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1.  Jack Edwards 
BMJ : British Medical Journal  2003;327(7418):813.
PMCID: PMC214177
2.  Developmental consequences of supplementing with matrix metallopeptidase-9 during in vitro maturation of heat-stressed bovine oocytes 
Because latent form of matrix metallopeptidase-9 (proMMP9) levels are positively related to blastocyst development, it was hypothesized that addition during maturation may improve development of heat-stressed oocytes. To test hypothesis, 0, 30 or 300 ng/ml human proMMP9 (hMMP9) was added at 18 h of in vitro maturation (hIVM) to cumulus-oocyte complexes matured at 38.5 or 41.0ºC (first 12 h only). Heat stress decreased 24 hIVM proMMP9 levels only in 0 and 30 ng/ml groups and increased progesterone in 0 and 300 ng/ml hMMP9 groups. Heat stress decreased cleavage and blastocyst development. Independent of maturation temperature, hMMP9 at 18 hIVM decreased blastocyst development. In a second study, cumulus-oocyte complexes were matured for 24 h at 38.5 or 41.0ºC (HS first 12 h only) with 0 or 300 ng/ml hMMP9 added at 12 hIVM. Without hMMP9, heat stress decreased 24 hIVM proMMP9 levels and increased progesterone production. Addition of 300 ng/ml of hMMP9 produced equivalent levels of proMMP9 at 24 hIVM (271 vs. 279 ± 77 for 38.5ºC and 41.0ºC treated oocytes, respectively). Heat stress did not affect ability of oocytes to cleave but reduced blastocyst development. Independent of temperature, hMMP9 decreased cleavage and blastocyst development. In summary, hMMP9 supplementation during IVM did not improve development of heat-stressed oocytes even when it was added for the entire maturation period. At doses tested, hMMP9 appeared detrimental to development when supplemented during the last 12 or 6 h of oocyte maturation.
PMCID: PMC5177972  PMID: 27440552
Cumulus cells; Heat stress; Matrix metallopeptidase-9 (MMP9); Oocyte maturation; Progesterone
3.  Persistence of Influenza A (H1N1) Virus on Stainless Steel Surfaces 
Applied and Environmental Microbiology  2016;82(11):3239-3245.
As annual influenza epidemics continue to cause significant morbidity and economic burden, an understanding of viral persistence and transmission is critical for public health officials and health care workers to better protect patients and their family members from infection. The infectivity and persistence of two influenza A (H1N1) virus strains (A/New Caledonia/20/1999 and A/Brisbane/59/2007) on stainless steel (SS) surfaces were evaluated using three different surface matrices (2% fetal bovine serum, 5 mg/ml mucin, and viral medium) under various absolute humidity conditions (4.1 × 105 mPa, 6.5 × 105 mPa, 7.1 × 105 mPa, 11.4 × 105 mPa, 11.2 × 105 mPa, and 17.9 × 105 mPa) for up to 7 days. Influenza A virus was deposited onto SS coupons (7.07 cm2) and recovered by agitation and sonication in viral medium. Viral persistence was quantified using a tissue culture-based enzyme-linked immunosorbent assay (ELISA) to determine the median (50%) tissue culture infective dose (TCID50) of infectious virus per coupon. Overall, both strains of influenza A virus remained infectious on SS coupons, with an approximate 2 log10 loss over 7 days. Factors that influenced viral persistence included absolute humidity, strain-absolute humidity interaction, and time (P ≤ 0.01). Further studies on the transfer of influenza A virus from fomites by hand and the impact of inanimate surface contamination on transmission should be performed, as this study demonstrates prolonged persistence on nonporous surfaces.
IMPORTANCE This study tested the ability of two influenza A (H1N1) virus strains to persist and remain infectious on stainless steel surfaces under various environmental conditions. It demonstrated that influenza A (H1N1) viruses can persist and remain infectious on stainless steel surfaces for 7 days. Additional studies should be conducted to assess the role played by contaminated surfaces in the transmission of influenza A virus.
PMCID: PMC4959249  PMID: 26994082
4.  Preparation, Characterization and Activity of a Peptide-Cellulosic Aerogel Protease Sensor from Cotton 
Sensors (Basel, Switzerland)  2016;16(11):1789.
Nanocellulosic aerogels (NA) provide a lightweight biocompatible material with structural properties, like interconnected high porosity and specific surface area, suitable for biosensor design. We report here the preparation, characterization and activity of peptide-nanocellulose aerogels (PepNA) made from unprocessed cotton and designed with protease detection activity. Low-density cellulosic aerogels were prepared from greige cotton by employing calcium thiocyanate octahydrate/lithium chloride as a direct cellulose dissolving medium. Subsequent casting, coagulation, solvent exchange and supercritical carbon dioxide drying afforded homogeneous cellulose II aerogels of fibrous morphology. The cotton-based aerogel had a porosity of 99% largely dominated by mesopores (2–50 nm) and an internal surface of 163 m2·g−1. A fluorescent tripeptide-substrate (succinyl-alanine-proline-alanine-4-amino-7-methyl-coumarin) was tethered to NA by (1) esterification of cellulose C6 surface hydroxyl groups with glycidyl-fluorenylmethyloxycarbonyl (FMOC), (2) deprotection and (3) coupling of the immobilized glycine with the tripeptide. Characterization of the NA and PepNA included techniques, such as elemental analysis, mass spectral analysis, attenuated total reflectance infrared imaging, nitrogen adsorption, scanning electron microscopy and bioactivity studies. The degree of substitution of the peptide analog attached to the anhydroglucose units of PepNA was 0.015. The findings from mass spectral analysis and attenuated total reflectance infrared imaging indicated that the peptide substrate was immobilized on to the surface of the NA. Nitrogen adsorption revealed a high specific surface area and a highly porous system, which supports the open porous structure observed from scanning electron microscopy images. Bioactivity studies of PepNA revealed a detection sensitivity of 0.13 units/milliliter for human neutrophil elastase, a diagnostic biomarker for inflammatory diseases. The physical properties of the aerogel are suitable for interfacing with an intelligent protease sequestrant wound dressing.
