Eighteen-month-old infants show distinct electrophysiological responses to their own faces.
Infants attain the developmental milestone of self-recognition around 18 to 24 months of age. At 18 months of age, half of the infant population typically shows signs of self-recognition in the classic mirror test. The current study examined the functional neural correlates of the perception of self in infancy. Eighteen-month-old infants observed photographs of their own face, the face of an unfamiliar infant, the face of their caregiver, and the face of an unfamiliar caregiver, while their EEG was registered. The results show that infants show an enhanced response to their own face compared to other faces. The N290, an established face-selective ERP component in infants, was larger for observation of their own face compared to others' faces. In addition to the EEG task, the mirror test was administered. Half of the infants in our sample recognized themselves in the mirror. However, there were no differences in the ERP responses between the infants who did and did not recognize themselves in the mirror. This suggests that a distinction between the neural response to self and to others does not necessarily express itself in self-recognition behavior.


[Point mutation of TP53 suppressor gene in pre-neoplastic and neoplastic lesions of the stomach].
In the current model for the development of gastric cancer, regions of multifocal atrophic gastritis give rise to intestinal metaplasia, dysplasia and finally, adenocarcinoma. To study the frequency and characteristics of TP53 gene mutations in preneoplastic and neoplastic lesions of the stomach. DNA sequencing of the TP53 gene was performed in 46 patients with gastric carcinoma. Normal mucosa, intestinal metaplasia and invasive adenocarcinoma tissues were obtained by scraping 6-micron histological sections from formalin-fixed and paraffin-embedded tissue. DNA sequencing of exons 5-9 of the TP53 gene demonstrated a mutation in 31% of patients. These findings were seen both in tumoral tissue (13 cases) and in intestinal metaplasia (2 cases). Most mutations were found in exons 5 and 8, and the majority of them were transitions (10 out of 19 mutations). Patients with gastric cancer showed a frequency of TP53 mutations similar to that previously communicated in populations with low gastric cancer risk. Moreover, there was a predominance of transitions, genetic alterations that are identified with carcinogenesis associated with N-nitrosamine compounds. Finally, mutations of TP53 gene were detected in areas of intestinal metaplasia.


Comparison between ivabradine and low-dose digoxin in the therapy of diastolic heart failure with preserved left ventricular systolic function.
Multicenter trials have demonstrated that in patients with sinus rhythm ivabradine is effective in the therapy of ischemic heart disease and of impaired left ventricular systolic function. Ivabradine is ineffective in atrial fibrillation. Many patients with symptomatic heart failure have diastolic dysfunction with preserved left ventricular systolic function, and many have asymptomatic paroxysmal atrial fibrillation. Ivabradine is not indicated in these conditions, but it happens that it is erroneously used. Digoxin is now considered an outdated and potentially dangerous drug and while effective in the mentioned conditions, is rarely used. The aim of the study was to compare the therapeutic effects of ivabradine in diastolic heart failure with preserved left ventricular systolic function. Patients were assigned to ivabradine or digoxin according to a randomization cross-over design. Data were single-blind analyzed. The analysis was performed using an intention-to-treat method. Forty-two coronary patients were selected. In spite of maximally tolerated therapy with renin-antagonists, diuretics and β-blockers, they had congestive diastolic heart failure with preserved systolic function. Both ivabradine and digoxin had positive effects on dyspnea, Nterminal natriuretic peptide, heart rate, duration of 6-min. walk-test and signs of diastolic dysfunction, but digoxin was high-statistically more effective. Side-effects were irrelevant. Data were obtained in a single-center and from 42 patients with ischemic etiology of heart failure. The number of patients is small and does not allow assessing mortality. In coronary patients with symptomatic diastolic heart failure with preserved systolic function low-dose digoxin was significantly more effective than ivabradine and is much cheaper. One should be more critical about ivabradine and low-dose digoxin in diastolic heart failure. To avoid possible negative effects on the cardiac function and a severe reduction of the cardiac output the resting heart rate should not be decreased to <65 beats/min.


Protein A-bearing Staphylococcus aureus as the solid phase in an enzyme immunoassay and its application to determination of urinary albumin.
Protein A-bearing Staphylococcus aureus was used as a solid-phase matrix in a sandwich-type enzyme immunoassay for urinary albumin. Heat-inactivated, formalin-fixed bacteria were coated with affinity-purified goat anti-human albumin, exposed to solutions containing standard or unknown concentrations of albumin, then challenged with an alkaline phosphatase/anti-human albumin conjugate obtained by periodate oxidation. Alkaline phosphatase activity bound to the bacteria was a function of albumin concentration from 25 to 1000 micrograms/L. This assay was applied to determinations of urinary albumin concentrations between 1.25 and 1000 mg/L. Between-run CV was 2.55 (63.9 mg/L concentration). Within-run CVs for albumin concentrations of 1.9, 38.1, and 638.0 mg/L were 3.7, 3.7, and 2.4%, respectively. Analytical recovery was 95 to 107% across the full working range of the assay. Bence Jones proteins and hemoglobin had no significant effect on the assay. Nonspecific binding of the enzyme-antibody conjugate was 1.3% (SD = 0.7%). Values agreed well with those by radial immunodiffusion.


Development of Beet necrotic yellow vein virus-based vectors for multiple-gene expression and guide RNA delivery in plant genome editing.
Many plant viruses with monopartite or bipartite genomes have been developed as efficient expression vectors of foreign recombinant proteins. Nonetheless, due to lack of multiple insertion sites in these plant viruses, it is still a big challenge to simultaneously express multiple foreign proteins in single cells. The genome of Beet necrotic yellow vein virus (BNYVV) offers an attractive system for expression of multiple foreign proteins owning to a multipartite genome composed of five positive-stranded RNAs. Here, we have established a BNYVV full-length infectious cDNA clone under the control of the Cauliflower mosaic virus 35S promoter. We further developed a set of BNYVV-based vectors that permit efficient expression of four recombinant proteins, including some large proteins with lengths up to 880 amino acids in the model plant Nicotiana benthamiana and native host sugar beet plants. These vectors can be used to investigate the subcellular co-localization of multiple proteins in leaf, root and stem tissues of systemically infected plants. Moreover, the BNYVV-based vectors were used to deliver NbPDS guide RNAs for genome editing in transgenic plants expressing Cas9, which induced a photobleached phenotype in systemically infected leaves. Collectively, the BNYVV-based vectors will facilitate genomic research and expression of multiple proteins, in sugar beet and related crop plants.


Barriers, Facilitators, and Potential Solutions to Advancing Interoperable Clinical Decision Support: Multi-Stakeholder Consensus Recommendations for the Opioid Use Case.
With the advent of interoperability standards such as FHIR, SMART, CDS Hooks, and CQL, interoperable clinical decision support (CDS) holds great promise for improving healthcare. In 2018, the Agency for Healthcare Research and Quality (AHRQ)-sponsored Patient-Centered CDS Learning Network (PCCDS LN) chartered a Technical Framework Working Group (TechFWG) to identify barriers, facilitators, and potential solutions for interoperable CDS, with a specific focus on addressing the opioid epidemic. Through an open, multi-stakeholder process that engaged 54 representatives from healthcare, industry, and academia, the TechFWG identified barriers in 6 categories: regulatory environment, data integration, scalability, business case, effective and useful CDS, and care planning and coordination. Facilitators and key recommendations were also identified for overcoming these barriers. The key insights were also extrapolated to CDS-facilitated care improvement outside of the specific opioid use case. If applied broadly, the recommendations should help advance the availability and impact of interoperable CDS delivered at scale.


