Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions.
The genes for the alpha and beta chains of a highly reactive anti-MART-1 T-cell receptor were isolated from T-lymphocytes that mediated in vivo regression of tumor in a patient with metastatic melanoma. These genes were cloned and inserted into MSCV-based retroviral vectors. After transduction, greater than 50% gene transfer efficiency was demonstrated in primary T-lymphocytes stimulated by an anti-CD3 antibody. The specificity and biologic activity of TCR gene-transduced T-cells was determined by cytokine production after coculture of T-cells with stimulator cells pulsed with MART-1 peptide. The production of interferon-gamma and granulocyte macrophage-colony stimulating factor (GM-CSF) was comparable to highly active MART-1 specific peripheral blood lymphocytes (PBL) in the amount of cytokine produced and transduced cells recognized peptide pulsed cells at dilutions similar to cytotoxic T lymphocyte (CTL) clones. Human leukocyte antigen (HLA) class I restricted recognition was demonstrated by mobilization of degranulation marker CD107a, by cell lysis, by cytokine production, and by proliferation in the presence of HLA-A2-positive but not HLA-A2-negative melanoma cell lines. Similar data was obtained when tumor-infiltrating lymphocytes (TIL) were transduced with the TCR genes, converting previously nonreactive cells to tumor reactive cells. TCR-transduced T-cells are thus attractive candidates for evaluation in cell transfer therapies of patients with cancer.


Evaluating the health impact of increased linseed consumption in the Danish population.
Consumption of linseeds has been suggested to have beneficial effects on human health. However, toxic constituents of linseed may compromise these benefits. We conducted a quantitative risk-benefit assessment to evaluate the overall health impact of increasing linseed intake up to 45 g/day in the Danish population (15-74 years). We quantified the risks associated with increased cadmium exposure and the benefits associated with increased intake of dietary fibre. Increased intakes of alpha-linoleic acid (ALA) were included in a sensitivity analysis. The overall health impact of different linseed intake scenarios was estimated in terms of Disability-Adjusted Life Years (DALYs). We found that the beneficial effects of linseed due to increased intake of dietary fibre outweighed the adverse health effects due to increased cadmium exposure in all scenarios. Up to 670 DALYs/100,000 individuals could be averted per year by increasing linseed consumption in the Danish population. The estimated beneficial health impact increased further when including ALA in the assessment. Different sources of uncertainty might affect the results, and more research is needed on both the health effects associated with intake of linseed and its constituents, and the bioavailability of ALA and cadmium from linseed to further improve the risk-benefit assessment.


Do not use epinephrine in digital blocks: myth or truth? Part II. A retrospective review of 1111 cases.
Epinephrine in digital blocks has been condemned by traditional medical theory. The authors provide a retrospective review of 1111 cases involving digital block anesthesia with epinephrine in conjunction with an extensive literature review. The authors conducted a retrospective review of 1111 cases involving digital and hand surgery. Observations were made concerning the location of and indication for surgery, age, sex, type of block used, type and dose of anesthetic, use of epinephrine and concentration, use of a tourniquet, follow-up, and complications. Dorsal and transthecal techniques were used exclusively. Patients with vascular compromise did not receive epinephrine and were excluded from the study. One thousand one hundred eleven cases were reviewed, distributed among 692 male patients and 419 female patients. Sites of surgery ranged throughout the hand and all fingers for a variety of indications. Five hundred patients received injections of 1% plain lidocaine with a dosage range of 2 to 10 cc and an average of 5.7 cc. Six hundred eleven patients received injections of 1% lidocaine with epinephrine (1:100,000) in a dose range of 0.5 to 10 cc and an average dose of 4.33 cc. Nine hundred eighty-six patients (88.75 percent) followed up in the clinic. No patients suffered from digital gangrene in the epinephrine group. After reviewing 1111 cases, there were no complications associated with the use of epinephrine in digital blocks. The authors suggest that correct application of epinephrine in digital blocks is appropriate, and defend its use.


[Precursor cells of newly formed connective tissue in inflammatory foci in various organs in mice].
The origin of fibroblast-like cells of the capsule around a foreign body in the spleen, liver, peritoneal cavity, subcutaneous connective tissue of mice, the localization of cells-precursors, their proliferative potencies and the ability to migrate through blood were studied using 3H-thymidine autoradiography. Precursors of the inflammation focus cells (irrespective of localization) reproduce intensively outside the limits of intraorganic connective tissue, supposedly, in hemopoietic organs of the bone marrow type and migrate, through the blood channel, into tissues (inflammation foci), where they terminate their differentiation.


Relationship between altitude and intensity of malaria transmission in the Usambara Mountains, Tanzania.
There is a consensus that malaria is a growing problem in African highlands. This is surprising because many parts of the highlands were considered too cold to support transmission. In this report, we examined how transmission of Plasmodium falciparum in six villages changed along an altitude transect in the Usambara Mountains, Tanzania, from 300 m to 1700 m. Routine entomological collections were made using spray catches and light traps for 15 mo. Direct estimates of entomological inoculation rates and indirect estimates of vectorial capacity suggested a >1000-fold reduction in transmission intensity between the holoendemic lowland and the hypoendemic highland plateau. Lowland transmission was perennial with a significant peak in the cool season after the long rains in May, when vectors densities were high. In the highlands, low temperatures prevented parasite development in mosquitoes during the cool season rains, and highland transmission was therefore limited to the warm dry season when vector densities were low. The primary effect of increasing altitude was a log-linear reduction in vector abundance and, to a lesser extent, a reduction in the proportion of infective mosquitoes. Highland malaria transmission was maintained at extraordinarily low vector densities. We discuss herein the implications of these findings for modeling malaria and suggest that process-based models of malaria transmission risk should be improved by considering the direct effect of temperature on vector densities. Our findings suggest that variation in the short rains in November and changes in agricultural practices are likely to be important generators of epidemics in the Usambaras.


Climate Change and Oncology Nursing: A Call to Action.
Climate change is a public health crisis that amplifies exposure to known carcinogens, leading to increased cases of cancer and other diseases. This clear link is a powerful reason for all oncology nurses concerned with cancer prevention and treatment to be involved in climate change solutions. The purpose of this review is to bring awareness to the consequences climate change has on the incidence and mortality of cancer, how it affects people living with cancer, and how oncology nurses can help mitigate these suboptimal outcomes.&nbsp.


Relationships between DMD mutations and neurodevelopment in dystrophinopathy.
We performed a prospective, cross-sectional analysis of neurodevelopmental concerns and psychosocial adjustment in relation to DMD mutations in young steroid-naive boys with dystrophinopathy. We evaluated 196 steroid-naive boys with dystrophinopathy who were enrolled in the Finding the Optimal Regimen for Duchenne Muscular Dystrophy trial. The neurodevelopmental concerns and psychosocial adjustment challenges were analyzed in relation to DMD mutation. A parent or legal guardian reported neurodevelopmental concerns in 4 domains (speech, learning and attentional difficulties, and autism spectrum disorder [ASD]) and completed the Personal Adjustment and Role Skills Scale to assess psychosocial adjustment. We also assessed whether boys of DMD carrier mothers were more vulnerable to speech delay and learning difficulties. We found that 39% of boys were reported to have speech delay with a mean age of speaking at 28 months (range 7-66 months). Learning difficulties were reported in 28% of participants. Inattentive-overactive and oppositional-defiant behavior was reported in 8% and 5% of participants, respectively. Psychosocial adjustment challenges were reported in 4% of participants. An ASD diagnosis was reported in 3 participants. Speech delay and learning difficulties were more common in boys with mutations downstream of DMD exon 45. Neurodevelopmental concerns were not associated with DMD deletion, duplication, or point mutation subtype. Boys of DMD carrier mothers did not have longer speech delay or more learning difficulties. Our data support evidence for a relationship between neurodevelopmental concerns and DMD mutation. A longitudinal assessment of developmental trajectory is necessary to evaluate how specific DMD mutations affect brain function.


Women veterans' healthcare delivery preferences and use by military service era: findings from the National Survey of Women Veterans.
The number of women Veterans (WVs) utilizing the Veterans Health Administration (VA) has doubled over the past decade, heightening the importance of understanding their healthcare delivery preferences and utilization patterns. Other studies have identified healthcare issues and behaviors of WVs in specific military service eras (e.g., Vietnam), but delivery preferences and utilization have not been examined within and across eras on a population basis. To identify healthcare delivery preferences and healthcare use of WVs by military service era to inform program design and patient-centeredness. Cross-sectional 2008-2009 survey of a nationally representative sample of 3,611 WVs, weighted to the population. Healthcare delivery preferences measured as importance of selected healthcare features; types of healthcare services and number of visits used; use of VA or non-VA; all by military service era. Military service era differences were present in types of healthcare used, with World War II and Korea era WVs using more specialty care, and Vietnam era-to-present WVs using more women's health and mental health care. Operations Enduring Freedom, Iraqi Freedom, New Dawn (OEF/OIF/OND) WVs made more healthcare visits than WVs of earlier military eras. The greatest healthcare delivery concerns were location convenience for Vietnam and earlier WVs, and cost for Gulf War 1 and OEF/OIF/OND WVs. Co-located gynecology with general healthcare was also rated important by a sizable proportion of WVs from all military service eras. Our findings point to the importance of ensuring access to specialty services closer to home for WVs, which may require technology-supported care. Younger WVs' higher mental health care use reinforces the need for integration and coordination of primary care, reproductive health and mental health care.


