bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency and characterization of known and novel RHD variant alleles in 37 782 Dutch D‐negative pregnant women
Authors: Stegmann Tamara C. , Veldhuisen Barbera , Bijman Renate , Thurik Florentine F. , Bossers Bernadette , Cheroutre Goedele , Jonkers Remco , Ligthart Peter , de Haas Masja , Haer‐Wigman Lonneke , van der Schoot C. Ellen 
Published: March 2016

SummaryTo guide anti‐D prophylaxis, Dutch D‐ pregnant women are offered a quantitative fetal‐RHD‐genotyping assay to determine the RHD status of their fetus. This allowed us to determine the frequency of different maternal RHD variants in 37 782 serologically D‐ pregnant women. A variant allele is present in at least 0·96% of Dutch D‐ pregnant women The D‐ serology could be confirmed after further serological testing in only 54% of these women, which emphasizes the potential relevance of genotyping of blood donors. 43 different RHD variant alleles were detected, including 15 novel alleles (11 null‐, 2 partial D‐ and 2 DEL‐alleles). Of those novel null alleles, one allele contained a single missense mutation (RHD*443C>G) and one allele had a single amino acid deletion (RHD*424_426del). The D‐ phenotype was confirmed by transduction of human D‐ erythroblasts, consolidating that, for the first time, a single amino acid change or deletion causes the D‐ phenotype. Transduction also confirmed the phenotypes for the two new variant DEL‐alleles (RHD*721A>C and RHD*884T>C) and the novel partial RHD*492C>A allele. Notably, in three additional cases the DEL phenotype was observed but sequencing of the coding sequence, flanking introns and promoter region revealed an apparently wild‐type RHD allele without mutations.
Levels of uninvolved immunoglobulins predict clinical status and progression‐free survival for multiple myeloma patients
Authors: Harutyunyan Nika M. , Vardanyan Suzie , Ghermezi Michael , Gottlieb Jillian , Berenson Ariana , Andreu‐Vieyra Claudia , Berenson James R. 
Published: March 2016

SummaryMultiple myeloma (MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M‐Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M‐Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite (HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression‐free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma.
Clinical trial designs to obtain marketing authorization of drugs for haematological malignancy in Japan, the EU and the US
Authors: Nagai Sumimasa , Ozawa Keiya 
Published: March 2016

SummaryDifferences in regulatory actions between Japan, the European Union (EU) and the United States (US) regarding the approval date and primary endpoints of pivotal trials have never been analysed comprehensively. This study aimed to examine such differences in haematological malignancy indications not only in applications for new molecular entity agents but also in supplemental applications for additional indications. A total of 101 haematological malignancy indications were examined for 58 drugs. Only 30 indications were approved by the regulatory agencies of all three regions with 25, 9 and 67 indications being first approved in Japan, the EU and the US, respectively. Regarding the 18 indications approved only in the US, 13 were approved based on results of single‐arm trials. The approval of all nine indications approved first in the EU was based on results of comparative trials. The primary endpoints were different between the EU and the US in 4 of 49 indications approved by both regulatory agencies, all of which were approved earlier in the US than in the EU. This analysis shows that the US Food and Drug Administration has taken the most active attitude to acceptance of surrogate endpoints in single‐arm trials. Therefore, not only shorter review time but also this attitude may lead to earlier approval in US.
Efferocytosis of apoptotic human papillomavirus‐positive cervical cancer cells by human primary fibroblasts
Authors: Hermetet François , Jacquin Elise , Launay Sophie , Gaiffe Emilie , Couturier Mélanie , Hirchaud Fabienne , Sandoz Patrick , Prétet Jean‐Luc , Mougin Christiane 
Published: March 2016