Timing-dependent actions of NGF required for cell differentiation.
Continuous NGF stimulation induces PC12 cell differentiation. However, why continuous NGF stimulation is required for differentiation is unclear. In this study, we investigated the underlying mechanisms of the timing-dependent requirement of NGF action for cell differentiation. To address the timing-dependency of the NGF action, we performed a discontinuous stimulation assay consisting of a first transient stimulation followed by an interval and then a second sustained stimulation and quantified the neurite extension level. Consequently, we observed a timing-dependent action of NGF on cell differentiation, and discontinuous NGF stimulation similarly induced differentiation. The first stimulation did not induce neurite extension, whereas the second stimulation induced fast neurite extension; therefore, the first stimulation is likely required as a prerequisite condition. These observations indicate that the action of NGF can be divided into two processes: an initial stimulation-driven latent process and a second stimulation-driven extension process. The latent process appears to require the activities of ERK and transcription, but not PI3K, whereas the extension-process requires the activities of ERK and PI3K, but not transcription. We also found that during the first stimulation, the activity of NGF can be replaced by PACAP, but not by insulin, EGF, bFGF or forskolin; during the second stimulation, however, the activity of NGF cannot be replaced by any of these stimulants. These findings allowed us to identify potential genes specifically involved in the latent process, rather than in other processes, using a microarray. These results demonstrate that NGF induces the differentiation of PC12 cells via mechanically distinct processes: an ERK-driven and transcription-dependent latent process, and an ERK- and PI3K-driven and transcription-independent extension process.


Regulation of the mRNA for monocyte-derived neutrophil-activating peptide in differentiating HL60 promyelocytes.
A cDNA library was constructed from HL60 human promyelocyte poly(A)+ RNA harvested 3 h after induction of macrophage differentiation with 12-O-tetradecanoyl phorbol-13-acetate in the presence of cycloheximide. We isolated from this library a 1.6-kilobase full-length clone designated b4 whose corresponding mRNA was greatly increased in abundance in cytoplasmic RNA under these conditions. Dideoxy sequencing revealed that this mRNA encoded MONAP (monocyte-derived neutrophil-activating peptide), a 10-kilodalton monokine with neutrophil-specific chemotactic and enzyme-releasing activities. The 3' untranslated region of this mRNA was found to be 1.2 kilobases long and possessed nine copies of the AUUUA sequence known to be associated with regulation of mRNA stability. Actinomycin D chase experiments yielded evidence that cytoplasmic stabilization was one of the means of regulation of MONAP expression. Analysis of cytoplasmic poly(A)- RNA revealed the presence of several discrete truncated species that shared a common 5' end and appeared to be intermediates of degradation. S1 mapping showed that the 3' ends of these molecules were distributed throughout the 3' untranslated region, preferentially in A + U-rich regions, broadly correlating with the distribution of AUUUA sites. Nuclear run-on experiments indicated that transcriptional induction accounted for less than 15% of the accumulation of MONAP mRNA. This mRNA was induced in HL60 cells by treatment with several differentiation-inducing agents: 12-O-tetradecanoyl phorbol-13-myristate alone, sodium butyrate, vitamin D3, and dimethyl sulfoxide. It was also induced in quiescent diploid lung fibroblasts stimulated to divide by serum, and it was constitutively overexpressed by some human tumor lines.


[Biochemical markers of strophanthin arrhythmia].
The increase of the concentration of fatty acids, the reduction in the concentration of serotonin, the lowering of the activity of glucose-6-phosphate dehydrogenase and transketolase, and the development of compensated metabolic acidosis were discovered in the stage that preceded strophanthine arrhythmia. These characteristics may be recommended for a wider use on the clinical basis for predicting arrhythmias in the treatment of cardiac glycosides.


Efficacy of artichoke leaf extract in non-alcoholic fatty liver disease: A pilot double-blind randomized controlled trial.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is potentially treatable, though there are few therapeutic agents available. Artichoke leaf extract (ALE) has shown potential as a hepatoprotective agent. This study sought to determine if ALE had therapeutic utility in patients with established NAFLD. In this randomized double-blind placebo-controlled parallel-group trial, 100 subjects with ultrasound-diagnosed NAFLD were randomized to either ALE 600 mg daily or placebo for a 2-month period. NAFLD response was assessed by liver ultrasound and serological markers including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and AST to platelet ratio index (APRI) score. Ninety patients completed the study (49 ALE and 41 placebo) with no side effects reported. ALE treatment compared with placebo: Doppler sonography showed increased hepatic vein flow (p < .001), reduced portal vein diameter (p < .001) and liver size (p < .001), reduction in serum ALT (p < .001) and AST (p < .001) levels, improvement in AST/ALT ratio and APRI scores (p < .01), and reduction in total bilirubin. ALE supplementation reduced total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and triglyceride concentrations (p = .01). This study has shown beneficial effects of ALE supplementation on both ultrasound liver parameters and liver serum parameters (ALT, AST, APRI ratio, and total bilirubin) in patients with NAFLD.


Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation.
Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required. We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(-)] (defined as <10-6) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRDNGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRDNGS(-) (n = 24) showed a significantly better PFS than those that were MRDNGS(+) (n = 15) (P =0.02). Moreover, MRDNGS(-) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRDNGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10-7) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33). Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.


[Research in the 21st century: Euroconference].
The INVESTEN group of the "Instituto de Salud Carlos III", INVESTEN-ISCIII, organized the first Euro-conference related with Nursing Research, "Building a European Nursing Research Strategy", which was held in Salamanca from 13-17 March 1999. The aim of the Euro-conference was to establish the priorities and recommendations for Nursing Research needed to potentiate Nursing Research in Europe at the Beginning of the next millennium. Fourty countries participated in the Euro-conference, which was partially financed by the European Union. Based on the Strasburg Recommendations, the Euro-conference included five main topics in Nursing Research: structure and organization, integrating nursing research into practice, training, financing and priorities. Topics were studied and discussed in working groups of 15-20 participants. Each group was coordinated by different members of the INVESTEN-ISCIII group, with experts on each subject and nurses working in teaching, investigation and clinical practice. The objective was to create a report reflecting the present state of Nursing Research.


Evaluation of BSP expression and apoptosis in the periodontal ligament during orthodontic relapse: a preliminary study.
To examine the expression of bone sialoprotein (BSP) and apoptosis in an in vivo orthodontic relapse model. Male mice (10-12 weeks old), either transgenic [green fluorescent protein (GFP) driven by the BSP promoter] or wild type, were used in this study. To achieve orthodontic tooth movement (OTM), maxillary right first molars were moved mesially using closed-coil springs. Animals were divided into an OTM group (14 days continuous orthodontic force - 11 animals) or Relapse group (10 days of force application followed by 4 days of relapse - 8 animals). The control group was comprised of the contralateral maxillary molars. The periodontal ligament (PDL) was analyzed in areas of compression and tension for transgenic expression, osteoclast localization, and the presence of apoptotic cells. There was a significant decrease in GFP-labeled cells on the compression and tension sides of the PDL in the OTM group compared with control. In the relapse group, GFP-labeled cells were significantly decreased only on the old compression side. Osteoclasts were localized on the compression side of the OTM group, whereas in the Relapse group, they were present on both sides. PDL apoptosis significantly increased on the compression side in OTM and Relapse groups. Both OTM and Relapse groups exhibited a decreased number of GFP-labeled cells in areas of compression and tension. There was significant PDL apoptosis in regions under compressive forces following OTM and to a lesser extent following relapse.


Protein dynamics govern the oxyferrous state lifetime of an artificial oxygen transport protein.
It has long been known that the alteration of protein side chains that occlude or expose the heme cofactor to water can greatly affect the stability of the oxyferrous heme state. Here, we demonstrate that the rate of dynamically driven water penetration into the core of an artificial oxygen transport protein also correlates with oxyferrous state lifetime by reducing global dynamics, without altering the structure of the active site, via the simple linking of the two monomers in a homodimeric artificial oxygen transport protein using a glycine-rich loop. The tethering of these two helices does not significantly affect the active site structure, pentacoordinate heme-binding affinity, reduction potential, or gaseous ligand affinity. It does, however, significantly reduce the hydration of the protein core, as demonstrated by resonance Raman spectroscopy, backbone amide hydrogen exchange, and pKa shifts in buried histidine side chains. This further destabilizes the charge-buried entatic state and nearly triples the oxyferrous state lifetime. These data are the first direct evidence that dynamically driven water penetration is a rate-limiting step in the oxidation of these complexes. It furthermore demonstrates that structural rigidity that limits water penetration is a critical design feature in metalloenzyme construction and provides an explanation for both the failures and successes of earlier attempts to create oxygen-binding proteins.