Effect of tagging marine turtles on nesting behaviour and reproductive success.
We studied green, Chelonia mydas, and loggerhead, Caretta caretta, turtles nesting on the island of Cyprus to determine the effects of flipper tagging on postovipositional behaviour and reproductive success. Tagging was undertaken immediately after oviposition (64 green turtles; 111 loggerheads). On 12 occasions, loggerheads immediately stopped covering the eggs and proceeded directly to the sea. No green turtles abandoned nesting. In all other cases, where sufficient data were collected, the duration of the two postovipositional phases of nesting behaviour (covering and camouflaging) and the speed of descent to the sea did not differ between tagged and untagged turtles. The durations of behaviours also did not differ between females not tagged, tagged once or tagged twice. There was no effect of tagging on the likelihood of hatching or on the hatching success of clutches in either species. Copyright 1999 The Association for the Study of Animal Behaviour.


Potential landscape and flux framework of nonequilibrium networks: robustness, dissipation, and coherence of biochemical oscillations.
We established a theoretical framework for studying nonequilibrium networks with two distinct natures essential for characterizing the global probabilistic dynamics: the underlying potential landscape and the corresponding curl flux. We applied the idea to a biochemical oscillation network and found that the underlying potential landscape for the oscillation limit cycle has a distinct closed ring valley (Mexican hat-like) shape when the fluctuations are small. This global landscape structure leads to attractions of the system to the ring valley. On the ring, we found that the nonequilibrium flux is the driving force for oscillations. Therefore, both structured landscape and flux are needed to guarantee a robust oscillating network. The barrier height separating the oscillation ring and other areas derived from the landscape topography is shown to be correlated with the escaping time from the limit cycle attractor and provides a quantitative measure of the robustness for the network. The landscape becomes shallower and the closed ring valley shape structure becomes weaker (lower barrier height) with larger fluctuations. We observe that the period and the amplitude of the oscillations are more dispersed and oscillations become less coherent when the fluctuations increase. We also found that the entropy production of the whole network, characterizing the dissipation costs from the combined effects of both landscapes and fluxes, decreases when the fluctuations decrease. Therefore, less dissipation leads to more robust networks. Our approach is quite general and applicable to other networks, dynamical systems, and biological evolution. It can help in designing robust networks.


A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker.
The neuron-restrictive silencer factor [NRSF (RE-1 silencing transcription factor/X box repressor)] is a transcriptional silencer, which we have previously implicated in deregulation of the vasopressin promoter in small cell lung cancer (SCLC). Here we describe a novel splice variant of the NRSF transcript, which is highly expressed in SCLCs. The variant was detected in both established cell lines and primary SCLC cultures as well as in some primitive neuroectodermal tumor biopsies. It was present at very low levels in human brain tissue, non-SCLC tumors, and normal bronchial epithelium. This human splice variant, which is massively overexpressed in SCLCs, incorporates a 50-bp insert between exons 5 and 6, introducing a stop codon and predicting translation of a truncated NRSF isoform. We propose that the encoded isoform may antagonize repression of the vasopressin promoter and other "neuronal" genes with neuron-restrictive silencer elements in SCLCs. Thus, up-regulated expression of this NRSF isoform may be a key early factor in defining the neuroendocrine phenotype of these tumors. The NRSF splice variant represents a specific clinical marker that could prove useful in detection of the majority of SCLCs.


PDBStat: a universal restraint converter and restraint analysis software package for protein NMR.
The heterogeneous array of software tools used in the process of protein NMR structure determination presents organizational challenges in the structure determination and validation processes, and creates a learning curve that limits the broader use of protein NMR in biology. These challenges, including accurate use of data in different data formats required by software carrying out similar tasks, continue to confound the efforts of novices and experts alike. These important issues need to be addressed robustly in order to standardize protein NMR structure determination and validation. PDBStat is a C/C++ computer program originally developed as a universal coordinate and protein NMR restraint converter. Its primary function is to provide a user-friendly tool for interconverting between protein coordinate and protein NMR restraint data formats. It also provides an integrated set of computational methods for protein NMR restraint analysis and structure quality assessment, relabeling of prochiral atoms with correct IUPAC names, as well as multiple methods for analysis of the consistency of atomic positions indicated by their convergence across a protein NMR ensemble. In this paper we provide a detailed description of the PDBStat software, and highlight some of its valuable computational capabilities. As an example, we demonstrate the use of the PDBStat restraint converter for restrained CS-Rosetta structure generation calculations, and compare the resulting protein NMR structure models with those generated from the same NMR restraint data using more traditional structure determination methods. These results demonstrate the value of a universal restraint converter in allowing the use of multiple structure generation methods with the same restraint data for consensus analysis of protein NMR structures and the underlying restraint data.


Proprotein convertase subtilisin/kexin type 6 promotes in vitro proliferation, migration and inflammatory cytokine secretion of synovial fibroblast‑like cells from rheumatoid arthritis via nuclear‑κB, signal transducer and activator of transcription 3 and extracellular signal regulated 1/2 pathways.
Our previous studies demonstrated that expression of proprotein convertase subtilisin/kexin type 6 (PCSK6) is greatly enhanced in rheumatoid arthritis fibroblast‑like synoviocytes (RASFs), and that PCSK6 inhibition decreases cell proliferation, migration and invasion. The present study aimed to investigate the functional role of PCSK6 in the hyperplasia of RASFs. Cultured RASFs from RA patients were stimulated with recombinant human (rh)PCSK6. Subsequent changes in proliferation, invasion, migration and the secretion of inflammatory cytokines were measured in vitro using MTT, wound healing and Transwell assays, and ELISA. Cell cycle and apoptosis were analyzed by flow cytometry. Influence on downstream gene expression levels were analyzed using reverse transcription‑quantitative polymerase chain reaction. Specific signaling pathways responsible for these effects were analyzed using western blotting and confirmed with pathway‑specific inhibitors. It was demonstrated that rhPCSK6 significantly increased RASF cell invasion, migration and proliferation, which was influenced through both reduced cell cycle arrest and reduced apoptosis. Furthermore, rhPCSK6 stimulated RASFs to secrete the inflammatory cytokines interleukin (IL)‑1α, IL‑1β and IL‑6, and exhibit altered expression of genes involved in angiogenesis, hypoxia, proliferation and inflammation. These cellular effects were mediated via the nuclear factor (NF)‑κB, signal transducer and activator of transcription 3 (STAT3) and extracellular signal regulated (ERK)1/2 signaling pathways. The results demonstrated that signaling via NF‑κB and STAT3 mediated cell cycle arrest, and signaling through NF‑κB mediated apoptosis in RASF cells stimulated with PCSK6. PCSK6 can activate NF‑κB, STAT3 and ERK1/2 signaling pathways in vitro to enhance cell proliferation, migration, invasion and inflammation in RASF cells. These findings suggest that PCSK6 may be an important therapeutic target in RA.


Dislocation of the triquetrum: case report.
A case of closed anterior dislocation of the triquetrum is reported. Because of delayed diagnosis the patient was not operated until four months after the injury, when the bone was excised. At follow-up 19 months later the power of grip was slightly reduced but the movements were unimpaired and the hand was painfree.


Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets.
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types. LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242). Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618-29. ©2016 AACR.


Immunochemical investigations on lipopolysaccharides and acidic polysaccharides from serum-sensitive and serum-resistant strains of Escherichia coli isolated from urinary-tract infections.
Factors that may determine the variable resistance of urinary strains of Escherichia coli to the bactericidal activity of normal human serum have been analysed. No statistically significant difference was found in the amount of lipopolysaccharide (LPS) that could be extracted from serum-sensitive and serum-resistant strains by either the phenol-water or warm-saline techniques. The ratio of LPS O-side-chain sugars to core sugars was not found to be significantly greater in serum-resistant than in serum-sensitive strains. A sugar resembling D-glycero-D-mannoheptose was found in LPS from some of the strains; in one case the sugar was shown to be associated with the O-side chain moiety. Lipopolysaccharides from all but two of the strains contained the E. coli R1 core structure. No consistent difference was observed between serum-sensitive and serum-resistant strains in either the amount of acidic polysaccharide extracted or its red-cell agglutination-inhibiting activity; nor was a clear relationship found between sensitivity to serum and sensitivity to R-specific bacteriophages. It is concluded that no one mechanism of serum resistance explains the response to serum of the E. coli strains examined in this study.


Diverse mobile genetic elements shaped the evolution of Streptomyces virulence.
Mobile genetic elements can innovate bacteria with new traits. In plant pathogenic Streptomyces, frequent and recent acquisition of integrative and conjugative or mobilizable genetic elements is predicted to lead to the emergence of new lineages that gained the capacity to synthesize Thaxtomin, a phytotoxin neccesary for induction of common scab disease on tuber and root crops. Here, we identified components of the Streptomyces-potato pathosystem implicated in virulence and investigated them as a nested and interacting system to reevaluate evolutionary models. We sequenced and analysed genomes of 166 strains isolated from over six decades of sampling primarily from field-grown potatoes. Virulence genes were associated to multiple subtypes of genetic elements differing in mechanisms of transmission and evolutionary histories. Evidence is consistent with few ancient acquisition events followed by recurrent loss or swaps of elements carrying Thaxtomin A-associated genes. Subtypes of another genetic element implicated in virulence are more distributed across Streptomyces. However, neither the subtype classification of genetic elements containing virulence genes nor taxonomic identity was predictive of pathogenicity on potato. Last, findings suggested that phytopathogenic strains are generally endemic to potato fields and some lineages were established by historical spread and further dispersed by few recent transmission events. Results from a hierarchical and system-wide characterization refine our understanding by revealing multiple mechanisms that gene and bacterial dispersion have had on shaping the evolution of a Gram-positive pathogen in agricultural settings.