PMCID: PMC5134448  PMID: 27792201
elastase peptide; cellulosic aerogels; human neutrophil elastase; biosensor; chronic wounds
5.  The relationship between tumour budding, the tumour microenvironment and survival in patients with invasive ductal breast cancer 
British Journal of Cancer  2015;113(7):1066-1074.
Tumour budding has previously been reported to predict survival in several solid organ tumours, including breast; however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between tumour budding, the tumour microenvironment and survival was examined in patients with invasive ductal breast cancer.
Patients presenting between 1995 and 1998 were studied (n=474). Using routine pathological sections, tumour budding was measured at the invasive margin and its association with clinicopathological characteristics and cancer-specific survival (CSS) was examined.
Tumour budding was associated with several adverse pathological characteristics, including lymph node involvement, lymph vessel invasion (LVI), increased tumour stroma percentage (TSP) and weaker local inflammatory infiltrative. Tumour budding was associated with reduced CSS (hazard ratio (HR) 2.08, 95% confidence interval (CI) 1.14–3.09, P=0.004), independent of nodal status, molecular subtypes, tumour necrosis, CD8+, CD138+, LVI, blood vessel invasion and TSP. Further, tumour budding was independently associated with reduced CSS in node-negative patients (HR 2.63, 95% CI 1.16–5.92, P=0.020) and those who have low TSP (HR 1.98, 95% CI 1.09–3.57, P=0.024) and high-grade local inflammatory infiltrative (HR 2.27, 95% CI 1.35–5.36, P=0.014).
Tumour budding was a significant predictor of survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. The present study further confirms the clinical utility of both tumour and host-based factors of tumour microenvironment.
PMCID: PMC4651125  PMID: 26263482
tumour budding; tumour microenvironment; breast cancer; survival
7.  Changes in BMI over 6 years: the role of demographic and neighborhood characteristics 
To undertake a 6-year longitudinal investigation of the relationship between the built environment (perceived and objectively measured) and change in body mass index (BMI). Specifically, this research examined whether change in BMI was predicted by objectively measured neighborhood walkability and socioeconomic status (SES), and perceived neighborhood characteristics (for example, crime, traffic and interesting things to look at) in addition to other factors such as age, gender, education, physical activity, fruit and vegetable consumption and smoking.
Longitudinal study
500 adults who provided complete data in 2002 and 2008 and who did not move over the course of the study (47.8% female; age in 2002: 18–90 years).
Telephone surveys in 2002 and 2008 measuring perceptions of their neighborhood environment and demographic factors. Objective measures of neighborhood characteristics were calculated using census data and geographical information systems in 2006.
Age, neighborhood SES and perceived traffic were significantly related to increased BMI over the 6 years. Younger participants and those in lower SES neighborhoods were more likely to have increased BMI. Agreement with the statement that traffic made it difficult to walk also predicted increased BMI.
This study adds to the literature to show that BMI increased in low SES neighborhoods. Although more research is needed to fully understand how neighborhood SES contributes to obesity, it is without question that individuals in socially disadvantaged neighborhoods face more barriers to health than their wealthier counterparts. This study also calls into question the relationship between walkability and changes in BMI and emphasizes the necessity of longitudinal data rather than relying on cross-sectional research.
PMCID: PMC5005067  PMID: 20157324 CAMSID: cams716
built environment; walkability; BMI change; longitudinal
8.  Ricebase: a breeding and genetics platform for rice, integrating individual molecular markers, pedigrees and whole-genome-based data 
Ricebase ( is an integrative genomic database for rice (Oryza sativa) with an emphasis on combining datasets in a way that maintains the key links between past and current genetic studies. Ricebase includes DNA sequence data, gene annotations, nucleotide variation data and molecular marker fragment size data. Rice research has benefited from early adoption and extensive use of simple sequence repeat (SSR) markers; however, the majority of rice SSR markers were developed prior to the latest rice pseudomolecule assembly. Interpretation of new research using SNPs in the context of literature citing SSRs requires a common coordinate system. A new pipeline, using a stepwise relaxation of stringency, was used to map SSR primers onto the latest rice pseudomolecule assembly. The SSR markers and experimentally assayed amplicon sizes are presented in a relational database with a web-based front end, and are available as a track loaded in a genome browser with links connecting the browser and database. The combined capabilities of Ricebase link genetic markers, genome context, allele states across rice germplasm and potentially user curated phenotypic interpretations as a community resource for genetic discovery and breeding in rice.
PMCID: PMC4980570  PMID: 27515824
9.  The burden of road traffic injuries in an emergency department in Addis Ababa, Ethiopia 
Public Health Action  2016;6(2):66-71.