Measurement of cystatin C functional activity in the cerebrospinal fluid of amyotrophic lateral sclerosis and control subjects.
Cystatin C is a constitutively expressed and abundant cysteine protease inhibitor within the cerebrospinal fluid (CSF). Recent studies have reported a significant reduction in cystatin C concentration in the CSF of patients with amyotrophic lateral sclerosis (ALS) and several other neurodegenerative diseases, relative to healthy controls. Cystatin C can exhibit both neuroprotective and neurotoxic properties, suggesting that altered CSF cystatin C concentrations could potentially impact the pathogenesis or progression of these disorders. However, it is unclear if alterations in cystatin C concentration result in physiologically relevant differences in its functional activity within the CSF. Measurements of the cysteine protease inhibitory activity of cystatin C within the CSF have not been reported, and the relationship between CSF cystatin C concentration and activity levels in different disease contexts has not been investigated. We used a papain inhibition assay to evaluate the total cystatin C activity in CSF samples from 23 ALS patients, 23 healthy controls, and 23 neurological disease controls. Cystatin C concentrations in these samples were previously measured by ELISA. Correlations between cystatin C concentration and activity were assessed with nonparametric statistics. Activity ratios were compared among diagnostic groups using both one-way ANOVA and repeated measures statistics. Total cystatin C activity was found to be directly proportional to its protein concentration in all subjects, and cystatin C activity was not altered in ALS patients. In addition, our data suggest that cystatin C is the predominant cysteine protease inhibitor in human CSF. Our data demonstrate the successful measurement of the functional activity of cystatin C in the CSF, and show that total cystatin C activity can be inferred from its total protein concentration. Our results also suggest that cystatin C is the major cysteine protease inhibitor in human CSF and altered CSF cystatin C concentration may play a role in the pathobiology of ALS and other neurological diseases.


Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism.
The human 'protective protein' (HPP) forms a multi-enzyme complex with beta-galactosidase and neuraminidase in the lysosomes, protecting these two glycosidases from degradation. In humans, deficiency of HPP leads to the lysosomal storage disease galactosialidosis. Proteolytic cleavage of the precursor form of HPP involves removal of a 2 kDa excision peptide and results in a carboxypeptidase activity. The physiological relevance of this activity is, as yet, unknown. The crystal structure of the 108 kDa dimer of the precursor HPP has been elucidated by making extensive use of twofold density averaging. The monomer consists of a 'core' domain and a 'cap' domain. Comparison with the distantly related wheat serine carboxypeptidase dimer shows that the two subunits in the HPP dimer differ by 15 degrees in mutual orientation. Also, the helical subdomain forming part of the cap domains is very different. In addition, the HPP precursor cap domain contains a 'maturation' subdomain of 49 residues which fills the active-site cleft. Merely removing the 'excision' peptide located in the maturation subdomain does not render the catalytic triad solvent accessible. The activation mechanism of HPP is unique among proteases with known structure. It differs from the serine proteases in that the active site is performed in the zymogen, but is blocked by a maturation subdomain. In contrast to the zinc metalloproteases and aspartic proteases, the chain segment physically rendering the catalytic triad solvent inaccessible in HPP is not cleaved off to form the active enzyme. The activation must be a multi-step process involving removal of the excision peptide and major conformational changes of the maturation subdomain, whereas the conformation of the enzymatic machinery is probably almost, or completely, unaffected.


[Resistance, capacitance and exchange functions of the vessels of the small intestine in acute hypothermia].
Shifts of vascular functions occurred in two phases in cats cooled from 37 degrees C to 25 degrees C: first, a considerable increase of the integral vascular pre- and postcapillary resistance as well as of the capillary hydrostatic pressure with obvious reduction of the capillary filtration coefficient (CFC) and stretching ability of the venous bed occurred at 31-29 degrees C in the organ under study; the second phase (25 degrees C) involved a decrease of the integral vascular pre- and postcapillary resistance, a considerable augmentation of venous vessels stretching ability and stabilizing of the CFC at the level reached at 31 degrees C. Experiments with decentralized intestine revealed no virtual differences of the vascular function shifts in hypothermia whereas the values of integral resistance of the intestine's vascular bed, precapillary resistance, capillary pressure and of the venous vessels stretching ability were considerably decreased.


[Ciliated hepatic foregut cyst: report of a case and a summary of the 24 cases reported in Japan].
We report a 52-year-old patient with a small hepatic mass which was ultrasonographically anechoic with scattered high echoic spots, and appearing slightly hyperattenuating relative to the surrounding parenchyma on unenhanced CT scans. Laparotomy revealed that the lesion was a unilocular cyst containing a mucinous fluid. The histologic diagnosis was ciliated hepatic foregut cyst (CHFC). The CHFC is a rare congenital cystic tumor which derives from the embryologic foregut. Up to 2006, only 24 cases, including our case, had been reported in Japan. The patients were 13 men and 11 women, aged between 41 years and 79 years. All of the lesions were solitary and unilocular. In 22 cases, the CHFC was located in the medial segment of the left lobe, mostly just beneath the hepatic surface. In all 24 Japanese cases, the cystic wall was benign histologically. However, reports of 3 malignant cases overseas indicates we should treat this disease cautiously.


Impact of the COVID-19 Pandemic on Child and Adolescent Psychiatric Emergencies.
By forcing closure of schools, curtailing outpatient services, and imposing strict social distancing, the COVID-19 pandemic has abruptly affected the daily life of millions worldwide, with still unclear consequences for mental health. This study aimed to evaluate if and how child and adolescent psychiatric visits to hospital emergency departments (EDs) changed during the pandemic lockdown, which started in Italy on February 24, 2020. We examined all ED visits by patients under 18 years of age in the 7 weeks prior to February 24, 2020, and in the subsequent 8 weeks of COVID-19 lockdown at two urban university hospitals, in Turin and Rome, Italy. ED visits during the corresponding periods of 2019 served as a comparison using Poisson regression modeling. The clinician's decision to hospitalize or discharge home the patient after the ED visit was examined as an index of clinical severity. During the COVID-19 lockdown, there was a 72.0% decrease in the number of all pediatric ED visits (3,395) compared with the corresponding period in 2019 (12,128), with a 46.2% decrease in psychiatric visits (50 vs 93). The mean age of psychiatric patients was higher in the COVID-19 period (15.7 vs 14.1 years). No significant changes were found in hospitalization rate or in the prevalence distribution of the primary reason for the psychiatric ED visit (suicidality, anxiety/mood disorders, agitation). In the first 8 weeks of the COVID-19-induced social lockdown, the number of child and adolescent psychiatric ED visits significantly decreased, with an increase in patient age. This decrease does not appear to be explained by severity-driven self-selection and might be due to a reduction in psychiatric emergencies or to the implementation of alternative ways of managing acute psychopathology.


Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems.
Cluster randomized trials randomly assign groups of individuals to examine research questions or test interventions and measure their effects on individuals. Recent emphasis on quality improvement, comparative effectiveness, and learning health systems has prompted expanded use of pragmatic cluster randomized trials in routine health-care settings, which in turn poses practical and ethical challenges that current oversight frameworks may not adequately address. The 2012 Ottawa Statement provides a basis for considering many issues related to pragmatic cluster randomized trials but challenges remain, including some arising from the current US research and health-care regulations. In order to examine the ethical, regulatory, and practical questions facing pragmatic cluster randomized trials in health-care settings, the National Institutes of Health Health Care Systems Research Collaboratory convened a workshop in Bethesda, Maryland, in July 2013. Attendees included experts in clinical trials, patient advocacy, research ethics, and research regulations from academia, industry, the National Institutes of Health Collaboratory, and other federal agencies. Workshop participants identified substantial barriers to implementing these types of cluster randomized trials, including issues related to research design, gatekeepers and governance in health systems, consent, institutional review boards, data monitoring, privacy, and special populations. We describe these barriers and suggest means for understanding and overcoming them to facilitate pragmatic cluster randomized trials in health-care settings.