Human papillomavirus type 16-specific T cell responses and their association with recurrence of cervical disease following treatment.
Human papillomavirus type 16 (HPV-16) L1- and E7-specific T cell responses were measured in 58 women with abnormal cervical cytology in a prospective study. On recruitment, patients responded most frequently and with the highest numbers of responding cells to the L1 region aa 311-345 and this response was significantly associated with the presence of cervical disease (P=0.041). Responses to the L1 peptide aa 281-295 were significantly higher in patients with CIN III than in those with HPV/CIN I or CIN II lesions (P=0.027). The E7 region aa 70-98 was the most immunogenic in patients with squamous intraepithelial lesions of the cervix (SIL) but the responses detected were not significantly higher than in patients without SIL. Following treatment, the T cell response profiles of patient groups did not change significantly. However, on analysis of the responses of individual patients with and without recurrent disease on follow-up, significant differences were found. Recurrence of disease was associated with T cell responses to the E7 region aa 70-98 at the patient's first clinic visit (P=0.017). Recurrence of disease was also accompanied by an increase in the total number of L1-specific short-term T cell lines (STLs) at follow-up, whereas absence of disease was accompanied by a decrease in L1-specific STLs. The data also suggested a possible link between E7 70-98-specific responses and acquisition of disease by patients who were previously disease-free. Further studies are warranted to determine whether this response could be useful as a marker of recurrent disease in some patients.


[Voltage-activated potassium channels of the inhibitory interneurons of the hippocampus in culture].
Potassium channels make up the largest family of voltage-activated channels and play a key role in maintenance of cell excitability and in transmission of information within the nervous system. The aim of this work was to find out the specific subtypes of voltage-activated potassium channels peculiar to GABAergic interneurons of rat hippocampal culture. It was shown that total depolarization-evoked outward potassium current in any interneuron studied had the activation threshold about -50 mV. The specific Kv1 channels' blocker a-DTX influenced neither amplitude nor kinetics of total current, thus we excluded the participation of these channels in its forming. The transient A-current made up 9.4+/-1.3% of the amplitude of total current and had low sensitivity to 4-AP that was an evidence of the presence of Kv4 channels in hippocampal interneurons. The slow inactivating component of integral potassium current was relatively small and had the time constant of inactivation 3 +/- 0.15 s that is typical for delayed rectifier potassium channels of Kv2 and Kv3 subfamilies. The main contribution (83 +/- 1.7 % of total amplitude) to the integral current belonged to the non-inactivating current. Prolonged depolarization of any interneuron tested to -20 mV evoked a steady non-inactivating outward current with amplitude 100-400 pA and activation threshold about -60 mV. Retigabine shifted its I-V plot to more negative values and increased the amplitude at -20 mV by 66+/-14%. These facts can be evidence of the participation of KCNQ channels subfamily in the forming of non-inactivating current. But selective blockers of KCNQ channels linopirdine and XE991 had very small influence on steady-state outward current that means the current appears owing to activity of linopirdine-insensitive forms of KCNQ channels or channels of a different, unknown family.


Changes in drug prescription utilization for diabetic and hypertensive outpatients after initiation of the National Health Insurance's Global Budget Program in Taiwan.
To examine changes in medicine utilization and prescription trends for diabetic (DM) and hypertensive (HT) patients upon initiation of the National Health Insurance (NHI) global budget (GB) program in Taiwan. Data on hospital-based outpatient prescriptions for DM and HT from the Taipei branch before and after the GB were analyzed from January 2002 to December 2004. A secondary analysis of reimbursed data, with descriptive and trend analyses of the four indicators, daily oral medication cost, daily tablets used, medicine items per prescription, and tablet cost, was conducted. The comparisons of before and after the GB were as follows: Daily oral medication cost increased from US $0.585 to $0.956 (64%) for the DM group and from $1.01 to $1.07 (6.12%) for the HT group. The increments for daily used tablets, medicine items per prescription, and tablet cost were 33.3%, 17.9%, and 26.5% for the DM group and 6.65%, 3.31%, and 0.27% for the HT group. Indicators for the DM group not only increased significantly compared with those of the HT group, but also had higher adjusted beta coefficients. The comparisons of before and after the GB showed that the increments for the DM group decreased slightly, but not those for the HT group. The indicators for DM were significantly higher than those of HT group during the implementation phase of the GB. The GB program implemented by the NHI in Taiwan slightly slowed the trend of hospital-based ambulatory prescription costs of DM, but not HT.


Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains.
Peak bone mineral density (BMD) is a highly heritable trait in humans and is currently the best predictor of skeletal fragility underlying osteoporosis. The SAMP6 mouse strain displays unusually low BMD at maturity, and age-dependent osteopenia associated with defective osteoblastogenesis. To identify quantitative trait loci (QTLs) influencing bone density, we constructed crosses between SAMP6 and either AKR/J or SAMP6, two related mouse strains of higher peak BMD. Due to common ancestry of these strains, intercross parents differed at only 39-40% of 227 highly-polymorphic genotyping markers, thus restricting our search to this informative portion of the genome and reducing the number of mice required for QTL significance. Using dual energy X-ray absorptiometry (DEXA), we measured spinal BMD in F2 cross progeny at 4 months of age, and selectively genotyped those in the highest and lowest quartiles for BMD. Based on linear regression of bone density on genotype, including Composite Interval Mapping to enhance mapping precision while adjusting for effects of distal markers, we identified multiple QTLs significantly affecting spinal BMD; these were mapped to regions of chromosomes 2 (two sites, one confirmed in both crosses), 7, 11, 13 and 16. One of these loci had been previously identified as a significant bone-density QTL, while 3 substantiate QTLs suggested by a low-power study of 24 recombinant-inbred mouse lines. Such recurrent appearance of QTLs, especially in crosses involving distantly-related strains, implies that polymorphism at these loci may be favored by evolution and might underlie variation in peak bone density among humans.


Multiple basal cell carcinomas in a young adult treated with imiquimod 5%: a case report and literature review.
We present a case of basal cell carcinoma that is unique in the literature with regard to the rare combination of age of onset and number of BCCs at initial presentation that was successfully treated with imiquimod 5%. The patient is a 28-year-old Caucasian man with no past medical or dermatological history. Physical exam was remarkable for seven pink translucent skin lesions on the forehead, alar ridge, zygoma, and upper back. There were no signs or symptoms of a syndrome or disease entity known to cause BCC. Shave biopsies revealed basal cell carcinoma in all 7 lesions. The patient was successfully treated with topical imiquimod 5% 6 days per week for 6 weeks. The presentation of this number of de novo BCCs in a patient this young in absence of a known BCC syndrome has, to the best of our knowledge, not previously been reported in the literature and was successfully treated with imiquimod 5%.


Marine copepod assemblages in the Arctic: The effect of frontal zones on biomass and productivity.
The Barents Sea, as the largest Arctic shelf region with high productivity, supports vital commercial fisheries. The region's ecosystem is significantly impacted by both warm Atlantic Water (AW) and cold Arctic Water (ARW), resulting in frontal zones that delineate differing water masses. Zooplankton populations serve as the primary link between primary producers and higher trophic levels. To evaluate the potential influence of frontal zones on copepods, we conducted a summer survey focusing on sites where diverse water masses interacted. Our findings revealed that species richness, diversity, biomass, and daily production of common copepods were highest in the Polar Front, separating AW and ARW, as well as in the eastern frontal zones (Barents Sea Water and Novaya Zemlya Coastal Water). Herbivorous copepods, such as Calanus spp. and Pseudocalanus spp., dominated in terms of total copepod biomass and production, whereas the small omnivore Oithona similis prevailed by abundance. Multivariate analysis demonstrated a strong correspondence between frontal zones and copepod assemblages. The primary factors explaining spatial variations in copepod biomass and production included the geographic positions of sampling stations, depth, and chlorophyll a concentration. Our research underscores the significance of oceanographic fronts as zones of critical importance for overall pelagic productivity in Arctic regions.


Efficacy of constant infusion of A-77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, in limiting acute HIV-1 infection in vitro.
A-77003, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is effective for both acute and chronic infection in vitro and was evaluated clinically by continuous intravenous infusion administration. The minimum effective dose (the concentration required to completely inhibit viral replication) was determined in vitro in a population of uninfected (99%) and HIV-infected (1%) cells exposed to A-77003 by continuous infusion in hollow-fiber bioreactors. The production of infectious HIV and release of p24 antigen from infected cells were completely inhibited in cultures exposed to A-77003 at or above a concentration of 0.5 microM. Measurement of unintegrated HIV-1 DNA synthesis and flow cytometric analysis for cells expressing HIV p24 antigen demonstrated that the spread of HIV to uninfected cells was also blocked at 0.5 microM A-77003. Dose deescalation to 0.25 microM or removal of A-77003 resulted in the limited spread of the virus throughout the culture, the resumption of viral DNA synthesis, and release of p24. HIV produced after exposure to 0.5 microM A-77003 was noninfectious for a period of 72 h after the removal of the drug. Addition of 1 mg of alpha 1-acid glycoprotein per ml to this in vitro system completely ablated the anti-HIV effect of 0.5 microM A-77003. These data suggest that determination of the minimum effective dose under conditions which simulate human pharmacodynamic patterns may be useful in determining the initial dose and schedule for clinical trials. However, other factors, such as serum protein binding, may influence the selection of a therapeutic regimen.