Setting: The emergency department (ED) of Zewditu Memorial Hospital, Addis Ababa, Ethiopia.
Objective: To document the proportion, trend, characteristics and outcomes of road traffic injury (RTI) related ED admissions (⩾15 years) between 2014 and 2015.
Design: A retrospective, cross-sectional study using routinely collected ED data.
Results: Of 10 007 ED admissions, 779 (8%) were RTI cases; this proportion peaked in the month of January (11%). Medical records were available for 522 (67%) of these RTI cases. The median age was 28 years and 69% were males. The majority were pedestrians (69%) injured by an automobile (78%). On triage, 32% were classified as needing urgent/immediate intervention. Head injuries (20%) were the second most common injury after lower limb injuries (36%). ED outcomes were as follows: discharged (68%), hospitalised (17%), referred (17%) and died (1%). Among the 78 hospitalised cases, respectively 62% and 16% were admitted to the surgical and orthopaedic departments. Of 146 RTI cases with head injuries, 25% were hospitalised, of whom 82% were admitted to the surgical department.
Conclusion: Our findings can guide policy makers in referral hospitals in improving the planning of hospital resources and the prioritisation of public health needs linked to further urban development. A comprehensive plan to prevent RTIs, particularly among pedestrians in Addis Ababa, is urgently needed.
PMCID: PMC4913687  PMID: 27358798
road traffic injuries; burden; Ethiopia; operational research
10.  Fungal Planet description sheets: 400–468 
Crous, P.W. | Wingfield, M.J. | Richardson, D.M. | Le Roux, J.J. | Strasberg, D. | Edwards, J. | Roets, F. | Hubka, V. | Taylor, P.W.J. | Heykoop, M. | Martín, M.P. | Moreno, G. | Sutton, D.A. | Wiederhold, N.P. | Barnes, C.W. | Carlavilla, J.R. | Gené, J. | Giraldo, A. | Guarnaccia, V. | Guarro, J. | Hernández-Restrepo, M. | Kolařík, M. | Manjón, J.L. | Pascoe, I.G. | Popov, E.S. | Sandoval-Denis, M. | Woudenberg, J.H.C. | Acharya, K. | Alexandrova, A.V. | Alvarado, P. | Barbosa, R.N. | Baseia, I.G. | Blanchette, R.A. | Boekhout, T. | Burgess, T.I. | Cano-Lira, J.F. | Čmoková, A. | Dimitrov, R.A. | Dyakov, M.Yu. | Dueñas, M. | Dutta, A.K. | Esteve-Raventós, F. | Fedosova, A.G. | Fournier, J. | Gamboa, P. | Gouliamova, D.E. | Grebenc, T. | Groenewald, M. | Hanse, B. | Hardy, G.E.St.J. | Held, B.W. | Jurjević, Ž. | Kaewgrajang, T. | Latha, K.P.D. | Lombard, L. | Luangsa-ard, J.J. | Lysková, P. | Mallátová, N. | Manimohan, P. | Miller, A.N. | Mirabolfathy, M. | Morozova, O.V. | Obodai, M. | Oliveira, N.T. | Ordóñez, M.E. | Otto, E.C. | Paloi, S. | Peterson, S.W. | Phosri, C. | Roux, J. | Salazar, W.A. | Sánchez, A. | Sarria, G.A. | Shin, H.-D. | Silva, B.D.B. | Silva, G.A. | Smith, M.Th. | Souza-Motta, C.M. | Stchigel, A.M. | Stoilova-Disheva, M.M. | Sulzbacher, M.A. | Telleria, M.T. | Toapanta, C. | Traba, J.M. | Valenzuela-Lopez, N. | Watling, R. | Groenewald, J.Z.
Novel species of fungi described in the present study include the following from Australia: Vermiculariopsiella eucalypti, Mulderomyces natalis (incl. Mulderomyces gen. nov.), Fusicladium paraamoenum, Neotrimmatostroma paraexcentricum, and Pseudophloeospora eucalyptorum on leaves of Eucalyptus spp., Anungitea grevilleae (on leaves of Grevillea sp.), Pyrenochaeta acaciae (on leaves of Acacia sp.), and Brunneocarpos banksiae (incl. Brunneocarpos gen. nov.) on cones of Banksia attenuata. Novel foliicolous taxa from South Africa include Neosulcatispora strelitziae (on Strelitzia nicolai), Colletotrichum ledebouriae (on Ledebouria floridunda), Cylindrosympodioides brabejum (incl. Cylindrosympodioides gen. nov.) on Brabejum stellatifolium, Sclerostagonospora ericae (on Erica sp.), Setophoma cyperi (on Cyperus sphaerocephala), and Phaeosphaeria breonadiae (on Breonadia microcephala). Novelties described from Robben Island (South Africa) include Wojnowiciella cissampeli and Diaporthe cissampeli (both on Cissampelos capensis), Phaeotheca salicorniae (on Salicornia meyeriana), Paracylindrocarpon aloicola (incl. Paracylindrocarpon gen. nov.) on Aloe sp., and Libertasomyces myopori (incl. Libertasomyces gen. nov.) on Myoporum serratum. Several novelties are recorded from La Réunion (France), namely Phaeosphaeriopsis agapanthi (on Agapanthus sp.), Roussoella solani (on Solanum mauritianum), Vermiculariopsiella acaciae (on Acacia heterophylla), Dothiorella acacicola (on Acacia mearnsii), Chalara clidemiae (on Clidemia hirta), Cytospora tibouchinae (on Tibouchina semidecandra), Diaporthe ocoteae (on Ocotea obtusata), Castanediella eucalypticola, Phaeophleospora eucalypticola and Fusicladium eucalypticola (on Eucalyptus robusta), Lareunionomyces syzygii (incl. Lareunionomyces gen. nov.) and Parawiesneriomyces syzygii (incl. Parawiesneriomyces gen. nov.) on leaves of Syzygium jambos. Novel taxa from the USA