maple syrup urine disease in Poll Shorthorns and genotyping Poll Shorthorns and Poll Herefords for maple syrup urine disease alleles.

The organisation of the E1alpha subunit of bovine branched-chain alpha-keto acid dehydrogenase gene was established. c DNA was cloned from Poll Shorthorn x Poll Hereford calves affected with Maple Syrup Urine Disease to identify the mutation responsible for the disease in Poll Shorthorns. Clones containing the c DNA sequences inherited from the Poll Shorthorn sire of the affected calves were identified. Paternal clones were sequenced and a cytidine to thymidine transition was found at nucleotide 1380. The mutation is predicted to substitute leucine in place of a highly conserved proline at codon 372. A polymerase chain reaction procedure was developed for detection of the 1380C-->T mutation in genomic DNA. Three Poll Shorthorn parents of affected calves and three affected Poll Shorthorn x Poll Hereford calves were heterozygous and an affected Poll Shorthorn calf was homozygous for this mutation. An improved polymerase chain reaction procedure was also devised to genotype Poll Herefords for the 248C-->T mutation. The procedures will facilitate disease prevention programs and assist in differential diagnosis of conditions in new-born calves that present with a rapid onset of progressive neurological disease and are characterised histologically by 'status spongiosus'. Maple Syrup Urine Disease (MSUD) is an autosomal recessive defect reported in humans (Danner and Elsas 1989), and in Poll Hereford (PH) and Poll Shorthorn (PS) calves (Harper et al 1986, Healy et al 1992). The clinical, biochemical and pathological manifestations of the disease are identical in the two breeds of cattle, and are characterised by the rapid onset of progressive neurological disease, leading to death within a few days of birth. The disease is caused by a deficiency of activity of the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKADH). This deficiency leads to elevated concentrations, in blood and tissues, of branched chain alpha-keto acids and their precursors, the branched chain amino acids, valine, leucine and isoleucine. BCKADH consists of four subunits E1alpha, E1beta, E2 and E3 that are encoded by separate genes, and MSUD may result from deficiency of any of the subunits. In PH s, the disease in caused by premature termination of translation, of the E1alpha subunit, that is induced by a cytidine to thymidine transition exon 2 (248C-->T), that converts the glutamine codon -6 to a stop codon (Q-6ST; Zhang et al 1990). We have shown that MSUD -affected PSxPH calves are heterozygous at the PH locus, illustrating molecular heterogeneity exists for bovine MSUD (Healy and Dennis 1994a). The fact that these crossbred calves are affected, indicates the PS, like the PH mutation, resides in the E1alpha subunit.