Think globally, measure locally: The MIREN standardized protocol for monitoring plant species distributions along elevation gradients.

Climate change and other global change drivers threaten plant diversity in mountains worldwide. A widely documented response to such environmental modifications is for plant species to change their elevational ranges. Range shifts are often idiosyncratic and difficult to generalize, partly due to variation in sampling methods. There is thus a need for a standardized monitoring strategy that can be applied across mountain regions to assess distribution changes and community turnover of native and non-native plant species over space and time. Here, we present a conceptually intuitive and standardized protocol developed by the Mountain Invasion Research Network (MIREN) to systematically quantify global patterns of native and non-native species distributions along elevation gradients and shifts arising from interactive effects of climate change and human disturbance. Usually repeated every five years, surveys consist of 20 sample sites located at equal elevation increments along three replicate roads per sampling region. At each site, three plots extend from the side of a mountain road into surrounding natural vegetation. The protocol has been successfully used in 18 regions worldwide from 2007 to present. Analyses of one point in time already generated some salient results, and revealed region-specific elevational patterns of native plant species richness, but a globally consistent elevational decline in non-native species richness. Non-native plants were also more abundant directly adjacent to road edges, suggesting that disturbed roadsides serve as a vector for invasions into mountains. From the upcoming analyses of time series, even more exciting results can be expected, especially about range shifts. Implementing the protocol in more mountain regions globally would help to generate a more complete picture of how global change alters species distributions. This would inform conservation policy in mountain ecosystems, where some conservation policies remain poorly implemented.

Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.

Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with "any event" was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20-1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P < 0.004). After a median follow-up of 7 years, women carrying the "low estrogen" alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17-0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592.

Multimodal Neuroimaging in Schizophrenia: Description and Dissemination.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).

Centre-level variation in dental treatment and oral health and individual- and area-level predictors of oral health in 5-year-old children with non-syndromic unilateral cleft lip and palate: the Cleft Care UK study. Part 3.

OBJECTIVES: To explore centre-level variation in fluoride treatment and oral health outcomes and to examine the association of individual- and area-level risk factors with dental decay in Cleft Care UK (CCUK). SETTING: Two hundred and sixty-eight 5-year-old British children with non-syndromic unilateral cleft lip and palate (UCLP). MATERIALS AND METHODS: Data on caries and developmental defects of enamel (DDE) were collected. The child's history of fluoride ingestion and postcode was used to assess exposure to fluoridated water. Centre-level variation in fluoride exposure and caries was examined using hierarchical regression. Poisson regression was used to estimate the association between individual- and area-level fluoride exposures and outcome. RESULTS: Children had high levels of caries, rampant caries and DDE. There was no evidence of variation between centres in the number of children with caries or rampant decay. There was evidence of variation in prescription of fluoride tablets and varnish and the type of toothpaste used. Area level of deprivation was associated with a higher risk of dental caries-risk ratio (RR) in the lowest quartile versus the rest was 1.43 (95% CI 1.13 to 1.81). Use of fluoride tablets and varnish was associated with higher risk of caries-RR 1.73 (95% CI 1.29 to 2.32) and RR 1.33 (95% CI 1.04 to 1.70), respectively, adjusted for age, sex and deprivation. CONCLUSION: The association with use of fluoride tablets and varnish probably reflects reverse causality but indicates the need for early preventative interventions in children with UCLP.

SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway.

BACKGROUND: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. METHODS: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. RESULTS: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E-11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. CONCLUSION: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

Caring for Pregnant Women with Opioid Use Disorder in the USA: Expanding and Improving Treatment.

PURPOSE OF THE REVIEW: Opioid use disorder in the USA is rising at an alarming rate, particularly among women of childbearing age. Pregnant women with opioid use disorder face numerous barriers to care, including limited access to treatment, stigma, and fear of legal consequences. This review of opioid use disorder in pregnancy is designed to assist health care providers caring for pregnant and postpartum women with the goal of expanding evidence-based treatment practices for this vulnerable population. RECENT FINDINGS: We review current literature on opioid use disorder among US women, existing legislation surrounding substance use in pregnancy, and available treatment options for pregnant women with opioid use disorder. Opioid agonist treatment (OAT) remains the standard of care for treating opioid use disorder in pregnancy. Medically assisted opioid withdrawal ("detoxification") is not recommended in pregnancy and is associated with high maternal relapse rates. Extended release naltrexone may confer benefit for carefully selected patients. Histories of trauma and mental health disorders are prevalent in this population; and best practice recommendations incorporate gender-specific, trauma-informed, mental health services. Breastfeeding with OAT is safe and beneficial for the mother-infant dyad. SUMMARY: Further research investigating options of OAT and the efficacy of opioid antagonists in pregnancy is needed. The US health care system can adapt to provide quality care for these mother-infant dyads by expanding comprehensive treatment services and improving access to care.