Precision isosurface rendering of 3D image data.
We address the task of rendering by ray tracing the isosurface of a high-quality continuous model of volumetric discrete and regular data. Based on first principles, we identify the quadratic B-spline as the best model for our purpose. The nonnegativity of this basis function allows us to confine the potential location of the isosurface within a binary shell. We then show how to use the space-embedding property of splines to further shrink this shell to essentially a single voxel width. Not all rays traced through a given shell voxel intersect the isosurface; many may only graze it, especially when the ray-tracing vantage point is close to or within the volume to be rendered. We propose an efficient heuristic to detect those cases. We present experiments to support our claims.


Characteristics of piRNAs and their comparative profiling in testes of sheep with different fertility.
As a novel class of small RNAs, piRNAs are highly expressed in the animal gonads and their main known role is to inhibit transposon activity for ensuring the correctness and integrity of genome. In order to explore the characteristics of piRNAs in sheep testis and their possible regulatory roles on male reproduction, deep sequencing technology was used to sequence small RNAs and identify piRNAs in testes of sheep. The length of piRNAs in sheep testes showed a unimodal distribution between 26 and 31 nt, with a peak at 29 nt. These piRNAs exhibited obvious ping-pong signature and strand specificity. In the genome, they were mainly aligned to CDS, intron, repetitive sequence regions and unannotated regions. Furthermore, in transposon analysis, piRNAs were aligned predominantly to LINE, SINE, and LTR types of retrotransposon in sheep testes, and the piRNAs derived from each type showed obvious ping-pong signature. The piRNA clusters identified in sheep testes were mainly distributed on chromosomes 3, 7, 15, 17, 18 and 20. The results combining semen determination with pathway enrichment analysis implied that differentially expressed piRNAs between the testes of rams with different fertility might participate in spermatogenesis by regulating multiple pathways closely related to stabilization of blood-testis barrier and renewal and differentiation of spermatogonial stem cell. Taken together, the study provided new insights into the characteristics, origin and expression patterns of piRNAs in sheep testes tissue, which would help us better understand the role of piRNAs in sheep reproduction.


Reciprocal stabilization of coagulation factor XIII-A and -B subunits determines plasma FXIII concentration.
Transglutaminase factor (F)XIII is essential for hemostasis, wound healing, and pregnancy maintenance. Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively. The subunits associate tightly in circulation as FXIII-A2B2. FXIII-B2 stabilizes the (pro)active site-containing FXIII-A subunits. Interestingly, people with genetic FXIII-A deficiency have decreased FXIII-B2, and therapeutic infusion of recombinant FXIII-A2 (rFXIII-A2) increases FXIII-B2, suggesting FXIII-A regulates FXIII-B secretion, production, and/or clearance. We analyzed humans (https://clinicaltrials.gov; NCT00978380) and mice with genetic FXIII-A deficiency and developed a mouse model of rFXIII-A2 infusion to define mechanisms mediating plasma FXIII-B levels. Like FXIII-A-deficient humans, mice with genetic FXIII-A deficiency had reduced circulating FXIII-B2, and infusion of FXIII-A2 increased FXIII-B2. FXIII-A-deficient mice had normal hepatic function and did not store FXIII-B in liver, indicating FXIII-A does not mediate FXIII-B secretion. Transcriptional analysis and polysome profiling indicated similar F13b levels and ribosome occupancy in FXIII-A-sufficient and -deficient mice and in FXIII-A-deficient mice infused with rFXIII-A2, indicating FXIII-A does not induce de novo FXIII-B synthesis. Unexpectedly, pharmacokinetic/pharmacodynamic modeling of FXIII-B antigen following rFXIII-A2 infusion in humans and mice suggested FXIII-A2 slows FXIII-B2 loss from plasma. Accordingly, comparison of free FXIII-B2 versus FXIII-A2-complexed FXIII-B2 (FXIII-A2B2) infused into mice revealed faster clearance of free FXIII-B2. These data show FXIII-A2 prevents FXIII-B2 loss from circulation and establish the mechanism underlying FXIII-B2 behavior in FXIII-A deficiency and during rFXIII-A2 therapy. Our findings reveal a unique, reciprocal relationship between independently synthesized subunits that mediate an essential hemostatic protein in circulation. NCT00978380.


Recurrent and multiple bladder tumors show conserved expression profiles.
Urothelial carcinomas originate from the epithelial cells of the inner lining of the bladder and may appear as single or as multiple synchronous tumors. Patients with urothelial carcinomas frequently show recurrences after treatment making follow-up necessary. The leading hypothesis explaining the origin of meta- and synchronous tumors assumes a monoclonal origin. However, the genetic relationship among consecutive tumors has been shown to be complex in as much as the genetic evolution does not adhere to the chronological appearance of the metachronous tumors. Consequently, genetically less evolved tumors may appear chronologically later than genetically related but more evolved tumors. Forty-nine meta- or synchronous urothelial tumors from 22 patients were analyzed using expression profiling, conventional CGH, LOH, and mutation analyses. We show by CGH that partial chromosomal losses in the initial tumors may not be present in the recurring tumors, by LOH that different haplotypes may be lost and that detected regions of LOH may be smaller in recurring tumors, and that mutations present in the initial tumor may not be present in the recurring ones. In contrast we show that despite apparent genomic differences, the recurrent and multiple bladder tumors from the same patients display remarkably similar expression profiles. Our findings show that even though the vast majority of the analyzed meta- and synchronous tumors from the same patients are not likely to have originated directly from the preceding tumor they still show remarkably similar expressions profiles. The presented data suggests that an expression profile is established early in tumor development and that this profile is stable and maintained in recurring tumors.


Glial cell line-derived neurotrophic factor induces cell migration and matrix metalloproteinase-13 expression in glioma cells.
Malignant gliomas are the most common primary brain tumors in adults and the second most common tumor in children. Gliomas are associated high morbidity and mortality because these tumors are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor in a variety of neuronal cell populations. However, the molecular mechanisms and pathologic roles underlying GDNF-induced glioma migration remain unclear. In this study, we found that application of recombinant human GDNF enhances the migration of U87 and U251 cells but not C6 cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) mRNA, protein and secretion increase in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. We then examined the involvement of mitogen-activated protein kinases (MAPKs) in glioma cell migration induced by GDNF. GDNF-induced MMP-13 expression and glioma migration were attenuated by MEK/extracellular signal-regulating kinase (ERK) and c-Jun N-terminal protein kinase (JNK) inhibitors, as well as ERK and JNK dominant-negative mutants. Treatment with GDNF-induced MEK/ERK and JNK/c-Jun activation and increased AP-1 DNA binding activity in a time-dependent manner. Treatment with AP-1 inhibitors (tanshinone IIA and curcumin) also reduced GDNF-induced glioma cell migration. In migration-prone sublines, cells with greater migration ability had higher GDNF expression. These results indicate that GDNF enhances migration of glioma cells through the increase of MMP-13 production and is mainly regulated by the MEK/ERK and JNK, c-Jun and AP-1 pathways.


Effects of psychiatric history on cognitive performance in old-age depression.
Cognitive deficits in old-age depression vary as a function of multiple factors; one rarely examined factor is long-term psychiatric history. We investigated effects of psychiatric history on cognitive performance in old-age depression and in remitted persons. In the population-based Swedish National Study on Aging and Care in Kungsholmen study, older persons (≥60 years) without dementia were tested with a cognitive battery and matched to the Swedish National Inpatient Register (starting 1969). Participants were grouped according to current depression status and psychiatric history and compared to healthy controls (n = 96). Group differences were observed for processing speed, attention, executive functions, and verbal fluency. Persons with depression and psychiatric inpatient history (n = 20) and late-onset depression (n = 49) performed at the lowest levels, whereas cognitive performance in persons with self-reported recurrent unipolar depression (n = 52) was intermediate. Remitted persons with inpatient history of unipolar depression (n = 38) exhibited no cognitive deficits. Heart disease burden, physical inactivity, and cumulative inpatient days modulated the observed group differences in cognitive performance. Among currently depressed persons, those with inpatient history, and late onset performed at the lowest levels. Importantly, remitted persons showed no cognitive deficits, possibly reflecting the extended time since the last admission (m = 15.6 years). Thus, the present data suggest that cognitive deficits in unipolar depression may be more state- than trait-related. Information on profiles of cognitive performance, psychiatric history, and health behaviors may be useful in tailoring individualized treatment.


Sprawling Quadruped Robot Driven by Decentralized Control With Cross-Coupled Sensory Feedback Between Legs and Trunk.
Quadruped animals achieve agile and highly adaptive locomotion owing to the coordination between their legs and other body parts, such as the trunk, head, and tail, that is, body-limb coordination. This study aims to understand the sensorimotor control underlying body-limb coordination. To this end, we adopted sprawling locomotion in vertebrate animals as a model behavior. This is a quadruped walking gait with lateral body bending used by many amphibians and lizards. Our previous simulation study demonstrated that cross-coupled sensory feedback between the legs and trunk helps to rapidly establish body-limb coordination and improve locomotion performance. This paper presented an experimental validation of the cross-coupled sensory feedback control using a newly developed quadruped robot. The results show similar tendencies to the simulation study. Sensory feedback provides rapid convergence to stable gait, robustness against leg failure, and morphological changes. Our study suggests that sensory feedback potentially plays an essential role in body-limb coordination and provides a robust, sensory-driven control principle for quadruped robots.