include Meristemomyces arctostaphylos (on Arctostaphylos patula), Ochroconis dracaenae (on Dracaena reflexa), Rasamsonia columbiensis (air of a hotel conference room), Paecilomyces tabacinus (on Nicotiana tabacum), Toxicocladosporium hominis (from human broncoalveolar lavage fluid), Nothophoma macrospora (from respiratory secretion of a patient with pneumonia), and Penidiellopsis radicularis (incl. Penidiellopsis gen. nov.) from a human nail. Novel taxa described from Malaysia include Prosopidicola albizziae (on Albizzia falcataria), Proxipyricularia asari (on Asarum sp.), Diaporthe passifloricola (on Passiflora foetida), Paramycoleptodiscus albizziae (incl. Paramycoleptodiscus gen. nov.) on Albizzia falcataria, and Malaysiasca phaii (incl. Malaysiasca gen. nov.) on Phaius reflexipetalus. Two species are newly described from human patients in the Czech Republic, namely Microascus longicollis (from toenails of patient with suspected onychomycosis), and Chrysosporium echinulatum (from sole skin of patient). Furthermore, Alternaria quercicola is described on leaves of Quercus brantii (Iran), Stemphylium beticola on leaves of Beta vulgaris (The Netherlands), Scleroderma capeverdeanum on soil (Cape Verde Islands), Scleroderma dunensis on soil, and Blastobotrys meliponae from bee honey (Brazil), Ganoderma mbrekobenum on angiosperms (Ghana), Geoglossum raitviirii and Entoloma kruticianum on soil (Russia), Priceomyces vitoshaensis on Pterostichus melas (Carabidae) (Bulgaria) is the only one for which the family is listed, Ganoderma ecuadoriense on decaying wood (Ecuador), Thyrostroma cornicola on Cornus officinalis (Korea), Cercophora vinosa on decorticated branch of Salix sp. (France), Coprinus pinetorum, Coprinus littoralis and Xerocomellus poederi on soil (Spain). Two new genera from Colombia include Helminthosporiella and Uwemyces on leaves of Elaeis oleifera. Two species are described from India, namely Russula intervenosa (ectomycorrhizal with Shorea robusta), and Crinipellis odorata (on bark of Mytragyna parviflora). Novelties from Thailand include Cyphellophora gamsii (on leaf litter), Pisolithus aureosericeus and Corynascus citrinus (on soil). Two species are newly described from Citrus in Italy, namely Dendryphiella paravinosa on Citrus sinensis, and Ramularia citricola on Citrus floridana. Morphological and culture characteristics along with ITS nrDNA barcodes are provided for all taxa.
PMCID: PMC4988374  PMID: 27616795
ITS DNA barcodes; LSU; novel fungal species; systematics
11.  Influences on the decision to use an osteoarthritis diagnosis in primary care: a cohort study with linked survey and electronic health record data 
Osteoarthritis and Cartilage  2016;24(5):786-793.
Clinicians may record patients presenting with osteoarthritis (OA) symptoms with joint pain rather than an OA diagnosis. This may have implications for OA research studies and patient care. The objective was to assess whether older adults recorded with joint pain are similar to those with a recorded OA diagnosis.
A study of adults aged ≥50 years in eight United Kingdom general practices, with electronic health records linked to survey data. Patients with a recorded regional OA diagnosis were compared to those with a recorded joint pain symptom on socio-demographics, risk factors, body region, pain severity, prescribed analgesia, and potential differential diagnoses. A sub-group was compared on radiographic knee OA.
Thirteen thousand eight hundred and thirty-one survey responders consented to record review. One thousand four hundred and twenty-seven (10%) received an OA (n = 616) or joint pain (n = 811) code with wide practice variation. Receiving an OA diagnosis was associated with age (75+ compared to 50–64 OR 3.25; 95% Credible intervals (CrI) 2.36, 4.53), obesity (1.72; 1.22, 2.33), and pain interference (1.45; 1.09, 1.92). Analgesia management was similar. Radiographic OA was common in both groups. A quarter of those with a joint pain record received an OA diagnosis in the following 6 years.
Recording OA diagnoses are less common than recording a joint pain symptom and associated with risk factors and severity. OA studies in primary care need to consider joint pain symptoms to understand the burden and quality of care across the spectrum of OA. Patients recorded with joint pain may represent early cases of OA with need for early intervention.
PMCID: PMC4850243  PMID: 26746149
Osteoarthritis; Computerized patient medical records; Primary health care
12.  Resistance to HSP90 inhibition involving loss of MCL1 addiction 
Oncogene  2015;35(12):1483-1492.
Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality.
PMCID: PMC4819782  PMID: 26096930
13.  Sugar-sweetened beverage consumption and age at menarche in a prospective study of US girls 
Is sugar-sweetened beverage (SSB) consumption associated with age at menarche?