Background informationEfficient clearance of apoptotic cells, named efferocytosis, is a fundamental physiological process for tissue development and homeostasis. The contribution of non‐professional phagocytes like fibroblasts to efferocytosis has been established, although the underlying mechanisms are not well understood. We recently demonstrated that horizontal DNA transfer can occur through the uptake of apoptotic human papillomavirus‐positive cancer cells by human primary fibroblasts leading to their transformation. The aim of this present study was to analyse the cellular and molecular mechanisms that drive the phagocytic activity of human primary fibroblasts in the context of apoptotic cervical cancer cell removal.ResultsHere we provide evidence that human primary fibroblasts engulf late more efficiently than early apoptotic cells, but their phagocytic ability remains limited compared to professional phagocytes such as human monocyte‐derived macrophages. The engulfment occurs in a time‐, temperature‐ and calcium‐dependent manner. Remodelling of actin‐fibers contributes to the biogenesis of apoptotic cell containing macroendocytic vacuoles. Both morphological analyses and pharmacological approaches confirmed the involvement of actin‐driven phagocytosis and likely macropinocytotic mechanisms in apoptotic target internalization. The uptake of apoptotic cells requires phosphatidylserine recognition, which is mainly mediated by phosphatidylserine‐receptor brain‐specific angiogenesis inhibitor 1. Confocal microscopy analyses with organelle‐specific markers revealed that internalised apoptotic material traffics into late phagolysosomes and specific features of microtubule‐associated protein 1 light chain 3‐associated phagocytosis were observed.ConclusionsOur in vitro data show that fibroblasts contribute to apoptotic tumour cell removal by phagocytosis and likely macropinocytotic mechanisms. Efferocytosis by fibroblasts involves phosphatidylserine receptor brain‐specific angiogenesis inhibitor 1, which participates in subsequent uptake orchestration via actin cytoskeleton remodelling.SignificanceOur results highlight the cellular and molecular mechanisms of fibroblast‐mediated clearance of apoptotic tumour cells. Consequences regarding alternative mechanism of carcinogenesis or tumour progression should be addressed.
Genesis, distribution and dynamics of lagoon marl extrusions along the Curonian Spit, southeast Baltic Coast
Authors: Sergeev Alexander Y. , Zhamoida Vladimir A. , Ryabchuk Daria V. , Buynevich Ilya V. , Sivkov Vadim V. , Dorokhov Dmitry V. , Bitinas Albertas , Pupienis Donatas 
Published: March 2016

A unique geological process of extrusion of lagoon marl from beneath massive migrating sand dunes is characteristic for large segments of the Curonian Spit – a ~100‐km‐long sandy barrier that separates the Curonian Lagoon from the Baltic Sea. Exposures of a composite set of Holocene organic sediments such as gyttja, clayey gyttja and gyttja clay, collectively referred to as ‘lagoon marl’, are common along the northern half of the lagoon coast of the spit. The marl outcrops rise up to 3–4 m above the lagoon level and owe their origin to extrusion from their 7–8 m in situ depth beneath the present regional water table. New detailed investigations of the Baltic Sea bottom along the southern half of the Curonian Spit using side‐scan sonar, a multibeam echosounder, seismic imaging, sediment sampling and video observations allowed identification and mapping of a unique underwater landscape formed by extensive outcrops of laminated and folded lagoon marl at water depths of 5–15 m. The combined onshore–offshore database indicates that relict lagoon marl was deformed, compacted and dehydrated by a massive dune‐covered coastal barrier migrating landward (retrograding) over these sediments during the Littorina Sea transgression in a processes termed ‘dune tectonics’. Spatial analysis of the relict sediments traced in offshore geophysical data helped to constrain the rates of the southeast migration of the dune massif. A conceptual model is presented to explain the present context of marl exposures above the regional water table, as well as the occurrence of relict lagoon marl extrusions (diapirs) on the underwater marine slope of the Curonian Spit.
Assessment of cortical bone thickness using ultrasound
Authors: Degen Katharina , Habor Daniel , Radermacher Klaus , Heger Stefan , Kern Jaana‐Sophia , Wolfart Stefan , Marotti Juliana 
Published: March 2016