Plug size selection protocol for the treatment of intractable patulous Eustachian tube with Kobayashi Plug.
Background: There have been no useful criteria for initial plug size selection protocol for the treatment of intractable patulous Eustachian tube (PET). Aims/objectives: To establish a method for appropriate plug size selection using tubal function test and subjective symptom severity in PET patients who were treated by Kobayashi Plug insertion. Material and methods: A retrospective survey of medical records identified 39 ears of 35 patients with PET who received insertion of the Kobayashi Plug and whose PET symptoms were thereafter controlled for at least 6 months after surgery. Method: The evaluation scale of PET handicap inventory-10 (PHI-10) was used to indicate PET subjective symptom severity. Tubal function tests (sonotubometry and tubo-tympano-aerodynamic-graphy: TTAG) were performed. Results: There was no correlation between the preoperative PHI 10 score and plug size (p = .157). There was a significant correlation between the preoperative sound attenuation from nostril to EAC measured by sonotubometry and plug size (p < .001). There was no correlation between the preoperative pressure transmission ratio estimated by TTAG and plug size (p = .271). Conclusions and Significance: Sonotubometry which evaluates sound attenuation from nostril to EAC can be a useful tool for selecting plug size.


Design and Validation of a Gene-Targeted, Next-Generation Sequencing Panel for Routine Diagnosis in Gliomas.
The updated 2016 World Health Organization (WHO) classification system for gliomas integrates molecular alterations and histology to provide a greater diagnostic and prognostic utility than the previous, histology-based classification. The increasing number of markers that are tested in a correct diagnostic procedure makes gene-targeted, next-generation sequencing (NGS) a powerful tool in routine pathology practice. We designed a 14-gene NGS panel specifically aimed at the diagnosis of glioma, which allows simultaneous detection of mutations and copy number variations, including the 1p/19q-codeletion and Epidermal Growth Factor Receptor (EGFR) amplification. To validate this panel, we used reference mutated DNAs, nontumor and non-glioma samples, and 52 glioma samples that were previously characterized. The panel was then prospectively applied to 91 brain lesions. A specificity of 100% and sensitivity of 99.4% was achieved for mutation detection. Orthogonal methods, such as in situ hybridization and immunohistochemical techniques, were used for validation, which showed high concordance. The molecular alterations that were identified allowed diagnosis according to the updated WHO criteria, and helped in the differential diagnosis of difficult cases. This NGS panel is an accurate and sensitive method, which could replace multiple tests for the same sample. Moreover, it is a rapid and cost-effective approach that can be easily implemented in the routine diagnosis of gliomas.


The Cl- channel in hog gastric vesicles is part of the function of H,K-ATPase.
Hog gastric vesicles showed Cl- conductance when treated with Cu2+-o-phenanthroline, an S-S cross-linking reagent. An IgG monoclonal antibody caused dose-dependent inhibition of Cl- conductance that had been induced by S-S cross-linking. The antibody did not cause intervesicular aggregation, as determined by measurement of vesicle size. These results show that Cl- conductance, the stimulation and inhibition of which are regulated reversibly by S-S----2SH transformation, is due to native, physiological channels. The antibody also dose dependently inhibited the activities of H,K-ATPase and p-nitrophenyl phosphatase in gastric vesicles, but did not inhibit Na,K-ATPase obtained from dog kidney. Immunoblotting with the antibody of vesicle proteins solubilized in sodium dodecyl sulfate-polyacrylamide gel showed that the antibody binds to a 95-kDa subunit of H,K-ATPase and its dimeric 180-kDa polypeptide. The antibody-binding sites of H,K-ATPase activity and the Cl- channel for the inhibition were present on the external (cytosolic) surface of the transmembraneous ATPase. A gastric antisecretory compound, 2-methyl-8-(phenylmethoxy)imidazo[1,2 alpha] pyridine-3-acetonitrile (SCH 28080), competitively bound to the high affinity site of K+ on the internal (luminal) surface of H,K-ATPase, and its half-maximal inhibitory concentration for H,K-ATPase activity in tight vesicles was 0.2 microM in the presence of valinomycin. SCH 28080 also dose dependently inhibited opening of Cl- channels by S-S cross-linking, the regulatory site being present on the cytosolic side and more internally than the antibody binding site. The half-inhibitory concentration of SCH 28080 was 0.3 microM. The present results with the antibody and SCH 28080 indicate that the Cl- channel is part of the function of H,K-ATPase.


Exploring the views of stakeholders about the feasibility of carrying out a randomised controlled trial of Individual Placement and Support for people unemployed with chronic pain based in primary care (the InSTEP study).
Individual Placement and Support (IPS) is a model of vocational rehabilitation originally developed to help people with severe mental illness obtain and maintain employment. Work disability is common amongst people with chronic pain conditions, yet few effective interventions exist. As part of mixed-methods feasibility research and as a forerunner to a pilot trial (In STEP), we investigated the barriers and facilitators to carrying out a future randomised controlled trial of IPS set in primary care amongst people unemployed with chronic pain. Semi-structured interviews and focus groups were conducted with: unemployed people with health conditions receiving IPS (clients), Employment Support Workers (ESWs) delivering IPS for people with chronic health conditions and primary healthcare professionals. Interviews and focus groups were transcribed verbatim and analysed with field notes using thematic analysis. All stakeholders generally viewed a future trial of IPS positively and deemed both the intervention and treatment as usual acceptable. Themes that emerged regarding potential barriers were recruitment, the importance of recruiting people voluntarily who wanted to return to work and were motivated to do so and giving them agency in the process; a need for additional training and support of the ESWs; and a risk of over-burdening participants with paperwork. Regarding facilitators however, the themes were offering the intervention early after unemployment, the importance of relationship and continuity with the ESWs and that an employment intervention could bring a range of health benefits. All stakeholders thought that a randomised trial was potentially feasible and highlighted some potential advantages of participation. Study no ISRCTN30094062.


Revision strategies in lumbar total disc arthroplasty.
Review of Literature. To review the published literature regarding revision lumbar total disc arthroplasty as well as potential options to avoid complications associated with the revision surgical approach. The use of lumbar total disc arthroplasty in the United States has not achieved the same popularity as seen in Europe, where studies have reported favorable short- and intermediate-term results. In the United States, despite recognition that disc replacement may reduce the incidence of adjacent segment disease, the risk of potential complications associated with primary and revision total disc arthroplasty have diminished surgeon enthusiasm for the procedure. The use of adhesion barriers may address some of these concerns. A series of Ovid Medline and Pubmed-National Library of Medicine/National Institutes of Health (www.ncbi.nlm.nih.gov) searches were performed. Only articles written in English journals or published with English translations were included. Level of evidence of the selected articles was assessed. The need for revision of lumbar total disc arthroplasty has been reported in a number of prospective, randomized trials (level I or II evidence). Suboptimal patient selection and/or surgical technique accounted for the majority of failed disc arthroplasties. Revision procedures have included posterior stabilization or anterior explantation with revision to arthroplasty or conversion to arthrodesis. The risk of injury to the great vessels and retroperitoneal structures is greater during revision than primary procedures. The use of a far lateral, or transpsoas approach to the anterior column may reduce these adverse events. The use of adhesion barriers has been shown to reduce adhesions in abdominal and pelvic surgery and may be of benefit in revision disc arthroplasty. Adherence to stringent indications and meticulous surgical technique may reduce the number ofrevision procedures. Further, the use of barriers to adhesion formation during the primary arthroplasty may also reduce risk to the retroperitoneal structures during revision approaches.


Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias.
Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown. We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution. Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2-8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR. Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.


Millimeter-Scale Single-Crystalline Semiconducting MoTe2 via Solid-to-Solid Phase Transformation.
Among the Mo- and W-based two-dimensional (2D) transition metal dichalcogenides, MoTe2 is particularly interesting for phase-engineering applications, because it has the smallest free energy difference between the semiconducting 2H phase and metallic 1T' phase. In this work, we reveal that, under the proper circumstance, Mo and Te atoms can rearrange themselves to transform from a polycrystalline 1T' phase into a single-crystalline 2H phase in a large scale. We manifest the mechanisms of the solid-to-solid transformation by conducting density functional theory calculations, transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy. The phase transformation is well described by the time-temperature-transformation diagram. By optimizing the kinetic rates of nucleation and crystal growth, we have synthesized a single-crystalline 2H-MoTe2 domain with a diameter of 2.34 mm, a centimeter-scale 2H-MoTe2 thin film with a domain size up to several hundred micrometers, and a seamless 1T'-2H MoTe2 coplanar homojunction. The 1T'-2H MoTe2 homojunction provides an elegant solution for ohmic contact of 2D semiconductors. The controlled solid-to-solid phase transformation in 2D limit provides a new route to realize wafer-scale single-crystalline 2D semiconductor and coplanar heterostructure for 2D circuitry.


The transport of 125I-labeled human high molecular weight urokinase across the intestinal tract in a dog model with stimulation of synthesis and/or release of plasminogen activators.
In an attempt to elucidate the mechanism of fibrinolytic enhancement by orally administered urokinase, studies on the intestinal transport of urokinase were carried out, using 125I-labeled human high mol wt urokinase, administered intraduodenally in the experimental dog model with a saphenous vein thrombus. Using the plasma sample obtained from blood 45 minutes after intraduodenal administration of the urokinase, protein fractions were isolated by a sequential two-step affinity chromatography method, first with [N alpha-(epsilon-aminocaproyl)-DL-homoarginine hexylester]-Sepharose followed by a specific anti-human low mol wt urokinase rabbit IgG-Sepharose (adsorbed-eluted and unadsorbed). Each of the isolated protein fractions was further purified by gel filtration on Sephacryl S-300. The proteins isolated by the two-step affinity chromatography method were transported human urokinase with radioactivity in the adsorbed-eluted fraction, and newly synthesized and/or released dog plasminogen activators, probably urokinase-type and tissue-activator type, without radioactivity. In an antibody quenching assay, dog urokinase and the immuno-affinity unadsorbed fraction were not neutralized, but the immuno-affinity adsorbed-eluted fraction was completely neutralized by the specific anti-urokinase IgG antibody. Proteins isolated from control plasma (after administration of saline) by the two-step affinity chromatography method in the unadsorbed fraction had negligible amounts of activator activity. In these studies, we were able to show that synthesis of plasminogen activators was stimulated, with the activators being released, from either the liver or the vascular endothelium. Also we showed that urokinase is transported across the intestinal tract in the dog model.