More frequent SSB consumption was associated with earlier menarche in a population of US girls.
SSB consumption is associated with metabolic changes that could potentially impact menarcheal timing, but direct associations with age at menarche have yet to be investigated.
The Growing up Today Study, a prospective cohort study of 16 875 children of Nurses' Health Study II participants residing in all 50 US states. This analysis followed 5583 girls, aged 9–14 years and premenarcheal at baseline, between 1996 and 2001. During 10 555 person-years of follow-up, 94% (n = 5227) of girls reported their age at menarche, and 3% (n = 159) remained premenarcheal in 2001; 4% (n = 197) of eligible girls were censored, primarily for missing age at menarche.
Cumulative updated SSB consumption (composed of non-carbonated fruit drinks, sugar-sweetened soda and iced tea) was calculated using annual Youth/Adolescent Food Frequency Questionnaires from 1996 to 1998. Age at menarche was self-reported annually. The association between SSB consumption and age at menarche was assessed using Cox proportional hazards regression.
More frequent SSB consumption predicted earlier menarche. At any given age between 9 and 18.5 years, premenarcheal girls who reported consuming >1.5 servings of SSBs per day were, on average, 24% more likely [95% confidence interval (CI): 13, 36%; P-trend: <0.001] to attain menarche in the next month relative to girls consuming ≤2 servings of SSBs weekly, adjusting for potential confounders including height, but not BMI (considered an intermediate). Correspondingly, girls consuming >1.5 SSBs daily had an estimated 2.7-month earlier menarche (95% CI: −4.1, −1.3 months) relative to those consuming ≤2 SSBs weekly. The frequency of non-carbonated fruit drink (P-trend: 0.03) and sugar-sweetened soda (P-trend: 0.001), but not iced tea (P-trend: 0.49), consumption also predicted earlier menarche. The effect of SSB consumption on age at menarche was observed in every tertile of baseline BMI. Diet soda and fruit juice consumption were not associated with age at menarche.
Although we adjusted for a variety of suspected confounders, residual confounding is possible. We did not measure SSB consumption during early childhood, which may be an important window of exposure.
More frequent SSB consumption may predict earlier menarche through mechanisms other than increased BMI. Our findings provide further support for public health efforts to reduce SSB consumption.
The Growing up Today Study is supported by grant R03 CA 106238. J.L.C. was supported by the Breast Cancer Research Foundation; Training Grant T32ES007069 in Environmental Epidemiology from the National Institute of Environmental Health Sciences, National Institutes of Health; and Training Grant T32HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development, National Institutes of Health. A.L.F. is supported by the American Cancer Society, Research Scholar Grant in Cancer Control. K.B.M. was supported in part by the National Cancer Institute at the National Institutes of Health (Public Health Service grants R01CA158313 and R03CA170952). There are no conflicts of interest to declare.
PMCID: PMC4325672  PMID: 25628346
diet; menarche; sugar-sweetened beverage
14.  Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention 
BMJ Open  2016;6(1):e010589.
Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure—a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development.
Methods and analysis
In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year.
Ethics and dissemination
PIT was approved by NRES Committee North West—Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018.
Trial registration number
ISRCTN04240319; NCT01604005; Pre-results.
PMCID: PMC4735163  PMID: 26817643
15.  Fungal Planet description sheets: 371–399 
Novel species of fungi described in the present study include the following from Australia: Neoseptorioides eucalypti gen. & sp. nov. from Eucalyptus radiata leaves, Phytophthora gondwanensis from soil, Diaporthe tulliensis from rotted stem ends of Theobroma cacao fruit, Diaporthe vawdreyi from fruit rot of Psidium guajava, Magnaporthiopsis agrostidis from rotted roots of Agrostis stolonifera and Semifissispora natalis from Eucalyptus leaf litter. Furthermore, Neopestalotiopsis egyptiaca is described from Mangifera indica leaves (Egypt), Roussoella mexicana from Coffea arabica leaves (Mexico), Calonectria monticola from soil (Thailand), Hygrocybe jackmanii from littoral sand dunes (Canada), Lindgomyces madisonensis from submerged decorticated wood (USA), Neofabraea brasiliensis from Malus domestica (Brazil), Geastrum diosiae from litter (Argentina), Ganoderma wiiroense on angiosperms (Ghana), Arthrinium gutiae from the gut of a grasshopper (India), Pyrenochaeta telephoni from the screen of a mobile phone (India) and Xenoleptographium phialoconidium gen. & sp. nov. on exposed xylem tissues of Gmelina arborea (Indonesia). Several novelties are introduced from Spain, namely Psathyrella complutensis on loamy soil, Chlorophyllum lusitanicum on nitrified grasslands (incl. Chlorophyllum arizonicum comb. nov.), Aspergillus citocrescens from cave sediment and Lotinia verna gen. & sp. nov. from muddy soil. Novel foliicolous taxa from South Africa include Phyllosticta carissicola from Carissa macrocarpa, Pseudopyricularia hagahagae from Cyperaceae and Zeloasperisporium searsiae from Searsia chirindensis. Furthermore, Neophaeococcomyces is introduced as a novel genus, with two new combinations, N. aloes and N. catenatus. Several foliicolous novelties are recorded from La Réunion, France, namely Ochroconis pandanicola from Pandanus utilis, Neosulcatispora agaves gen. & sp. nov. from Agave vera-cruz, Pilidium eucalyptorum from Eucalyptus robusta, Strelitziana syzygii from Syzygium jambos (incl. Strelitzianaceae fam. nov.) and Pseudobeltrania ocoteae from Ocotea obtusata (Beltraniaceae emend.). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.