Between-country analysis of implementing an obesity prevention intervention using RE-AIM: HENRY in Israel and UK.
Health Exercise Nutrition for the Really Young (HENRY) is a UK community-based early childhood obesity prevention intervention that was adopted and implemented in Israel between 2013 and 2018. The aim of this study was to explore the implementation process in Israel and compare it with that of the 'parent' programme in the UK, in order to throw light on the challenges of introducing complex interventions into different countries and cultures. Published reports from HENRY and Haifa University's evaluation of the Israeli implementation were reviewed and comparisons between the UK and Israel were carried out utilizing the RE-AIM framework. In both countries, the intention was to implement in lower SES communities. When comparing the individual items, Reach and Effectiveness, we found a difference in the Reach although Effectiveness was similar: Reach was proportionally lower in Israel, but parent and professional changes in behaviour were positive in both countries. For the organizational items Adoption, Implementation and Maintenance, we found large differences between the countries. Major challenges identified in Israel included: failing to take adequate account when planning and implementing the intervention of the different ways social and health services are organized and how local authorities are structured and provide services. In addition, differences in culture beyond language and professional variations were challenges, when trying to transfer the intervention with high fidelity from the UK to Israel. Lessons learnt may benefit others in attempting cross-country implementation of complex interventions.


Outcomes of COVID-19 in patients with lymphomas participating in registered clinical trials: A real-world study from China in the Omicron outbreak era.
This real-world study investigated the outcome of COVID-19 in lymphoma patients participating in registered clinical trials and explored potential risk factors with the outcome of COVID-19 during the first wave of the Omicron outbreak in China. One hundred and ten patients participating in registered clinical trials and diagnosed with COVID-19 in our center between December 1, 2022, and January 31, 2023, were included. Four (3.6%) patients were identified as severe COVID-19 and 2 (1.8%) as critical COVID-19, respectively. The mortality rate observed was 2.73% for the entire cohort, 33.3% for the severe/critical COVID-19 group, and 18.8% for the hospitalized group. The 90-day OS was 98.2% for the entire cohort, 66.7% for the severe/critical COVID-19 group, and 87.5% for the hospitalized group. Advanced age (≥70 years), comorbidities, and PI3K inhibitor-containing regimen were significantly associated with the severity of COVID-19. Patients with indolent B-cell non-Hodgkin lymphomas were less likely to be hospitalized for COVID-19. This study reported similar clinical features of COVID-19 in our cohort with that of non-hematological malignancy (HM) patients, while the proportion of severe/critical COVID-19 and the mortality rate were relatively higher than non-HM patients. Our findings provided valuable experience to aid clinical researchers with managing lymphoma patients participating in registered clinical trials during the ongoing pandemic of the Omicron variant.


Structured event complexes in the medial prefrontal cortex support counterfactual representations for future planning.
We propose that counterfactual representations for reasoning about the past or predicting the future depend on structured event complexes (SECs) in the human prefrontal cortex (PFC; 'What would happen if X were performed in the past or enacted in the future?'). We identify three major categories of counterfactual thought (concerning action versus inaction, the self versus other and upward versus downward thinking) and propose that each form of inference recruits SEC representations in distinct regions of the medial PFC. We develop a process model of the regulatory functions these representations serve and draw conclusions about the importance of SECs for explaining the past and predicting the future.


The pharmacological treatment of acquired nystagmus.
We review the latest literature on the neuropharmacological treatments for acquired nystagmus.Nystagmus may have a significant [corrected] impact on health, yet there is little scientific evidence on which to make firm recommendations for treatment. Acquired pendular nystagmus may respond to gabapentin or memantine; downbeat and upbeat nystagmus to aminopyridines; and periodic alternating nystagmus to baclofen. To improve treatment we need multi-centre, randomised controlled trials using standardised techniques in reporting objective outcomes, with good follow-up duration and careful reporting of side effects.


Regional differences in architecture and mineralization of developing mandibular bone.
The goal of this study was to investigate the mutual relationship between architecture and mineralization during early development of the pig mandible. These factors are considered to define the balance between the requirements for bone growth on the one hand and for load bearing on the other. Architecture and mineralization were examined using micro-CT, whereas the mineral composition was assessed spectrophotometrically in groups of fetal and newborn pigs. The development of the condyle coincided with a reorganization of bone elements without an increase in bone volume fraction, but with an increase in mineralization and a change in mineral composition. In the corpus, the bone volume fraction and mineralization increased simultaneously with a restructuring of the bone elements and a change in mineral composition. The growth of the condyle was reflected by regional differences in architecture and mineralization. The anterior and inferior regions were characterized by a more dense bone structure and a higher mineralization as compared to posterior and superior regions, respectively. In the corpus, growth was mainly indicated by differences between buccal and lingual plates as well as between anterior, middle, and posterior regions characterized by a more compact structure and higher mineralization in the lingual and middle regions. In conclusion, the architecture and mineralization in the condyle and corpus started to deviate early during development toward their destiny as trabecular and cortical bone, respectively. These results were compatible with those obtained with mineral composition analysis. Regional differences within condyle and corpus reflected known developmental growth directions.


Chance and risk of controlling rabies in large-scale and long-term immunized fox populations.
The large-scale immunization of European fox populations against rabies is currently under the microscope for reducing the considerable expenditure without putting public health at risk. Empirical knowledge is inadequate to interpret the lasting sporadic incidences and, therefore, to verify the final success of the immunization campaigns. By using a proven simulation model we show that rabies can persist on a very low level in the form of spatio-temporal moving infection clusters within a highly immunized fox population. We found further: (i) the existence of a threshold after which the chance of eradicating the disease by vaccination increases clearly, and (ii) that at least six years of 70% mean immunization rate are required to guarantee a likely success.


Enhancing soluble phosphorus removal within buffer strips using industrial by-products.
Using industrial by-products (IBPs) in conjunction with buffer strips provides a potentially new strategy for enhancing soluble phosphorus (P) removal from agricultural runoff. Here, we investigate the feasibility of this approach by assessing the P sorption properties of IBPs at different solution-IBPs contact time (1-120 min) and solution pH (3, 5.5, 7.5), as well as possible adverse environmental effects including P desorption or heavy metal mobilisation from IBPs. Batch experiments were carried out on two widely available IBPs in the UK that demonstrated high P sorption capacity but different physicochemical characteristics, specifically ochre and Aluminium (Al) based water treatment residuals (Al-WTR). A series of kinetic sorption-desorption experiments alongside kinetic modelling were used to understand the rate and the mechanisms of P removal across a range of reaction times. The results of the kinetic experiments indicated that P was initially sorbed rapidly to both ochre and Al-WTR, followed by a second phase characterised by a slower sorption rate. The excellent fits of kinetic sorption data to a pseudo-second order model for both materials suggested surface chemisorption as the rate-controlling mechanism. Neither ochre nor Al-WTR released substantial quantities of either P or heavy metals into solution, suggesting that they could be applied to buffer strip soils at recommended rates (≤30 g kg(-1) soil) without adverse environmental impact. Although the rate of P sorption by freshly-generated Al-WTR applied to buffer strips reduced following air-drying, this would not limit its practical application to buffer strips in the field if adequate contact time with runoff was provided.