Bioanalytical method transfer considerations of chromatographic-based assays.

Bioanalysis is an important part of the modern drug development process. The business practice of outsourcing and transferring bioanalytical methods from laboratory to laboratory has increasingly become a crucial strategy for successful and efficient delivery of therapies to the market. This chapter discusses important considerations when transferring various types of chromatographic-based assays in today's pharmaceutical research and development environment.

Two new species of Indigofera L. (Leguminosae) from the Sneeuberg Centre of Floristic Endemism, Great Escarpment (Eastern and Western Cape, South Africa).

Two new species of Indigofera L. (Leguminosae) are described from the Sneeuberg Centre of Floristic Endemism on the southern Great Escarpment, Eastern and Western Cape Provinces, South Africa. Both species are localised high-altitude endemics. Indigoferamagnifica Schrire & V.R. Clark is confined to the summit plateau of the Toorberg-Koudeveldberg-Meelberg west of Graaff-Reinet, and complements other western Sneeuberg endemics such as Ericapasserinoides (Bolus) E.G.H. Oliv. and Faurearecondita Rourke & V.R. Clark. Indigoferaasantasanensis Schrire & V.R. Clark is confined to a small area east of Graaff-Reinet, and complements several other eastern Sneeuberg endemics such as Euryopsexsudans B. Nord & V.R. Clark and Euryopsproteoides B. Nord. & V.R. Clark. Based on morphology, both new species belong to the Cape Clade of Indigofera, supporting a biogeographical link between the Cape Floristic Region and the Sneeuberg, as well as with the rest of the eastern Great Escarpment.

Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole.

PURPOSE: We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites. EXPERIMENTAL: Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays. RESULTS: 649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug. CONCLUSIONS: We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer.

TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression.

We performed a discovery genome-wide association study to identify genetic factors associated with variation in plasma estradiol (E2) concentrations using DNA from 772 postmenopausal women with estrogen receptor (ER)-positive breast cancer prior to the initiation of aromatase inhibitor therapy. Association analyses showed that the single nucleotide polymorphisms (SNP) (rs1864729) with the lowest P value (P = 3.49E-08), mapped to chromosome 8 near TSPYL5. We also identified 17 imputed SNPs in or near TSPYL5 with P values < 5E-08, one of which, rs2583506, created a functional estrogen response element. We then used a panel of lymphoblastoid cell lines (LCLs) stably transfected with ERα with known genome-wide SNP genotypes to demonstrate that TSPYL5 expression increased after E2 exposure of cells heterozygous for variant TSPYL5 SNP genotypes, but not in those homozygous for wild-type alleles. TSPYL5 knockdown decreased, and overexpression increased aromatase (CYP19A1) expression in MCF-7 cells, LCLs, and adipocytes through the skin/adipose (I.4) promoter. Chromatin immunoprecipitation assay showed that TSPYL5 bound to the CYP19A1 I.4 promoter. A putative TSPYL5 binding motif was identified in 43 genes, and TSPYL5 appeared to function as a transcription factor for most of those genes. In summary, genome-wide significant SNPs in TSPYL5 were associated with elevated plasma E2 in postmenopausal breast cancer patients. SNP rs2583506 created a functional estrogen response element, and LCLs with variant SNP genotypes displayed increased E2-dependent TSPYL5 expression. TSPYL5 induced CYP19A1 expression and that of many other genes. These studies have revealed a novel mechanism for regulating aromatase expression and plasma E2 concentrations in postmenopausal women with ER(+) breast cancer.

The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma.

BACKGROUND: Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. AIM: To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. METHODS: We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time. RESULTS: Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point. CONCLUSION: Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

Impact of tDCS on performance and learning of target detection: interaction with stimulus characteristics and experimental design.

We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits)-Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (ß). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed.

Multidisciplinary management of an obstetric patient with glycogen storage disease type 3.

A 22-year-old primiparous woman with known glycogen storage disease type 3a presented to our hospital during her 12th week of pregnancy. Glycogen storage disease type 3 is a rare inherited disorder resulting from a deficiency of the glycogen debranching enzyme, causing the accumulation of abnormal short-chain glycogen in liver, blood cells, myocardium and striated muscle. Symptoms improve after puberty but the increased metabolism of pregnancy predisposes to hypoglycaemia, ketosis and lactic acidosis. Cardiomyopathy, distal weakness and peripheral neuropathy may present after the third decade. The patient was managed antenatally with regular cornflour feeds and was scheduled for elective caesarean delivery. She presented in early labour at 38 weeks and delivered a healthy neonate by urgent caesarean delivery under spinal anaesthesia. Intravenous dextrose infusion and regular blood glucose monitoring were used during the perinatal period to prevent hypoglycaemia. An arterial line was inserted in the operating room for frequent blood sampling and to avoid muscle cramps which could be induced by the intermittent inflation of the automated blood pressure cuff. Obstetric, anaesthetic and neonatal outcomes were uneventful.