AbstractPurposeThe aim of the study was to analyze the accuracy of measuring the cortical bone thickness using a combination of low‐ and high‐frequency ultrasound (US) compared with cone‐beam computed tomography (CBCT) and using stereomicroscopy as reference method.Material and MethodsTen jawbone models were prepared using bovine ribs and porcine gingiva. A dental implant was placed in each model. All models were investigated by US, CBCT, and stereomicroscopy. The cortical bone thickness was measured directly above and 4 mm beside the implant with each method in different slices.ResultsThe median deviation of US measurements compared to the reference method was 0.23 mm. The CBCT method was slightly more accurate (median percent deviation of 9.2%) than the US method (10.3%). However, US measurements directly above the implant were more accurate than CBCT measurements with a median percent deviation of 10.5% for US vs. 11.8% for CBCT.ConclusionUltrasound showed a high potential to supplement CBCT for measurements of the cortical bone thickness.
Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two‐center experience
Authors: Jackson Whitney E. , Hanouneh Mohamad , Apfel Tehilla , Alkhouri Naim , John Binu V. , Zervos Xaralambos , Zein Nizar N. , Hanouneh Ibrahim A. 
Published: March 2016

AbstractBackgroundThe interferon‐free antiviral regimen, sofosbuvir (SOF) and simeprevir (SIM) without ribavirin has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT).Aim and methodsWe aim to report the safety, tolerability and efficacy of SOF + SIM to treat LT recipients with recurrent HCV GT1 in a multicenter cohort study.ResultsEighty‐one patients with HCV GT1 met criteria to be considered for treatment. Sixty‐seven patients received SOF + SIM following LT to date: 69% male, 39% with HCV RNA >6 000 000 IU/mL, 22% advanced hepatic fibrosis (stage 3–4), 6% cholestatic recurrence. Fifty‐eight percent previously failed or did not tolerate interferon‐based treatments. Mean time from LT to treatment was 6.1 ± 5.2 yr. All patients had estimated GFR >30 mL/min. Tacrolimus was primary immunosuppression in 84% of patients and minimal immunosuppression dose adjustments were required during treatment. In intention‐to‐treat analysis, 90% achieved end‐of‐treatment virologic response and 88% achieved SVR.ConclusionsSofosbuvir + SIM combination therapy without ribavirin is well tolerated and results in high virologic response rates in recurrent HCV GT1 infection after liver transplantation.
Efficacy and safety of combination therapy with vildagliptin and metformin versus metformin uptitration in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy: a randomized, open‐label, prospective study (VISION)
Authors: Ji L.‐N. , Pan C.‐Y. , Lu J.‐M. , Li H. , Zhu D.‐L. , Li Q. , Li Q.‐F. , Peng Y.‐D. , Tian H.‐M. , Yao C. , Zhao Z.‐G. , Wang L. , Wang B.‐H. ,   for the VISION Study Group
Published: March 2016

AimsTo compare the efficacy and safety of combination of vildagliptin and metformin therapy with metformin uptitration in Chinese patients with type 2 diabetes (T2DM) inadequately controlled with low‐dose metformin.MethodsIn this 24‐week prospective, randomized, multicentre, open‐label study, patients with T2DM inadequately controlled with metformin ≤1000 mg daily were divided 1 : 1 : 1 : 1 into four prespecified subgroups based on age and body mass index (BMI). Patients in each subgroup were randomized 5 : 1 to receive either vildagliptin (50 mg twice daily) plus metformin [500 mg twice daily; vildagliptin and low‐dose metformin (VLDM) group] or metformin uptitration [1000 mg twice daily; high‐dose metformin (HDM) group]. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline at week 24. The key secondary endpoints included percentage of patients achieving target HbA1c without adverse gastrointestinal (GI) events and mean change in fasting plasma glucose (FPG) from baseline to week 24.ResultsA total of 3084 patients were randomized. HbA1c reduction of 0.54% at week 24 in the VLDM group was non‐inferior and statistically superior compared with 0.40% in the HDM group (P < 0.0001). VLDM's non‐inferiority to HDM was confirmed in the four subgroups and its superiority was shown for all subgroups (p < 0.05) except for the subgroup of patients aged <60 years with a BMI of ≥24 kg/m2. Compared with HDM, VLDM significantly increased the percentage of patients achieving HbA1c ≤6.5% and HbA1c ≤6.5% without GI events. FPG levels in the VLDM group were lower at week 24 numerically than in the HDM group. The two treatment arms had similar safety profiles.ConclusionsVLDM was non‐inferior and statistically superior to HDM in glycaemic control in Chinese patients with T2DM inadequately controlled with low‐dose metformin.
Effect of Age on Left Ventricular Global Dyssynchrony in Asymptomatic Individuals: A Population Study
Authors: Vancheri Federico , Vancheri Sergio , Henein Michael Y. 
Published: March 2016