Survival outcomes of very low birth weight infants with trisomy 18.
Trisomy 18 (T18) is one of the most commonly diagnosed aneuploidies leading to poor survival outcome. However, little is known about the dual risk of T18 and very low birth weight (VLBW, weighing <1500 g at birth). We aimed to investigate the survival and clinical features of VLBW infants with T18. In this observational cohort study, infants with T18 admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2019 were eligible. Among 30 infants with T18 who were enrolled as study participants, 11 (37%) were born with VLBW. VLBW infants had lower gestational age (34.4 vs. 39.4 weeks, p < 0.01) and a higher incidence of esophageal atresia (64% vs. 11%, p < 0.01) than non-VLBW infants. The proportions of patients who underwent any surgery (55% vs. 5%, p < 0.01) and positive pressure ventilation (82% vs. 32%, p = 0.02) were higher in VLBW than non-VLBW infants. One-year overall survival rate (45% vs. 26%, p = 0.32 by log-rank test) did not differ between the two groups. In conclusion, being born at VLBW may not be fatal for infants with T18 undergoing active interventions.


Corpus callosal microstructure influences intermanual transfer in chimpanzees.
Learning a new motor skill with one hand typically results in performance improvements in the alternate hand. The neural substrates involved with this skill acquisition are poorly understood. We combined behavioral testing and non-invasive brain imaging to study how the organization of the corpus callosum was related to intermanual transfer performance in chimpanzees. Fifty-three chimpanzees were tested for intermanual transfer of learning using a bent-wire task. Magnetic resonance and diffusion tensor images were collected from 39 of these subjects. The dominant hand showed greater performance benefits than the nondominant hand. Further, performance was associated with structural integrity of the motor and sensory regions of the CC. Subjects with better intermanual transfer of learning had lower fractional anisotropy values. The results are consistent with the callosal access model of motor programming.


Key Factors Influencing Rates of Heterotrophic Sulfate Reduction in Active Seafloor Hydrothermal Massive Sulfide Deposits.
Hydrothermal vents are thermally and geochemically dynamic habitats, and the organisms therein are subject to steep gradients in temperature and chemistry. To date, the influence of these environmental dynamics on microbial sulfate reduction has not been well constrained. Here, via multivariate experiments, we evaluate the effects of key environmental variables (temperature, pH, H2S, [Formula: see text], DOC) on sulfate reduction rates and metabolic energy yields in material recovered from a hydrothermal flange from the Grotto edifice in the Main Endeavor Field, Juan de Fuca Ridge. Sulfate reduction was measured in batch reactions across a range of physico-chemical conditions. Temperature and pH were the strongest stimuli, and maximum sulfate reduction rates were observed at 50°C and pH 6, suggesting that the in situ community of sulfate-reducing organisms in Grotto flanges may be most active in a slightly acidic and moderate thermal/chemical regime. At pH 4, sulfate reduction rates increased with sulfide concentrations most likely due to the mitigation of metal toxicity. While substrate concentrations also influenced sulfate reduction rates, energy-rich conditions muted the effect of metabolic energetics on sulfate reduction rates. We posit that variability in sulfate reduction rates reflect the response of the active microbial consortia to environmental constraints on in situ microbial physiology, toxicity, and the type and extent of energy limitation. These experiments help to constrain models of the spatial contribution of heterotrophic sulfate reduction within the complex gradients inherent to seafloor hydrothermal deposits.


Cancer risks in the Druze Isifya Village: Reasons and RF/MW antennas.
The present study was initiated to examine the claims of the residents of the Druze Isifya Village in Northern Israel that their high cancer rates were associated with the past exposures to radiation from radio and cellular transmitters. To investigate the association between past exposure to RF/MW transmitters and cancer risks, taking into account familial cancer history, occupational exposures and indicators of life-style. We carried out a population-based case-control study involving 307 residents, of whom 47 were diagnosed between 1989 and 2007 with different types of cancer and 260 controls. Cancer diagnoses were obtained from medical the records. Exposure status of individual houses were determined from a map, based on the distances between each house and RF/MW antennas, and were calculated using geographic information systems (GIS) tools. Data on additional risk factors for cancer, like smoking and occupation, were obtained from individual questionnaires. The analysis was adjusted for measures of life style and occupational exposure, and Binary multiple logistic regressions was used, for all cancer sites and for individual cancer types for those cancers with at least 5 documented cases. Past occupational exposures to chemicals (e.g., pesticides) and electronics, were found to be strongly associated with increased cancer risks (all sites: OR=2.79; CI=1.14-6.82; P<0.05), but no discernible trend in overall cancer risk was associated with proximity to sources of past RF/MW radiation exposure (n=47 OR=1.00; CI=0.99-1.02; P>0.4). Colorectal cancer showed a negligible elevated adjusted risk associated with radiation intensity (n=11 OR=1.03; CI=1.01-1.05; P<0.01). There was evidence for an increased risk of cancers which were associated with chemicals in manufacturing and agriculture and electronics, where there may have been exposures to EMF, but the study did not confirm the suspicion of increased cancer risks associated with radiation for most cancer types in this village. Misclassification of past exposures could explain the negative finding.


Gigantism and comparative life-history parameters of tyrannosaurid dinosaurs.
How evolutionary changes in body size are brought about by variance in developmental timing and/or growth rates (also known as heterochrony) is a topic of considerable interest in evolutionary biology. In particular, extreme size change leading to gigantism occurred within the dinosaurs on multiple occasions. Whether this change was brought about by accelerated growth, delayed maturity or a combination of both processes is unknown. A better understanding of relationships between non-avian dinosaur groups and the newfound capacity to reconstruct their growth curves make it possible to address these questions quantitatively. Here we study growth patterns within the Tyrannosauridae, the best known group of large carnivorous dinosaurs, and determine the developmental means by which Tyrannosaurus rex, weighing 5,000 kg and more, grew to be one of the most enormous terrestrial carnivorous animals ever. T. rex had a maximal growth rate of 2.1 kg d(-1), reached skeletal maturity in two decades and lived for up to 28 years. T. rex's great stature was primarily attained by accelerating growth rates beyond that of its closest relatives.


Polyacrylonitrile microfibers pose a significant threat to the early-stage survival of zebrafish.
Microplastic pollution, especially microfibers (MFs), presents a critical global environmental challenge in natural water bodies. Yet, research on the toxic effects of MFs, particularly during early fish development, is limited. This study aimed to investigate MFs' toxic effects and mechanisms on early-stage zebrafish. Zebrafish embryos were exposed to varying concentrations of polyacrylonitrile microfibers (PanMfs) for 7 days. Results revealed PanMfs adhering to the embryos' surface, with higher concentrations accelerating heart rate and causing pericardial edema in post-hatching larvae. Larvae ingested PanMfs, leading to their accumulation in the intestines and increased levels of reactive oxygen species (ROS) and mitochondrial quantity. Notably, lipid metabolism and calcium ion related signaling pathways underwent significant changes. Low concentration MFs affected glycometabolism pathways, with potential roles for aldob and cacng1a, exhibiting pronounced increases in ROS levels. High concentration of MFs had the most profound impact on signal transduction-related pathways, and possibly triggering micromitophagy and apoptosis in zebrafish intestinal epithelial cells through the Kras/MAPK signaling pathway, with potential roles for kras and mapk9. Although ROS increase was somewhat alleviated, it resulted in decreased survival rates and restricted growth in high concentration of MFs group. These findings highlight the significant threat of MFs to the early survival of fish. MFs pollution prevention and control hold great significance in the conservation of fishery resources.


Health literacy and knowledge of antenatal care among pregnant women.
Health literacy has a direct impact on pregnancy from the perspectives of both the mother and the baby. This study aimed to determine the level of health literacy and assess the knowledge of antenatal care among pregnant women. From among all pregnant women who presented to the hospital's obstetric polyclinic during the study's timeline, the study group consisted of 460 women who agreed to take part (492 women were invited and a response rate of 93.5% was achieved). A questionnaire prepared based on the literature in line with the study's objectives was completed by the participants under supervision. The Turkish Health Literacy Scale (THLS-32) was used to assess health literacy. In order to determine the women's prenatal care knowledge levels, a total of 20 knowledge-testing statements prepared using the literature were applied, 14 of which were true and six of which were false. The internal consistency of antenatal information questions during pregnancy was made and the Cronbach alpha coefficient was calculated as 0.77. It was determined that 33.9% of the participants had a sufficient level of health literacy. Health literacy was sufficient in young married women (19 years and less) in their first pregnancy and those who had regular reading habits, participated in healthcare activities and received postpartum care at a family health clinic (p < 0.05 for each). While the most accurately evaluated statement about antenatal care was 'It is normal to experience nausea/vomiting in the first trimester of pregnancy', the least accurately evaluated statement was 'Over 35% of women incorrectly believed it was normal to gain 20 kg of weight during pregnancy'. It was found that pregnant women with sufficient health literacy had higher levels of knowledge about antenatal care (p < 0.05). In this study, it was determined that approximately two-thirds of the participants had insufficient health literacy and the women with insufficient health literacy had low levels of knowledge about antenatal care.