Psoralea margaretiflora (Psoraleeae, Fabaceae): A new species from the Sneeuberg Centre of Floristic Endemism, Eastern Cape, South Africa.

A new species of Psoralea is described. Psoralea margaretiflora C.H. Stirton & V.R. Clark is endemic to the Sneeuberg Centre of Floristic Endemism, Eastern Cape, South Africa. This resprouter is characterised by its small greenish-white flowers with a small trifid purple nectar patch and translucent veins; 5(-7)-pinnate leaflets; multi-branching erect short seasonal flowering shoots; and tall habit of many stiff bare stems with the seasonal shoots massed at the apex. It is most similar to Psoralea oligophylla Eckl. & Zeyh., a widespread species found in the Eastern Cape. The reseeder Psoralea oligophylla differs in its lax virgate spreading habit with numerous long glaucous seasonal shoots; single stem, 1(-3)- glaucous leaflets; more numerous white flowers; and standard petals with a purple ring surrounding a bright yellow nectar patch.

Transcranial direct current stimulation's effect on novice versus experienced learning.

Transcranial direct current stimulation (TDCS) is a non-invasive form of brain stimulation applied via a weak electrical current passed between electrodes on the scalp. In recent studies, TDCS has been shown to improve learning when applied to the prefrontal cortex (e.g., Kincses et al. in Neuropsychologia 42:113-117, 2003; Clark et al. Neuroimage in 2010). The present study examined the effects of TDCS delivered at the beginning of training (novice) or after an hour of training (experienced) on participants' ability to detect cues indicative of covert threats. Participants completed two 1-h training sessions. During the first 30 min of each training session, either 0.1 mA or 2.0 mA of anodal TDCS was delivered to the participant. The anode was positioned near F8, and the cathode was placed on the upper left arm. Testing trials immediately followed training. Accuracy in classification of images containing and not-containing threat stimuli during the testing sessions indicated: (1) that mastery of threat detection significantly increased with training, (2) that anodal TDCS at 2 mA significantly enhanced learning, and (3) TDCS was significantly more effective in enhancing test performance when applied in novice learners than in experienced learners. The enhanced performance following training with TDCS persisted into the second session when TDCS was delivered early in training.

The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma.

BACKGROUND: Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy. AIM: To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC. METHODS: Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected. RESULTS: A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60years, good performance status (0-1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24ng/mL. Median follow-up was 12months and median time on sorafenib was 6months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand-foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6months. Overall median survival rate was 18.5months (95% CI 16.1-20.9months). CONCLUSION: Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.

Natural history of small duct primary sclerosing cholangitis: a case series with review of the literature.

BACKGROUND AND AIMS: Information about the natural history of small duct primary sclerosing cholangitis (SDPSC) remains scant despite literature suggesting that it constitutes 6-16% of all cases of primary sclerosing cholangitis (PSC). We combined clinical data on SDPSC cases from two tertiary care institutions with liver transplantation programs with the aim of studying the natural history of SDPSC. METHODS: Medical records of 25 individuals with SDPSC were reviewed. Diagnosis of SDPSC was based on liver biopsy findings consistent with PSC, a normal cholangiogram, and elimination of known causes of secondary sclerosing cholangitis. Demographic information, symptoms, past medical history, laboratory values, and histologic data were evaluated. Our primary outcome measure was liver transplantation or death. Secondary outcome measures included evidence of end-stage liver disease, development of cholangiocarcinoma, and/or the development of classic PSC on a repeat cholangiogram. RESULTS: Data on 25 individuals (13 males, 12 females; mean age 40 ± 15 years) diagnosed with SDPSC were analyzed. Upon presentation, 11 patients had symptoms including abdominal pain, fatigue, and pruritus. Inflammatory bowel disease was present in 14 patients (56%) at diagnosis. On initial liver biopsy, 60% had early-stage disease (I or II) and none had cirrhosis. On follow-up (1-168 months, median 17 months), malignancy or progression to classic large duct PSC was not noted. Two (8%) patients had evidence of varices and one of the two also developed ascites; one of these patients underwent liver transplantation and the other one died due to sepsis. CONCLUSIONS: SDPSC, a mild disease at presentation typically runs a benign course and likely is not an early stage of classic PSC. Further studies with a control group of classic PSC and longer follow-up are needed to study the natural history of SDPSC.