Background and AimLeft ventricular (LV) segmental dyssynchrony is common in patients with heart failure or myocardial activation abnormalities and is associated with increased cardiovascular risk. Total isovolumic time (t‐IVT) and Tei index are sensitive indexes of global ventricular dyssynchrony. The aim of this study was to investigate the effect of age on t‐IVT and Tei index.MethodsWe evaluated 410 individuals with no evidence for coronary heart disease or activation abnormalities. T‐IVT was calculated as 60 − (total ejection time + total filling time) and Tei index as t‐IVT/total ejection time. The relationship between age, LV systolic and diastolic function parameters as well as t‐IVT and Tei index was studied.ResultsEjection fraction and stroke volume did not change with age, whereas early diastolic filling velocity fell and atrial systolic velocity increased, reducing the E/A ratio. Isovolumic contraction time (IVCT) and isovolumic relaxation time (IVRT) lengthened. With every 10 years of age, total LV ejection time shortened by 1.5 sec/min and total filling time by 2.1 sec/min. T‐IVT and Tei index increased with age and strongly correlated with IVCT and E/A, but not with ejection fraction or QRS duration.ConclusionNormal aging is associated with worsening of LV global dyssynchrony shown by prolongation of isovolumic times resulting in shortening of filling and ejection times. Age also affects diastolic function as shown by E/A but not systolic function parameters, ejection fraction or stroke volume. Worsening of global dyssynchrony correlates with that of diastolic function but not with QRS duration.
Partial Posteromedial Papillary Muscle Rupture Caused by Myocardial Ischemia Only without Myocardial Infarction
Authors: Tsujimoto Masanaga , Tanaka Hidekazu , Matsumoto Kensuke , Inoue Takeshi , Okita Yutaka , Hirata Ken‐ichi 
Published: March 2016

Mini‐AbstractA 66‐year‐old woman with a history of exertional chest pain was admitted to our hospital. Transthoracic echocardiography displayed an ejection fraction of 71% without regional wall‐motion abnormalities. Transesophageal echocardiography revealed severe mitral regurgitation due to prolapse of P2 scallop with posteromedial papillary muscle (PPM) rupture. Coronary angiography showed 90% stenosis in the left circumflex artery (LCx), and myocardial ischemia without infarction in the lateral wall was observed by means of stress scintigraphy. The surgical inspection and histological finding confirmed diagnosis of P2 scallop prolapse with partial PPM rupture. PPM rupture due to only myocardial ischemia was extremely rare.
First episode psychosis in the over 35 s: is there a role for early intervention?
Authors: Greenfield Philippa , Joshi Snehita , Christian Suneel , Lekkos Petros , Gregorowicz Anna , Fisher Helen L. , Johnson Sonia 
Published: March 2016

AbstractAimThe early intervention (EI) model appears to improve outcomes of psychosis for younger people, and there is now interest in implementing it in older groups. In the UK, the National Institute of Clinical Excellence advised that EI should be accessible to all individuals with first episode psychosis (FEP). We aimed to explore the likely impact on EI workloads and clinical populations of extending age range.MethodsData were collected on all patients aged 36–65 years who were referred to an inner London EI service from 2011–2014 using the MiData 2 tool at entry and at 1‐year follow up.ResultsPeople aged between 36 and 65 represented 30% of all referrals to the service. There were high levels of recorded past trauma in the sample (62.5%), half had dependent children (58.3%) and just under half physical comorbidity (48.6%). Duration of untreated psychosis was less than a year for the majority. At 1‐year follow up, inpatient admission rates were lower than in previously studied younger EI populations, but only 15% experienced a single episode with full remission.ConclusionsThese findings indicate that admitting over 35‐year‐olds to EI results in a substantial increase in workload. A large proportion had become unwell relatively recently, indicating that the concept of EI may not be redundant in this age range. Evidence is needed on EI effectiveness in this group.
Gender differences in pathways to care for early psychosis
Authors: Ferrari Manuela , Flora Nina , Anderson Kelly K. , Haughton Asante , Tuck Andrew , Archie Suzanne , Kidd Sean , McKenzie Kwame ,   on behalf of the ACE Project Team
Published: March 2016