Controlling the anisotropic magnetic dipolar interactions of PbSe self-assembled nanoparticles on GaAs.
We report on the observation of an anisotropic magnetic dipolar interaction that results from binding PbSe nanoparticles (NPs) to GaAs surfaces by an organic linker. The observed dependence of the blocking temperature on the alignment of the linking molecule relative to the surface normal indicates that the anisotropy is caused by the attachment of the organic linker to the NPs. The presented results may serve as a strategy for fine-tuning the magnetic interactions and anisotropy on surfaces.


The Xenopus Brachyury promoter is activated by FGF and low concentrations of activin and suppressed by high concentrations of activin and by paired-type homeodomain proteins.
The mesoderm of Xenopus laevis arises through an inductive interaction in which signals from the vegetal hemisphere of the embryo act on overlying equatorial cells. One candidate for an endogenous mesoderm-inducing factor is activin, a member of the TGFbeta superfamily. Activin is of particular interest because it induces different mesodermal cell types in a concentration-dependent manner, suggesting that it acts as a morphogen. These concentration-dependent effects are exemplified by the response of Xbra, expression of which is induced in ectodermal tissue by low concentrations of activin but not by high concentrations. Xbra therefore offers an excellent paradigm for studying the way in which a morphogen gradient is interpreted in vertebrate embryos. In this paper we examine the trancriptional regulation of Xbra2, a pseudoallele of Xbra that shows an identical response to activin. Our results indicate that 381 bp 5' of the Xbra2 transcription start site are sufficient to confer responsiveness both to FGF and, in a concentration-dependent manner, to activin. We present evidence that the suppression of Xbra expression at high concentrations of activin is mediated by paired-type homeobox genes such as goosecoid, Mix.1, and Xotx2.


Pulmonary lymphoma or pseudolymphoma: a diagnostic dilemma.
The clinical significance of pulmonary pseudolymphoma remains unresolved. We report a case which highlights the lymphoma versus pseudolymphoma dilemma. An elderly lady followed up for more than ten years with a slowly enlarging right lung mass had on biopsy, lymphoid hyperplasia consistent with a lymphoma or pseudolymphoma. Laboratory investigations revealed hyperglobulinemia due to a biclonal gammopathy with elevated serum immunoglobulin M and G fractions. Monoclonal production of immunoglobulin is today considered more indicative of a neoplasia than a hyperplasia.


Simultaneous determination of 226Ra and 228Ra in food samples using liquid scintillation counting.
The 228Ra and 226Ra isotopes of radium are significant contaminants in food, raising public concern because of their radiotoxicity. Several methods are available for determining 228Ra and 226Ra. However, the application of these procedures is not focused on food but only on water and environmental matrices. In this study, a cost-effective method for the simultaneous determination of 226Ra and 228Ra radioactivity in food samples using liquid scintillation counting was developed. The overall efficiencies of 226Ra and 228Ra in the food samples are 69.4-78.4% and 30.1-35.8%, respectively. The minimum detectable activities of 226Ra and 228Ra are 11.3 mBq/g and 33.4 mBq/g, respectively, in our food sample, obtained using a 1.0 g ash sample and 60 min of counting time. The method was validated using IAEA-certified reference materials and compared with data obtained using gamma spectrometry in tea, kelp, and oyster samples.


Quality of life assessment: its integration in rehabilitation care through a model of daily living.
To integrate quality of life assessment with rehabilitation care, some correspondence is required between the concepts of quality of life and of rehabilitation. A notion of quality of life is presented in which quality is conceived as degree of goodness, and life as daily living. Rehabilitation is considered both a process of adaptation and assistance to that process. These notions of quality of life and of rehabilitation can together be operationalized through a model of daily living. An individual's appraisal of his own situation in relation to adaptation can be explained, assuming a hierarchy of internal standards. Explaining appraisal by others requires external standards. Both types of appraisal are important grounds for decisions regarding assistance. In addition, general ideas on justification of rehabilitation as assistance may influence such decisions. The model integrates both objective and subjective appraisal and ideas on justification into rehabilitation, thereby offering opportunities for theoretical underpinning of the practice.


Deep-sequencing transcriptome analysis of low temperature perception in a desert tree, Populus euphratica.
Compared with other Populus species, Populus euphratica Oliv. exhibits better tolerance to abiotic stress, especially those involving extreme temperatures. However, little is known about gene regulation and signaling pathways involved in low temperature stress responses in this species. Recent development of Illumina/Solexa-based deep-sequencing technologies has accelerated the study of global transcription profiling under specific conditions. To understand the gene network controlling low temperature perception in P. euphratica, we performed transcriptome sequencing using Solexa sequence analysis to generate a leaf transcriptome at a depth of 10 gigabases for each sample. Using the Trinity method, 52,081,238 high-quality trimmed reads were assembled into a non-redundant set and 108,502 unigenes with an average length of 1,047 bp were generated. After performing functional annotations by aligning all-unigenes with public protein databases, 85,584 unigenes were annotated. Differentially expressed genes were investigated using the FPKM method by applying the Benjamini and Hochberg corrections. Overall, 2,858 transcripts were identified as differentially expressed unigenes in at least two samples and 131 were assigned as unigenes expressed differently in all three samples. In 4 °C-treated sample and -4 °C-treated sample, 1,661 and 866 differently expressed unigenes were detected at an estimated absolute log2-fold change of > 1, respectively. Among them, the respective number of up-regulated unigenes in C4 and F4 sample was 1,113 and 630, while the respective number of down-regulated ungenes is 548 and 236. To increase our understanding of these differentially expressed genes, we performed gene ontology enrichment and metabolic pathway enrichment analyses. A large number of early cold (below or above freezing temperature)-responsive genes were identified, suggesting that a multitude of transcriptional cascades function in cold perception. Analyses of multiple cold-responsive genes, transcription factors, and some key transduction components involved in ABA and calcium signaling revealed their potential function in low temperature responses in P. euphratica. Our results provide a global transcriptome picture of P. euphratica under low temperature stress. The potential cold stress related transcripts identified in this study provide valuable information for further understanding the molecular mechanisms of low temperature perception in P. euphratica.


Integrated AlGaInAs-silicon evanescent race track laser and photodetector.
Here we report a racetrack resonator laser integrated with two photo-detectors on the hybrid AlGaInAs-silicon evanescent device platform. Unlike previous demonstrations of hybrid AlGaInAs-silicon evanescent lasers, we demonstrate an on-chip racetrack resonator laser that does not rely on facet polishing and dicing in order to define the laser cavity. The laser runs continuous-wave (c.w.) at 1590 nm with a threshold of 175 mA, has a maximum total output power of 29 mW and a maximum operating temperature of 60 C. The output of this laser light is directly coupled into a pair of on chip hybrid AlGaInAs-silicon evanescent photodetectors used to measure the laser output.