Ultrasound-Mediated Co-Delivery of miR-34a and sPD-1 Complexed with Microbubbles for Synergistic Cancer Therapy.
miR-34a was downregulated and PD-L1 was upregulated in cervical cancer; however, the treatment of cervical cancer lacks precision and targeting. This study explored the ultrasound-mediated co-delivery of miR-34a and sPD-1 complexes with microbubbles for synergistic cancer therapy. Cationic lipid microbubbles (CLMBs) were prepared by membrane hydration and mechanical oscillation. U14 subcutaneous xenograft mice were injected with CLMBs-loaded sPD-1 and miR-34a combined with ultrasound targeted destruction, and tumor volume and tumor weight of mice were measured. TUNEL apoptosis test and the mRNA expression of apoptosis-related gene Bcl-2 and Bax were analyzed by qRT-PCR. Antitumor immune-related cytokines IFN-γ were investigated by qRT-PCR, LDH Cytotoxicity Assay Kit were performed to test cytotoxic T lymphocytes (CTL). CLMBs were successfully prepared and the plasmid bound to its surface. The tumor volume and weight were specifically decreased by ultrasound-mediated co-delivery of miR-34a and sPD-1 complexes with microbubbles, apoptosis was induced and the apoptosis suppressor gene Bcl-2 was downregulated and proapoptotic gene Bax were upregulated. qRT-PCR analysis revealed that antitumor immunity-related IFN-γ was strongly upregulated in mice, which were treated with CLMBs-loaded sPD-1 and miR-34a combined with ultrasound targeted destruction, and the percentage of CTL was increased. These findings from the study demonstrated that CLMBs could deliver miR-34a and sPD-1, combined with ultrasound targeted destruction, could suppress the tumor tissue growing, induce apoptosis and enhance antitumor immunity in U14 subcutaneous xenograft mice.


Correction: Whose shoulders is health research standing on? Determining the key actors and contents of the prevailing biomedical research agenda.
[This corrects the article DOI: 10.1371/journal.pone.0249661.].


Generalized green synthesis and formation mechanism of sponge-like ferrite micro-polyhedra with tunable structure and composition.
This paper describes a green versatile glucose-engineered precipitation-sintering process that allows for the selective and mass preparation of spongy porous ferrite (M = Fe, Zn, Co, Ni, Mn, etc.) micro-polyhedra with tunable morphology, texture, and composition. Some kinetic factors, such as the molar ratio of glucose to metal nitrates, reaction temperature, sintering temperature and time, and type of metal nitrates, can be expediently employed to modulate their aspect ratio, shape, size, composition, and textural properties. In this protocol, glucose functions as a reductant, protecting agent, structure-directing agent, and a sacrificial template to guide the assembly of sheet-like nuclei into polyhedral precursors and the formation of spongy porous structures. Owing to larger EM parameters, multiresonant behavior, and dissipative current, spongy porous Fe3O4 polyhedra exhibited enhanced microwave-absorbing properties. This endows them with important potential applications in magnetic devices, catalysis, sorption, photoluminescence, electromagnetic wave absorbing materials, anode materials, and so on. Meanwhile, this general approach can be extended to synthesize other porous sponges with regular geometric configuration because it is simple, inexpensive, environmentally benign, and suitable for extensive production.


Factors linked to transitions in adherence to antiretroviral therapy among HIV-infected illicit drug users in a Canadian setting.
HIV-positive people who use illicit drugs typically achieve lower levels of adherence to antiretroviral therapy and experience higher rates of sub-optimal HIV/AIDS treatment outcomes. Given the dearth of longitudinal research into ART adherence dynamics, we sought to identify factors associated with transitioning into and out of optimal adherence to ART in a longitudinal study of HIV-infected people who use illicit drugs (PWUD) in a setting of universal no-cost HIV/AIDS treatment. Using data from a prospective cohort of community-recruited HIV-positive illicit drug users confidentially linked to comprehensive HIV/AIDS treatment records, we estimated longitudinal factors associated with losing or gaining ≥95% adherence in the previous six months using two generalized linear mixed-effects models. Among 703 HIV-infected ART-exposed PWUD, becoming non-adherent was associated with periods of homelessness (adjusted odds ratio [AOR] = 2.52, 95% confidence interval [95% CI]: 1.56-4.07), active injection drug use (AOR = 1.25, 95% CI: 1.01-1.56) and incarceration (AOR = 1.54, 95% CI: 1.10-2.17). Periods of sex work (AOR = 0.51, 95% CI: 0.34-0.75) and injection drug use (AOR = 0.62, 95% CI: 0.50-0.77) were barriers to becoming optimally adherent. Methadone maintenance therapy was associated with becoming optimally adherent (AOR = 1.87, 95% CI: 1.50-2.33) and was protective against becoming non-adherent (AOR = 0.52, 95% CI: 0.41-0.65). In conclusion, we identified several behavioural, social and structural factors that shape adherence patterns among PWUD. Our findings highlight the need to consider these contextual factors in interventions that support the effective delivery of ART to this population.


Magnetic Resonance Imaging of Myocardial Strain After Acute ST-Segment-Elevation Myocardial Infarction: A Systematic Review.
The purpose of this systematic review is to provide a clinically relevant, disease-based perspective on myocardial strain imaging in patients with acute myocardial infarction or stable ischemic heart disease. Cardiac magnetic resonance imaging uniquely integrates myocardial function with pathology. Therefore, this review focuses on strain imaging with cardiac magnetic resonance. We have specifically considered the relationships between left ventricular (LV) strain, infarct pathologies, and their associations with prognosis. A comprehensive literature review was conducted in accordance with the PRISMA guidelines. Publications were identified that (1) described the relationship between strain and infarct pathologies, (2) assessed the relationship between strain and subsequent LV outcomes, and (3) assessed the relationship between strain and health outcomes. In patients with acute myocardial infarction, circumferential strain predicts the recovery of LV systolic function in the longer term. The prognostic value of longitudinal strain is less certain. Strain differentiates between infarcted versus noninfarcted myocardium, even in patients with stable ischemic heart disease with preserved LV ejection fraction. Strain recovery is impaired in infarcted segments with intramyocardial hemorrhage or microvascular obstruction. There are practical limitations to measuring strain with cardiac magnetic resonance in the acute setting, and knowledge gaps, including the lack of data showing incremental value in clinical practice. Critically, studies of cardiac magnetic resonance strain imaging in patients with ischemic heart disease have been limited by sample size and design. Strain imaging has potential as a tool to assess for early or subclinical changes in LV function, and strain is now being included as a surrogate measure of outcome in therapeutic trials.


Prevalence of renal artery stenosis in patients with peripheral vascular disease and hypertension.
The aim of this study was to evaluate the prevalence of renal artery stenosis in patients with clinical signs of peripheral vascular disease and hypertension. One hundred patients, mean age 69 years (range 45-88) with symptoms and clinical signs of severe peripheral ischemia, underwent aortography to determine the degree of peripheral vascular disease and possible renal artery stenosis. History of claudication, and measurement of systolic distal blood pressure (BP) and calculation of the Ankle Brachial Index was used to define the severity of peripheral vascular disease. A total of 31% had renal artery stenosis (14% greater than 50% reduction in luminal diameter). In a subgroup of patients with hypertension and peripheral vascular disease (n = 74), 34% had renal artery stenosis. In the subgroup of patients with renal artery stenosis, 81% have hypertension. Patients with renal artery stenosis and lumen reduction of more than 50%, 93% have hypertension (P < or = 0.001). In conclusion this study shows that the combination of peripheral vascular disease and hypertension is an important clinical clue for renovascular disease. Examination for reno-vascular disease in this population should be considered, since the prevalence of the condition is high. Furthermore examination for renal vascular disease in this population is mandatory, before treatment with angiotensin converting enzyme (ACE) inhibitors is initiated, since treatment might lead to serious renal function impairment.


Regulating preimplantation genetic diagnosis: a criminal model versus a professional model.
This article examines a criminal and professional approach to the regulation of preimplantation diagnosis (PGD) in the two Australian States of Victoria and New South Wales. Under the Assisted Reproductive Treatment Act 2008 (Vic), Victorian medical practitioners face criminal sanctions if they ignore legal requirements. The criminal sanctions do not apply directly to patients, but those seeking PGD treatment have to satisfy guiding legislative principles, statutory rules and the controversial new "presumption against treatment" hurdle. On the other hand, the Assisted Reproductive Technology Act 2008 (NSW) does not specifically address PGD and medical practitioners in New South Wales are not subject to criminal sanctions but must follow the National Health and Medical Research Council Guidelines. As far as patients in New South Wales are concerned, PGD is essentially a medical procedure. In both Victoria and New South Wales, PGD practice is relatively liberal compared to that in many other countries, although the Victorian approach is clearly the more restrictive model of regulation with the threat of criminal sanctions overriding the medical practitioner's ethical duty to act in the best interests of a patient.