AbstractAimsGender is a critical demographic determinant in first‐episode psychosis research. We used data from the ACE Pathways to Care Project, which examined pathways to care in African‐origin, Caribbean‐origin and European‐origin participants, to investigate the role of gender in pathways to early intervention programmes.MethodA qualitative approach was used to examine gender differences in the routes to care. We conducted four focus groups and four individual in‐depth interviews with 25 service users of early intervention services from African‐origin, Caribbean‐origin and European‐origin populations.ResultsGender stereotypes negatively influence the first service contact for women, and the early phase of the help seeking process for men. Women reported trying to seek care. However, family members and service providers often questioned their calls for help. Men described having difficulties in talking about their symptoms, as the act of seeking help was perceived as a sign of weakness by peers.ConclusionsThe findings of this study suggest that gender stereotypes shape the journey to specialized care in different ways for men and women. Awareness of the impact that gender stereotypes have when a young person is seeking care for psychosis could help to promote a shift in attitudes among health‐care providers and the provision of more compassionate and patient‐centred care during this critical time.
An overview of stress physiology of fish transport: changes in water quality as a function of transport duration
Authors: Sampaio Flávia D F , Freire Carolina A 
Published: March 2016

AbstractThis study brings an integrated analysis about the relationship between water deterioration and its physiological consequences in live fish transport. The analysis was focused on the transport water and its deterioration, and physiological challenges imposed on the fish. Usual commercial handling procedures employed to mitigate fish stress during transport were discussed. Future topics of research for the establishment of safer fish transport protocols were proposed. Transport was classified into short (≤8 h) or long transport (>8 h). The main issue in short transports should be the prevention of water pH reduction, while in long transports it is the increase in ammonia. Plasma cortisol is the most employed marker for stress and is acutely elevated upon short episodes of transport, but remains elevated even in long‐transport events. Plasma glucose is perhaps a better marker for handling stress. Plasma lactate, pH, osmolality CO2 and ions should be more often evaluated. Plasma Na+ and Cl‐ are very useful markers of acidosis, due to their respective exchange for H+ and , for acid–base regulation. The establishment of species‐specific transport protocols should be preceded by such combined analyses of water and physiological parameters.
Effects of sites and years on the coefficients of rising plate meter calibration under varying coefficient models
Authors: Nakagami Koji 
Published: March 2016

AbstractAn existing varying coefficient calibration method for estimating herbage mass from rising plate meter reading was validated using datasets for different years and pastures, and the variation among these in the coefficients of the model was structurally assessed using a linear mixed effects model to develop a versatile calibration equation. The calibration's advantage was confirmed by the lower Akaike's information criterion values in the two current pooled models than those in the model that assumes fixed coefficients throughout the year. While sites affect the degree of gradual change after the reproductive stage in the slope coefficient, years affect the degree of steep change before the reproductive stage in the intercept coefficient. Further, the shift in the levels of both coefficients was detected by site and year.
On the complexity of the {k}‐packing function problem
Authors: Dobson M. Patricia , Hinrichsen Erica , Leoni Valeria 
Published: March 2016

AbstractGiven a positive integer k, the “‐packing function problem” (PF) is to find in a given graph G, a function f that assigns a nonnegative integer to the vertices of G in such a way that the sum of over each closed neighborhood is at most k and over the whole vertex set of G (weight of f) is maximum. It is known that PF is linear time solvable in strongly chordal graphs and in graphs with clique‐width bounded by a constant. In this paper we prove that PF is NP‐complete, even when restricted to chordal graphs that constitute a superclass of strongly chordal graphs. To find other subclasses of chordal graphs where PF is tractable, we prove that it is linear time solvable for doubly chordal graphs, by proving that it is so in the superclass of dually chordal graphs, which are graphs that have a maximum neighborhood ordering.