Dielectric perturbations: anomalous resonance frequency shifts in optical resonators.
Small perturbations in the dielectric environment around resonant dielectric structures usually lead to a frequency shift of the resonator modes directly proportional to the polarizability of the perturbation. Here, we report experimental observations of strong frequency shifts that can oppose and even exceed the contribution of the perturbations' polarizability. We show in particular how the mode frequencies of a lithium niobate whispering-gallery-mode resonator are shifted by planar substrates-of refractive indices ranging from 1.50 to 4.22-contacting the resonator rim. Both blue- and redshifts are observed, as well as an increase in mode linewidth, when substrates are moved into the evanescent field of the whispering gallery mode. We compare the experimental results to a theoretical model by Foreman et al. [J. Opt. Soc. Am. B33, 2177 (2016)JOBPDE0740-322410.1364/JOSAB.33.002177] and provide an additional intuitive explanation based on the Goos-Hänchen shift for the optical domain, with applications to dielectric structures ranging from meta-surfaces to photonic crystal cavities.


Composted biosolids and treated wastewater as sources of pharmaceuticals and personal care products for plant uptake: A case study with carbamazepine.
Irrigation with treated wastewater (TWW) and application of biosolids to arable land expose the agro-environment to pharmaceuticals and personal care products (PPCPs) which can be taken up by crops. In this project, we studied the effect of a carrier medium (e.g., biosolids and TWW) on plant (tomato, wheat and lettuce) uptake, translocation and metabolism of carbamazepine as a model for non-ionic PPCPs. Plant uptake and bioconcentration factors were significantly lower in soils amended with biosolids compared to soils irrigated with TWW. In soils amended with biosolids and irrigated with TWW, the bioavailability of carbamazepine for plant uptake was moderately decreased as compared to plants grown in soils irrigated with TWW alone. While TWW acts as a continuous source of PPCPs, biosolids act both as a source and a sink for these compounds. Moreover, it appears that decomposition of the biosolids in the soil after amendment enhances their adsorptive properties, which in turn reduces the bioavailability of PPCPs in the soil environment. In-plant metabolism of carbamazepine was found to be independent of environmental factors, such as soil type, carrier medium, and absolute amount implemented to the soil, but was controlled by the total amount taken up by the plant.


Intraocular Lens Calculation for Cataract Treated with Photorefractive Keratectomy Using Ray Tracing Method.
Purpose: Conventional methods (such as the SRK-II formula) do not accurately calculate the power of the intraocular lens (IOL) after refractive surgery. Therefore, we compared a new formula including a ray tracing method to the conventional method for foldable IOL lens implantation.Method: Foldable IOLs (MA 60 BM) were implanted in 26 patients (32 eyes) using the phakoemulsification technique. The power of the IOL was measured preoperatively using the SRK-II formula in all cases. From the results of postoperative refractive errors of these cases, the power of IOL calculated by the ray tracing method was compared to the SRK-II formula. Cataract patients first treated with photorefractive keratectomy (PRK) received IOL implants using our ray tracing method and their postoperative refraction was measured.Results: The average postoperative refractive error was 1.32 D in SRK-II formula, 0.95 D in the ray tracing method with Ray 1 used and 0.89 D with Ray 2 used. Postoperative refraction of both eyes first treated with PRK was -1.00 D.Conclusion: The average postoperative refractive error was reduced in the ray tracing method using Olsen's predicted ACD (Ray 2) compared to SRK-II formula. This new tracing method appears to be useful for determination of IOL power and it may be applied for IOL calculation for cataract surgery after refractive surgery.


Digestion proteomics: tracking lactoferrin truncation and peptide release during simulated gastric digestion.
The extent to which nutritional and functional benefit is derived from proteins in food is related to its breakdown and digestion in the body after consumption. Further, detailed information about food protein truncation during digestion is critical to understanding and optimising the availability of bioactives, in controlling and limiting allergen release, and in minimising or monitoring the effects of processing and food preparation. However, tracking the complex array of products formed during the digestion of proteins is not easily accomplished using classical proteomics. We here present and develop a novel proteomic approach using isobaric labelling to mapping and tracking protein truncation and peptide release during simulated gastric digestion, using bovine lactoferrin as a model food protein. The relative abundance of related peptides was tracked throughout a digestion time course, and the effect of pasteurisation on peptide release assessed. The new approach to food digestion proteomics developed here therefore appears to be highly suitable not only for tracking the truncation and relative abundance of released peptides during gastric digestion, but also for determining the effects of protein modification on digestibility and potential bioavailability.


A Modern Flexitarian Dietary Intervention Incorporating Web-Based Nutrition Education in Healthy Young Adults: Protocol for a Randomized Controlled Trial.
The trend of flexitarian eating patterns is on the rise, with young adults among the biggest adopters claiming health and environmental reasons to reduce red meat intake. Nutrient-dense meat and animal products are often the lynchpin of these diets, even when consumed only occasionally and in moderate amounts. Red meat provides forms and concentrations of essential proteins, lipids, and micronutrients that are scarce in exclusively vegetarian regimens. The aim of this study is to consider the effects of moderate consumption of lean red meat as part of an otherwise vegetarian balanced diet and its impact on biomarkers of sustained health and well-being. A cohort of healthy, young (20-34 years old, n=80) male and female participants will take part in a 2-arm, parallel randomized controlled trial (RCT) for a duration of 12 weeks, with a 3-month posttrial follow-up. The trial will commence with a 2-week assessment period followed by allocation to the intervention arms. The intervention will include the consumption of red meat or meat alternatives 3 times per week for 10 weeks. Blood samples of the participants will be collected to measure changes in erythrocyte fatty acid distribution, circulating amino acids, neurotransmitters, markers of mineral status, and inflammatory markers. Questionnaires to assess well-being and mental health will be undertaken every 2 weeks. Body composition, physical function, and blood parameters will be assessed at allocation (t0), week 5 into the intervention (t5), and post intervention (t10). The protocol has been developed using the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist and the outcomes will be reported in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines. The trial was approved by the New Zealand Ministry of Health's Health and Disability Ethics Committees (protocol 20/STH/157). The results of this study will be communicated via publication. To our knowledge, this is the first RCT investigating the overarching health consequences of consuming pasture-fed red meat or no meat as part of a healthy diet. ClinicalTrials.gov NCT04869163; https://clinicaltrials.gov/ct2/show/NCT04869163. PRR1-10.2196/30909.


Prevention of cataracts by statins: a meta-analysis.
Current data indicate a persisting concern about possible cataractogenecity of statins. To perform a meta-analysis of studies pertaining to statins and cataract. We identified 363 records by a systematic search of the MedLine, Web of Knowledge, Cochrane database, and ClinicalTrials.gov. After exclusion of duplicates, studies without cataract as an outcome, reviews, and animal or basic science studies, we analyzed 14 studies. Two end points were examined: clinical cataract (requiring extraction or reported by the patient) and lens opacities discovered by slit-lamp examination. Using random effects meta-analysis, a statistically significant decrease in cataracts with statins was observed among studies examining clinical cataract (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.71-0.93, P = .0022). Absolute risk reduction was 1.4% ± 0.015%, 95% CI 1.1%-1.7%, P < .0001, corresponding to 71, 95% CI 59-91, number needed to treat. The effect was larger for the harder end point of cataract extraction (OR 0.66, 95% CI 0.61-0.71, P < .0001). Metaregression indicated an increase in benefit with longer duration of statin use with OR varying from 0.54 for a treatment duration of 14 years to 0.95 for a treatment duration of 6 months. Older age was associated with lower benefit (OR 1.03 for persons in their 70s to OR 0.49 for persons in their 40s), and there were no differences by gender. Several sensitivity analyses confirmed the results. Limitations of this analysis include the combination of randomized and observational studies and imprecise ascertainment of exposure and incomplete adjustment for confounders in several observational studies. This meta-analysis indicates a clinically relevant protective effect of statins in preventing cataracts. The effect is more pronounced in younger patients and with longer duration of follow-up, while there is no difference by gender.


Computational maturation of a single-domain antibody against Aβ42 aggregation.
The expansion of structural databases and the increase in computing power are enabling approaches for antibody discovery based on computational design. It has already been shown that it is possible to use this approach to generate antibodies for specific epitopes on challenging targets. Here we describe an application of this procedure for antibody maturation through the computational design of mutational variants of increased potency. We illustrate this procedure in the case of a single-domain antibody targeting an epitope in the N-terminal region of Aβ42, a peptide whose aggregation is closely associated with Alzheimer's disease. We show that this approach enables the generation of an antibody variant with over 200-fold increased potency against the primary nucleation process in Aβ42 aggregation. Our results thus demonstrate that potentiated antibody variants can be obtained by computational maturation.