Intention to comply with mandatory hurricane evacuation orders among persons living along a coastal area.
We examined the intention to comply with mandatory hurricane evacuation orders among respondents living in coastal areas with pronounced poverty by demographic and location characteristics. A 3-county door-to-door survey was conducted with 1 randomly selected resident per household. Households were selected using a 2-stage cluster sampling strategy and stratified by county. The final sample included 3088 households in 100 census tracts across 3 counties. Findings suggest that the majority of residents living in areas prone to hurricanes intend to comply with mandatory evacuation orders regardless of income level. Variation in intention to comply with mandatory evacuation orders is shown by age, gender, ethnicity, education, acculturation, county, and distance from shoreline. The demonstrated high intention to comply with evacuation orders in impoverished areas suggests a need for improved planning to evacuate the most vulnerable residents. Demographic and location characteristics associated with decreased intention to comply may be considered for targeting messages and education before disasters to modifying intentions and plans to evacuate.


Effect of ether, ethanol and aqueous extracts of ginseng on cardiovascular function in dogs.
Ether, ethanol and aqueous extracts of ginseng were serially prepared from Korean ginseng plants. Each extract in the dose of 40 mg/kg was administered intravenously to ten dogs under light halothane anesthesia while 11 cardiovascular variables were compared during the ensuing two hours. The variable included cardiac output, stroke volume, heart rate, mean arterial pressure, pulse pressure, central venous pressure, total peripheral resistance, pH, PaCO2, PaO2 and base deficit. Following the administration of the ether extract (40 mg/kg) the heart rate and the central venous pressure decreased significantly. The administration of ethanol extract (40 mg/kg) caused a significant decrease in the heart rate and the mean arterial pressure. After the administration of the aqueous extract (40 mg/kg) the cardiac output, stroke volume and central venous pressure were significantly decreased, while the total peripheral resistance was significantly increased.


Parental information needs in chronic renal failure and diabetes mellitus.
The information needs of parents of children with end stage renal failure (ESRF) or with insulin dependent diabetes mellitus (IDDM) were assessed by questionnaires over a 2-year period. Questionnaires were posted on seven occasions at 4-monthly intervals and were sent to both mothers and fathers. Most information needs were reported to be for detailed test results, for new information about the condition and about the child's future social development. Questions responsible for the three highest scores were concerned with the future: the child's fertility; their social, career and marriage prospects; and the hope for a new improved treatment. For the IDDM mothers, scores were significantly different depending on age of the child (P = 0.02). Change in treatment mode had no significant effect on the information needs of parents of children with ESRF (P = 0.81). Occupation was significantly associated with the mean general information needs scores for parents, with occupations of a lower socioeconomic status associated with higher information needs scores. There were no significant differences between the reported mean general information needs scores of parents of children with ESRF and of parents of children with IDDM (P = 0.69) or between mothers and fathers mean general information needs scores (P = 0.58). Multidisciplinary team members need to tailor information to the needs of the individual families and be sensitive to socioeconomic factors and communication issues.


Net effects explains the benefits to children from maternal fish consumption despite methylmercury in fish.
In 2001 the U.S. Food and Drug Administration (FDA) issued precautionary advice to pregnant women to limit fish consumption over concern that the methylmercury content might harm their children's neurodevelopment. This concern was based largely on results from an epidemiological study of mothers primarily exposed to methylmercury from consuming pilot whale. Subsequently, FDA and the World Health Organization/Food and Agriculture Organization (WHO/FAO) undertook independent assessments of fish consumption that considered net effects from both fish nutrients, primarily omega-3 fatty acids, as beneficial and methylmercury as harmful. Both assessments estimated that when mothers regularly consume fish during pregnancy, their children are likely to have improved neurodevelopment compared to children of non-fish eaters despite their exposure to methylmercury. These estimated improvements included gains of two to over five full scale IQ points from levels of maternal consumption that are achievable in most of the world. Consistent with those estimates, human research on fish consumption and child neurodevelopment from more than 200,000 mother-child pairs now collectively reports 51 beneficial associations with neurodevelopmental outcomes and three adverse associations, the latter with no discernable pattern. These associations include full scale IQ gains similar to, or somewhat higher than, those estimated by FDA and FAO/WHO. Also consistent with the FDA and FAO/WHO estimates, research has reported beneficial associations with fish consumption when pregnant women are exposed to methylmercury from fish in excess of the U.S. Environmental Protection Agency's (EPA) Reference Dose (RfD). Our analysis evaluates how the net effects approach as utilized by FDA and FAO/WHO provides a holistic explanation for these results with implications for public health policy. This concordance of net effects modeling and empirical scientific evidence supports a clarification of current public health recommendations to focus on greater fish consumption by pregnant women for their children's neurodevelopment.


Keloids and Hypertrophic Scars.
Keloids and hypertrophic scars are abnormal responses to wound-healing. While hypertrophic scars remain limited to the areas of trauma, keloids most often develop over several years, growing out from the limits of the initial wound area. Both lesions may cause itching, burning, and pain, and they may lead to significant impairment of self-esteem, socialization, and quality of life. Although they might be observed in all races, they are far more common in Africans and African descendants than in Caucasians.We extensively reviewed their treatment, including compression with pressure garments, occlusion with siliconized and non-siliconized gel sheets, gels, corticosteroid and antineoplastic injections, and the use of lasers and intense pulsed light (IPL) therapy. We also reviewed new therapies, including botulinum toxin injection, and addressed outcomes of various studies. (SKINmed. 2022;20:432-443).


Vitamin A in experimental herpetic keratitis.
Systemic vitamin A palmitate at three dosage levels was evaluated for its effect on experimental herpes simplex virus (HSV) keratitis in corticosteroid-treated rabbits. High-dose vitamin A palmitate reduced the severity of herpetic keratitis, but the low or moderate doses did not, and none of the vitamin A treatments affected virus recovery. Vitamin A treatment, however, produced substantial weight loss in uninfected rabbits and in corticosteroid-treated, HSV-infected rabbits. Steroid treatment alone significantly increased the antibody response to HSV, but this effect was not enhanced by vitamin A. The slight beneficial effect on HSV keratitis could be attributed to the known effect of vitamin A on promoting epithelial healing rather than an enhancement of immunity. For this purpose, local application of vitamin A may be just as effective and much less toxic than administration for systemic effect.


Marital satisfaction predicts weight gain in early marriage.
Prior research makes competing predictions regarding whether marital satisfaction is positively or negatively associated with weight gain. The health regulation model suggests that satisfying relationships facilitate the functions of marriage that promote health. Thus, spouses should be most likely to gain weight when either partner is less satisfied because marital strain causes stress that interferes with self-regulatory behaviors. The mating market model, in contrast, suggests that weight maintenance is motivated primarily by the desire to attract a mate. Thus, spouses should be least likely to gain weight when either partner is less satisfied because they should feel an increased need to attract a new mate. This longitudinal study of 169 newlywed couples evaluated each possibility. Spouses completed measures of height, weight, marital satisfaction, stress, steps toward divorce, and several covariates biannually for 4 years. Supporting the mating market model, own and partner satisfaction were positively associated with changes in weight, and this association was mediated by steps toward divorce: Spouses who were less satisfied than usual or had partners who were less satisfied than usual were more likely to consider divorce and thus less likely to gain weight. These findings challenge the idea that quality relationships always benefit health, suggesting instead that spouses in satisfying relationships relax their efforts to maintain their weight because they are no longer motivated to attract a mate. Interventions to prevent weight gain in early marriage may therefore benefit from encouraging spouses to think about their weight in terms of health rather than appearance.


Factors influencing the perceived importance of oral health within a rural Aboriginal and Torres Strait Islander community in Australia.
Indigenous Australians suffer from higher rates of oral disease and have more untreated dental problems and tooth extractions than the general population. Indigenous Australians also have lower rates of accessing oral health services and are more likely to visit for a problem rather than a check-up. Multiple issues effect health service and prevention programs including: characteristics of health services such as distances to health services; existence of social and cultural barriers; available wealth and social support; and, characteristics of the individual and community including the importance given to the disease. This paper seeks to explore the perceived importance of oral health within a rural Indigenous community in Australia and the factors influencing this perception. The study used a phenomenology research design incorporating focus group discussions and in-depth interviews. It was undertaken in partnership with communities' Health Action Group who guided the focus, implementation and reporting of the research. A convenience sample was recruited from established community groups. Thematic analysis on the transcripts was completed. Twenty-seven community members participated in three focus groups and twelve in-depth interviews. The study found that the community gives high priority to oral health. Factors influencing the importance include: the perceived severity of symptoms of oral disease such as pain experienced due to tooth ache; lack of enabling resources such as access to finance and transport; the social impact of oral disease on individuals including impact on their personal appearance and self-esteem; and health beliefs including oral health awareness. Participants also noted that the importance given to oral health within the community competed with the occurrence of multiple health concerns and family responsibilities. This paper highlights the high importance this rural Indigenous community gives to oral health. Its findings suggest that under-utilisation of oral health services is influenced by both major barriers faced in accessing oral health services; and the number and severity of competing health and social concerns within the community. The study results confirm the importance of establishing affordable, culturally appropriate, community-based oral health care services to improve the oral health of rural Indigenous communities.