PMCID: PMC4713108  PMID: 26823636
ITS DNA barcodes; LSU; novel fungal species; systematics
16.  MS2 Coliphage as a Surrogate for 2009 Pandemic Influenza A (H1N1) Virus (pH1N1) in Surface Survival Studies on N95 Filtering Facepiece Respirators 
Research on influenza viruses regarding transmission and survival has surged in the recent years due to infectious emerging strains and outbreaks such as the 2009 Influenza A (H1N1) pandemic. MS2 coliphage has been applied as a surrogate for pathogenic respiratory viruses, such as influenza, as it’s safe for personnel to handle and requires less time and labor to measure virus infectivity. However, direct comparisons to determine the effectiveness of coliphage as a surrogate for influenza virus regarding droplet persistence on personal protective equipment such as N95 filtering facepiece respirators (FFRs) are lacking. Persistence of viral droplets deposited on FFRs in healthcare settings is important to discern due to the potential risk of infection via indirect fomite transmission. The objective of this study was to determine if MS2 coliphage could be applied as a surrogate for influenza A viruses for studying persistence when applied to the FFRs as a droplet. The persistence of MS2 coliphage and 2009 Pandemic Influenza A (H1N1) Virus on FFR coupons in different matrices (viral media, 2% fetal bovine serum, and 5 mg ml−1 mucin) were compared over time (4, 12, 24, 48, 72, and 144 hours) in typical absolute humidity conditions (4.1 × 105 mPa [18°C/20% relative humidity (RH)]). Data revealed significant differences in viral infectivity over the 6-day period (H1N1- P <0.0001; MS2 - P <0.005), although a significant correlation of viral log10 reduction in 2% FBS (P <0.01) was illustrated. Overall, MS2 coliphage was not determined to be a sufficient surrogate for influenza A virus with respect to droplet persistence when applied to the N95 FFR as a droplet.
PMCID: PMC4615560  PMID: 26500392
Pandemic influenza A virus; H1N1; MS2 coliphage; infectivity; surrogate; respirator
17.  Self-reported quality care for knee osteoarthritis: comparisons across Denmark, Norway, Portugal and the UK 
RMD Open  2015;1(1):e000136.
To assess and compare patient perceived quality of osteoarthritis (OA) management in primary healthcare in Denmark, Norway, Portugal and the UK.
Participants consulting with clinical signs and symptoms of knee OA were identified in 30 general practices and invited to complete a cross-sectional survey including quality indicators (QI) for OA care. A QI was considered as eligible if the participant had checked ‘Yes’ or ‘No’, and as achieved if the participant had checked ‘Yes’ to the indicator. The median percentage (with IQR and range) of eligible QIs achieved by country was determined and compared in negative binominal regression analysis. Achievement of individual QIs by country was determined and compared using logistic regression analyses.
A total of 354 participants self-reported QI achievement. The median percentage of eligible QIs achieved (checked ‘Yes’) was 48% (IQR 28%, 64%; range 0–100%) for the total sample with relatively similar medians across three of four countries. Achievement rates on individual QIs showed a large variation ranging from 11% (referral to services for losing weight) to 67% (information about the importance of exercise) with significant differences in achievement rates between the countries.
The results indicated a potential for improvement in OA care in all four countries, but for somewhat different aspects of OA care. By exploring these differences and comparing healthcare services, ideas may be generated on how the quality might be improved across nations. Larger studies are needed to confirm and further explore the findings.
PMCID: PMC4623369  PMID: 26535147
Osteoarthritis; Quality Indicators; Health services research; Patient perspective
18.  Impact of heat stress on germinal vesicle breakdown and lipolytic changes during in vitro maturation of bovine oocytes 
Two studies were conducted with the overarching goal of determining the extent to which lipolytic changes relate to germinal vesicle breakdown (GVBD) in bovine oocytes matured under thermoneutral or hyperthermic conditions. To this end, cumulus-oocyte complexes underwent in vitro maturation for 0, 2, 4, 6 or 24 h at 38.5 (first study) or 38.5 and 41.0 C (second study; heat stress applied up through first 12 h only, then shifted to 38.5 C). Independent of maturation temperature, triglyceride and phospholipid content decreased markedly by 2 h of in vitro maturation (hIVM; P < 0.0005). Content was lowest at 24 hIVM with no detectable impact of heat stress when exposure occurred during first 12 hIVM. Germinal vesicle breakdown occurred earlier in oocytes experiencing heat stress with effects observed as soon as 4 hIVM (P < 0.0001). Germinal vesicle breakdown was associated with lipolytic changes (R2 = 0.2123 and P = 0.0030 for triglyceride content; R2 = 0.2243 and P = 0.0026 for phospholipid content). ATP content at 24 hIVM was higher in oocytes experiencing heat stress (P = 0.0082). In summary, GVBD occurs sooner in heat-stressed oocytes. Although marked decreases in triglyceride and phospholipid content were noted as early as 2 hIVM and preceded GVBD, lipolytic changes such as these are not likely serving as an initial driver of GVBD in heat-stressed oocytes because changes occurred similarly in oocytes matured at thermoneutral conditions.