A Unique Factor XIII Mutation in Southeastern Iran with an Unexpectedly High Prevalence: Khash Factor XIII.
Congenital factor XIII (FXIII) deficiency is an extremely rare hemorrhagic disorder characterized by a deficiency of FXIII and associated with a high rate of morbidity and mortality. The disorder is more frequent in Iran, especially in Khash, a city in the southeast of the country. As identified in the current report, the prevalence of FXIII deficiency in this city is 1 homozygote per approximately 500 population (which is ∼4,000 times higher than the worldwide prevalence) with 3.5% heterozygotes. The disorder is accompanied by a high rate of mortality in rural areas of Khash, given an averaged observed rate of approximately three deaths per each family with FXIII deficiency, mostly due to late-diagnosis and/or misdiagnosis, and fetal consequences of both umbilical cord and central nervous system bleeding. Almost all patients with FXIII deficiency in the southeast Iran have a unique mutation in F13A gene (Trp187Arg), which leads to a severe FXIII deficiency. This mutation is used for pre-marriage and prenatal diagnosis, as well as for carrier detection and diagnostic confirmation. Fibrogammin P has been used worldwide for about one decade, along with different therapeutic regimens for prophylaxis treatment, major and minor surgeries, and successful delivery. Due to the rapid increase in the number of patients identified to have congenital FXIII deficiency, and the high rate of related morbidity and mortality, a comprehensive regional preventive program is necessary to prevent further expansion of this condition and decrease the burden on the health care system. The area of Khash city provides novel insights into severe FXIII deficiency due to its high prevalence in this region. This report also provides a review of FXIII deficiency, its diagnosis, prevalence, molecular basis, clinical manifestations, management, and treatment, with a particular focus on Iran, representing a hotspot for this disorder.


Nucleolar necklaces in chick embryo fibroblast cells. II. Microscope observations of the effect of adenosine analogues on nucleolar necklace formation.
The round nucleoli of chick embryo fibroblast cells, when exposed to adenosine (2 mM)or to a number of adenosine analogues, lose material and unravel over a period of several hours to become beaded strands, 20 mu M in length, termed nucleolar necklaces (NN). Light microscope observations on this process are described. Biochemical experiments have revealed that most of these analogues interfere with both messenger RNA synthesis and ribosome synthesis, causing extensive degradation of the preribosome species containing 32S RNA although most of the preribosomes containing 18S RNA survive. We suggest that it is the depletion from the nucleolus of the adhesive 32S and 28S RNA preribosomes which allows the remaining nucleolar apparatus to spread apart into the NN configuration. Also required for the maintenance of the NN structure is the synthesis of some ribosomal RNA (rRNA) possibly present as rRNA "feathers" on the DNA. The addition of inhibitors of rRNA synthesis such as actinomycin D to the NN-containing cells causes loss of rRNA. Then a contraction and collapse of the NN structure into small dense spheres is observed.


Development of cellular immune responses against PAX5, a novel target for cancer immunotherapy.
PAX5 is a member of the PAX family of developmental transcription factors with an important role in B-cell development. Its expression in normal adult tissue is limited to the hemopoietic system, but it is aberrantly expressed in a number of solid cancers and leukemias where it functions as an oncogene. We therefore hypothesized that anti-PAX5 immune responses could be used to target a number of malignancies without significant toxicity. We screened PAX5 peptides for the ability to bind HLA-A2 and identified a novel sequence, TLPGYPPHV (referred to as TLP). CTL lines against TLP were generated from peripheral blood of five normal HLA-A2-positive blood donors and showed specific HLA-A2-restricted killing against PAX5-expressing target cells. We generated high-avidity CTL clones from these lines capable of killing cells pulsed with <1 nmol/L of TLP and killing a range of PAX5-expressing malignant cell lines. I.v. injection of an anti-PAX5 CTL clone into immunodeficient mice bearing s.c. human tumors resulted in specific growth inhibition of PAX5-expressing tumors. This knowledge can be used for the therapeutic generation of CTL lines or the cloning of high-avidity T-cell receptor genes for use in adoptive immunotherapy.


Physiological correlates of densely calcified coronary lesions on coronary computed tomography angiography among patients with low-to-intermediate coronary artery disease likelihood.
Coronary computed tomography angiography (CCTA) is often used to assess the extent and severity of atherosclerosis. A major limitation of CCTA are densely calcified coronary plaques that obscure the underlying lumen rendering assessment difficult. The purpose of this study was to evaluate the hemodynamic importance of densely calcified coronary lesions on CCTA in patients with low-to-intermediate likelihood of coronary artery disease. We studied 92 patients (64±10 years, 75% men) who underwent CCTA and stress perfusion cardiovascular magnetic resonance (CMR). Coronary stenoses were categorized as none, less than 50%, 50-70%, and greater than 70%, or densely calcified. Coronary arteries were considered densely calcified if the artery had a calcified lesion obscuring the underlying lumen and did not have another stenosis of greater than 50%. CMR was considered abnormal if there was reversible ischemia or myocardial scar determined by the presence of late gadolinium enhancement. Among the 92 patients, 271 vessels were analyzed of which 44 (16%) were considered densely calcified. Among these 44 coronary territories, six (14%) had abnormal CMR findings. On a per-vessel analysis, a proportional increase in the number of myocardial segments with reversible ischemia or the presence of late gadolinium enhancement was associated with an increase of CCTA stenosis ranging from 2% in patients without coronary plaque to 70% in patients with a greater than 70% stenosis (P<0.0001). In conclusion, the vast majority (86%) of densely calcified lesions were not hemodynamically significant in our study. As our study was in patients with relatively low-to-intermediate likelihood of coronary artery disease, a prospective study is warranted to assess if our findings are generalizable to other patient populations.


EM-Driven Unsupervised Learning for Efficient Motion Segmentation.
In this paper, we present a CNN-based fully unsupervised method for motion segmentation from optical flow. We assume that the input optical flow can be represented as a piecewise set of parametric motion models, typically, affine or quadratic motion models. The core idea of our work is to leverage the Expectation-Maximization (EM) framework in order to design in a well-founded manner a loss function and a training procedure of our motion segmentation neural network that does not require either ground-truth or manual annotation. However, in contrast to the classical iterative EM, once the network is trained, we can provide a segmentation for any unseen optical flow field in a single inference step and without estimating any motion models. We investigate different loss functions including robust ones and propose a novel efficient data augmentation technique on the optical flow field, applicable to any network taking optical flow as input. In addition, our method is able by design to segment multiple motions. Our motion segmentation network was tested on four benchmarks, DAVIS2016, SegTrackV2, FBMS59, and MoCA, and performed very well, while being fast at test time.


Analysing interpretation and reinterpreting analysis: exploring the logic of critical reflection.
This paper examines the distinction that is sometimes drawn between analysis and interpretation in the context of qualitative research, and the processes of critical analysis that underpin reflective practice. The authors consider the complementary logical processes involved in analysis and interpretation, and propose a cycle of reductive, inductive and hypothetico-deductive testing that is both rational and creative. The authors argue that the goal of critical reflection and qualitative data analysis is not to produce knowledge that can be justified in terms of 'correspondence' to 'reality'. Instead we propose a pragmatic, coherence view of knowledge that emphasizes the centrality of dialogue with texts, evidence, beliefs and practice. We conclude that evidence and belief are inextricably linked and that combined processes of reductive, inductive and hypothetico-deductive logic need to be used in a transparent manner to establish the credibility of an interpretation. Although there is no clear demarcation between what is found and what is constructed, a commitment to coherence is the basis of a pragmatic theory of knowledge.


A unique alpha-1,3 mannosyltransferase of the pathogenic fungus Cryptococcus neoformans.
The major virulence factor of the pathogenic fungus Cryptococcus neoformans is an extensive polysaccharide capsule which surrounds the cell. Almost 90% of the capsule is composed of a partially acetylated linear alpha-1,3-linked mannan substituted with D-xylose and D-glucuronic acid. A novel mannosyltransferase with specificity appropriate for a role in the synthesis of this glucuronoxylomannan is active in cryptococcal membranes. This membrane-associated activity transfers mannose in vitro from GDP-mannose to an alpha-1, 3-dimannoside acceptor, forming a second alpha-1,3 linkage. Product formation by the transferase is dependent on protein, time, temperature, divalent cations, and each substrate. It is not affected by amphomycin or tunicamycin but is inhibited by GDP and mannose-1-phosphate. The described activity is not detectable in the model yeast Saccharomyces cerevisiae, consistent with the absence of a similar polysaccharide structure in that organism. A second mannosyltransferase from C. neoformans membranes adds mannose in alpha-1,2 linkage to the same dimannoside acceptor. The two activities differ in pH optimum and cation preference. While the alpha-1,2 transferase does not have specificity appropriate for a role in glucuronoxylomannan synthesis, it may participate in production of mannoprotein components of the capsule. This study suggests two new targets for antifungal drug discovery.


Mitochondria and vesicles differ between adult and prepubertal sheep oocytes during IVM.
Oocytes from prepubertal animals have a reduced ability to undergo normal embryo development and produce viable offspring. The correct quantity, activity and cytoplasmic distribution of oocyte organelles are essential for oocyte maturation, fertilisation and subsequent embryo development. The aim of this study was to quantify the ultrastructural differences between oocytes from prepubertal lamb and adult ewes using electron microscopy and stereology. We also determined whether quantitative polymerase chain reaction (qPCR) methods give comparable estimates of mitochondrial number to stereology. Mean storage vesicle volume was greater in adult compared with lamb oocytes before IVM and decreased during maturation in both adult and lamb oocytes. Mitochondrial volume and number increased in adult oocytes during maturation; however, no increase was observed in lamb oocytes. Mitochondrial DNA copy number measured by qPCR showed no differences between adult and lamb oocytes. A different distribution of mitochondria was observed in lamb oocytes before maturation, while the percentage of hooded mitochondria increased during maturation in adult oocytes and decreased in the lamb. In conclusion, the present study has identified differences in the vesicles and mitochondria between adult and lamb oocytes from ewes that may contribute to reduced developmental competence in prepubertal oocytes.