PMCID: PMC4623152  PMID: 26120041
Heat stress; Lipolysis; Oocyte; Oocyte Maturation; Triglyceride-Phospholipid Content
20.  Extreme ultraviolet imaging of three-dimensional magnetic reconnection in a solar eruption 
Nature Communications  2015;6:7598.
Magnetic reconnection, a change of magnetic field connectivity, is a fundamental physical process in which magnetic energy is released explosively, and it is responsible for various eruptive phenomena in the universe. However, this process is difficult to observe directly. Here, the magnetic topology associated with a solar reconnection event is studied in three dimensions using the combined perspectives of two spacecraft. The sequence of extreme ultraviolet images clearly shows that two groups of oppositely directed and non-coplanar magnetic loops gradually approach each other, forming a separator or quasi-separator and then reconnecting. The plasma near the reconnection site is subsequently heated from ∼1 to ≥5 MK. Shortly afterwards, warm flare loops (∼3 MK) appear underneath the hot plasma. Other observational signatures of reconnection, including plasma inflows and downflows, are unambiguously revealed and quantitatively measured. These observations provide direct evidence of magnetic reconnection in a three-dimensional configuration and reveal its origin.
Magnetic reconnection is a fundamental energy release process taking place in various astrophysical environments, but it is difficult to observe it directly. Here, the authors provide evidence of three-dimensional magnetic reconnection in a solar eruption using combined perspectives of two spacecraft.
PMCID: PMC4491808  PMID: 26113464
21.  Chronic Ethanol Consumption Increases Myocardial Mitochondrial DNA Mutations: A Potential Contribution by Mitochondrial Topoisomerases 
Aims: Alcoholic cardiomyopathy (ACM) presents as decreased myocardial contractility, arrhythmias and secondary non-ischemic dilated cardiomyopathy leading to heart failure. Mitochondrial dysfunction is known to have a significant role in the development and complications of ACM. This study investigated if chronic ethanol feeding promoted myocardial mitochondrial topoisomerase dysfunction as one underlying cause of mitochondrial DNA (mtDNA) damage and mitochondrial dysfunction in ACM. Methods: The impact of chronic ethanol exposure on the myocardial mitochondria was examined in both neonatal cardiomyocytes using 50 mM ethanol for 6 days and in rats assigned to control or ethanol feeding groups for 4 months. Results: Chronic ethanol feeding led to significant (P < 0.05) decreases in M-mode Fractional Shortening, ejection fraction, and the cardiac output index as well as increases in Tau. Ethanol feeding promoted mitochondrial dysfunction as evidenced by significantly decreased left ventricle cytochrome oxidase activity and decreases in mitochondrial protein content. Both in rats and in cultured cardiomyocytes, chronic ethanol presentation significantly increased mtDNA damage. Using isolated myocardial mitochondria, both mitochondrial topoisomerase-dependent DNA cleavage and DNA relaxation were significantly altered by ethanol feeding. Conclusion: Chronic ethanol feeding compromised cardiovascular and mitochondrial function as a result of a decline in mtDNA integrity that was in part the consequence of mitochondrial topoisomerase dysfunction. Understanding the regulation of the mitochondrial topoisomerases is critical for protection of mtDNA, not only for the management of alcoholic cardiomyopathy, but also for the many other clinical treatments that targets the topoisomerases in the alcoholic patient.
PMCID: PMC4060737  PMID: 24852753
22.  The relationship between the tumour stroma percentage, clinicopathological characteristics and outcome in patients with operable ductal breast cancer 
British Journal of Cancer  2014;111(1):157-165.
The percentage of tumour stroma (TSP) has recently been reported to be a novel independent predictor of outcome in patients with a variety of common solid organ tumours. The aim of this study was to examine the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease.
A total of 361 patients with primary operable invasive ductal breast cancer were included in this study. The TSP was assessed visually on the haematoxylin and eosin-stained tissue sections. With a cutoff value of 50% TSP, patients with ⩽50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group.
A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had more Her-2-positive tumours (P=0.029), low-grade tumour inflammatory infiltrate (P=0.034), low CD68+macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter cancer-specific survival (P<0.001). In node-negative patients (n=207), high TSP was associated with low CD68+macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter cancer-specific survival (P=0.005). In triple negative patients (n=151), high TSP was associated with high tumour grade (P=<0.001), lymph node positivity (P=0.027), low CD68+macrophage infiltrate (P=0.011) and shorter cancer-specific survival (P=0.035). The 15-year cancer-specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. In multivariate survival analysis, a high TSP was associated with reduced cancer-specific survival in the whole cohort (P=0.001), node-negative patients (P=0.007) and those who received systemic adjuvant therapy (P=0.021), independent of other pathological characteristics including host inflammatory response. However, TSP was not an independent prognostic factor for triple negative patients (P=0.151).
A high TSP in primary operable invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with primary operable ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with invasive ductal breast cancer.
PMCID: PMC4090742  PMID: 24874480
tumour stroma; tumour microenvironment; breast cancer; survival
23.  Quality indicators for the primary care of osteoarthritis: a systematic review 
Annals of the Rheumatic Diseases  2013;74(3):490-498.
To identify valid and feasible quality indicators for the primary care of osteoarthritis (OA).
Systematic review and narrative synthesis.
Data sources
Electronic reference databases (MEDLINE, EMBASE, CINAHL, HMIC, PsychINFO), quality indicator repositories, subject experts.
Eligibility criteria
Eligible articles referred to adults with OA, focused on development or implementation of quality indicators, and relevant to UK primary care. An English language restriction was used. The date range for the search was January 2000 to August 2013. The majority of OA management guidance has been published within this time frame.
Data extraction
Relevant studies were quality assessed using previous quality indicator methodology. Two reviewers independently extracted data. Articles were assessed through the Outcome Measures in Rheumatology filter; indicators were mapped to management guidance for OA in adults. A narrative synthesis was used to combine the indicators within themes.
10 853 articles were identified from the search; 32 were included in the review. Fifteen indicators were considered valid and feasible for implementation in primary care; these related to assessment non-pharmacological and pharmacological management. Another 10 indicators were considered less feasible, in various aspects of assessment and management. A small number of recommendations had no published corresponding quality indicator, such as use of topical non-steroidal anti-inflammatory drugs. No negative (‘do not do’) indicators were identified.
Conclusions and implications of key findings
There are well-developed, feasible indicators of quality of care for OA which could be implemented in primary care. Their use would assist the audit and quality improvement for this common and frequently disabling condition.
PMCID: PMC4345981  PMID: 24288012
Osteoarthritis; Quality Indicators; Analgesics; NSAIDs
24.  Electrokinetic and Hemostatic Profiles of Nonwoven Cellulosic/Synthetic Fiber Blends with Unbleached Cotton 
Greige cotton contains waxes and pectin on the outer surface of the fiber that are removed when bleached, but these components present potential wound dressing functionality. Cotton nonwovens blended with hydrophobic and hydrophilic fibers including viscose, polyester, and polypropylene were assessed for clotting activity with thromboelastography (TEG) and thrombin production. Clotting was evaluated based on TEG measurements: R (time to initiation of clot formation), K (time from end of R to a 20 mm clot), α (rate of clot formation according to the angle tangent to the curve as K is reached), and MA (clot strength). TEG values correlate to material surface polarity as measured with electrokinetic parameters (ζplateau, Δζ and swell ratio). The material surface polarity (ζplateau) varied from −22 to −61 mV. K values and thrombin concentrations were found to be inversely proportional to ζplateau with an increase in material hydrophobicity. An increase in the swell ratios of the materials correlated with decreased K values suggesting that clotting rates following fibrin formation increase with increasing material surface area due to swelling. Clot strength (MA) also increased with material hydrophobicity. Structure/function implications from the observed clotting physiology induced by the materials are discussed.
PMCID: PMC4285407  PMID: 25459983
nonwoven cotton; hemostasis; thromboelastography; electrokinetic properties; accelerated clotting; contact angle
25.  The in situ local immune response, tumour senescence and proliferation in colorectal cancer 
British Journal of Cancer  2013;109(8):2207-2216.
Immune cell infiltrates are important determinants of colorectal cancer (CRC) outcome. Their presence may be driven by tumour or host-specific factors. From previous studies in mice, senescence, a state of cell cycle arrest, may moderate tumour progression through upregulation of antitumour immune responses. The relationships between senescence and immune infiltrates have not previously been studied in humans. We explore whether a marker of senescence (p16ink4a) in combination with low level expression of a proliferation marker (ki-67) relate to T cell infiltrates in CRC, and whether p16ink4a, Ki-67 and immune infiltrates have similar prognostic value.
Immunostaining of p16inka and Ki-67 was performed within a CRC tissue microarray. Nuclear p16inka and Ki-67 were categorised as high/low. T-cell markers, CD3, CD45RO, CD8 and FOXP3 were scored separately as high/low grade in three areas of the tumour: the invasive margin (IM), tumour stroma and cancer cell nests (CCNs).
Two hundred and thirty stage I–III cancers were studied. High nuclear p16ink4a was expressed in 63% and high proliferation (Ki-67 >15%) in 61%. p16ink4a expression was associated with reduced CD45RO+ cells at the IM (P<0.05) and within the stroma (P<0.05) and reduced CD8+ cells at the IM (P<0.01). A low Ki-67 proliferative index was associated with reduced density of CD3+ cells in CCNs (P<0.01), reduced CD45RO+ cells at the IM (P<0.05) and within the CCNs (P<0.001), reduced FOXP3+ cells at the IM (P<0.001), within the stroma (P=0.001) and within CCNs (P<0.001) and reduced CD8+ cells at the IM (P<0.05) and within the CCNs (P<0.05). Tumours with both a low proliferative index and expression of p16ink4a demonstrated similar consistent relationships with reduced densities of T-cell infiltrates. On multivariate analysis, TNM stage (P<0.001), low CD3 cells at the IM (P=0.014), low CD8 cells at the IM (P=0.037), low proliferation (Ki-67; P=0.013) and low senescence (p16ink4a; P=0.002) were independently associated with poorer cancer survival.
Senescence, proliferation and immune cell infiltrates are independent prognostic factors in CRC. Although related to survival, p16ink4a-associated senescence is not associated with an upregulation of antitumour T-cell responses.
PMCID: PMC3798960  PMID: 24022192
immune cells; senescence; proliferation; colorectal cancer; p16ink4a; CDKN2A

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