Overexpression of BRCA1 attenuates the sensitivity of PC9 cells to gefitinib.
Gefitinib is an orally active antitumor agent which inhibits uncontrolled cell proliferation by interrupting epidermal growth factor receptor (EGFR) signaling pathways. Various in vitro and in vivo studies have revealed that the upregulated expression of breast cancer susceptibility gene 1 (BRCA1) is associated with chemoresistance and reduced survival following chemotherapies. In this study, a gefitinib-highly-sensitive cell line, PC-9, was used to investigate the effect of BRCA1 expression on the sensitivity of PC-9 cells to gefitinib. PC-9 cells were stably transfected with BRCA-1 (HA-tagged). Transfected and untransfected PC-9 cells were treated with gefitinib, phosphorylated γH2AX was examined by western blot to determine the DNA damages. Following the treatment of gefitinib, the inhibition of proliferation of the PC-9 cells, PC-9-pcDNA3.1 cells, and BRCA1-transfected PC-9 cells were determined. Also, a comet assay was performed to determine the DNA damage caused by gefitinib. The treatment of gefitinib for 6 hr, 12 h, and 24 hr significantly increased the cellular expression of phosphorylated γH2AX. With the treatment of gefitinib, the inhibition of proliferation of BRCA-1 overexpressed PC-9 cells was significantly lower than that of the non-transfected PC-9 cells, indicating the overexpression of BRCA1 plays a role in attenuating the sensitivity of PC-9 cells to gefitinib. The comet assay revealed that BRCA1 transfected cells showed a shorter comet tail, indicating the overexpression of BRCA1 attenuated the DNA damages caused by gefitinib. The overexpression of BRCA1 reduced the DNA damages, and enhanced DNA repair mechanisms. Also, gefitinib-mediated inhibition of cell proliferation is attenuated by the expression of BRCA1.


Sexuality in spondyloarthritis--the impact of the disease.
The impact of rheumatic diseases on patients' sexual life has been gathering the attention of the scientific community over the last decade. The existing studies are scarce, especially related to spondyloarthritis, and particularly to psoriatic arthritis. Several factors associated with the disease may condition sexual function: pain, stiffness, decreased range of motion, joint swelling and extraarticular features such as fatigue, enthesopathy and cutaneous lesions in psoriatic arthritis. To assess sexual satisfaction and limitations in sexual activity in a cohort of patients with spondyloarthritis. An anonymous questionnaire was performed, consisting in two parts. One part consisted in a questionnaire filled by the doctor with data on the disease; the other part was filled by the patient, with demographic data, multiple choice questions and questions to be answered through a visual analogic scale, including items approached in some validated indexes of sexual function and satisfaction assessment. Statistical treatment was performed using SPPS system, version 17.0. 76 patients with the diagnosis of spondyloarthritis were enrolled; 31 had psoriatic arthritis, 30 had ankylosing spondylitis, 9 had undifferentiated spondyloarthritis and 6 had inflammatory bowel disease spondyloarthritis. In a visual analogic scale, the perception of conditioning in the conjugal relationship was 33.68±31.56 mm; limitation on sexual activity was 32.72±31.06 mm; limitation imposed by pain, joint swelling, fatigue, stiffness, decreased range of motion, decreased libido and cutaneous lesions ranged from 29.17±28.51 mm (swelling) to 46.94±32.31 mm (fatigue); there was no significant difference between sexes, diagnose and type of involvement. A strong correlation was identified between some analysed factors and ASQoL and HAQ values, but only moderate between them and disease function and activity indexes. Most of patients did not talk about their sexual limitations with their partners or with health professionals. This work highlights the impact of spondyloarthritis on patients' sexual function. The type of disease and joint involvement didn't imply statistically significant differences on the analyzed parameters in this cohort. This work also emphasizes the unawareness of health professionals towards this subject, whose approach is equally difficult to the patients, and might deserve greater attention.


Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation.
Intrathecal oligoclonal bands of the cerebrospinal fluid are considered the most important immunological biomarkers of multiple sclerosis. They typically consist of clonally expanded IgG antibodies that underwent affinity maturation during sustained stimulation by largely unknown antigens. In addition, ∼40% of patients with multiple sclerosis have oligoclonal bands that consist of expanded IgM antibodies. We investigated the molecular composition of IgM- and IgG-chains from cerebrospinal fluid of 12 patients with multiple sclerosis, seven patients with other neurological diseases, and eight healthy control subjects by high-throughput deep-sequencing and single-cell PCR. Further, we studied the expression of activation-induced cytidine deaminase, the key enzyme for affinity maturation of antibodies, in cerebrospinal fluid samples of 16 patients. From the cerebrospinal fluid of two multiple sclerosis patients we isolated single B cells and investigated the co-expression of antibody chains with activation-induced cytidine deaminase. In striking contrast to IgM-chains from peripheral blood, IgM-chains from cerebrospinal fluid of patients with multiple sclerosis or neuroborreliosis showed a high degree of somatic hypermutation. We found a high content of mutations that caused amino acid exchanges as compared to silent mutations. In addition, more mutations were found in the complementarity determining regions of the IgM-chains, which interact with yet unknown antigens, as compared to framework regions. Both observations provide evidence for antigen-driven affinity maturation. Furthermore, single B cells from the cerebrospinal fluid of patients with multiple sclerosis co-expressed somatically hypermutated IgM-chains and activation-induced cytidine deaminase, an enzyme that is crucial for somatic hypermutation and class switch recombination of antibodies and is normally expressed during activation of B cells in germinal centres. Clonal tracking of particular IgM(+) B cells allowed us to relate unmutated ancestor clones in blood to hypermutated offspring clones in CSF. Unexpectedly, however, we found no evidence for intrathecal isotype switching from IgM to IgG. Our data suggest that the intrathecal milieu sustains a germinal centre-like reaction with clonal expansion and extensive accumulation of somatic hypermutation in IgM-producing B cells.


[Dynamics of the functional state of the oxygen transport system following surgical correction of mitral valve stenosis].
Twenty-one male and 32 female patients were examined, using spiroergometry with simultaneous measurement of maximum oxygen consumption, in a study of natural adaptation after surgical correction of mitral stenosis. It was demonstrated that the transformation in the oxygen transport system after closed mitral commissurotomy continued throughout the first post-operative year and resulted in considerably improved physical working capacity; two phases can apparently be distinguished here: during the first phase, working capacity mostly expands at the expense of improved pump function of the heart, and in the second phase, due to better peripheral circulation in working muscles.


Dominance-based ranking functions for interval-valued intuitionistic fuzzy sets.
The ranking of interval-valued intuitionistic fuzzy sets (IvIFSs) is difficult since they include the interval values of membership and nonmembership. This paper proposes ranking functions for IvIFSs based on the dominance concept. The proposed ranking functions consider the degree to which an IvIFS dominates and is not dominated by other IvIFSs. Based on the bivariate framework and the dominance concept, the functions incorporate not only the boundary values of membership and nonmembership, but also the relative relations among IvIFSs in comparisons. The dominance-based ranking functions include bipolar evaluations with a parameter that allows the decision-maker to reflect his actual attitude in allocating the various kinds of dominance. The relationship for two IvIFSs that satisfy the dual couple is defined based on four proposed ranking functions. Importantly, the proposed ranking functions can achieve a full ranking for all IvIFSs. Two examples are used to demonstrate the applicability and distinctiveness of the proposed ranking functions.


Riboflavin as a redox mediator accelerating the reduction of the azo dye mordant yellow 10 by anaerobic granular sludge.
Azo dyes are important persistent pollutants of textile industry effluents. Reduction of these dyes to their corresponding aromatic amines under anaerobic conditions can be used to initiate biodegradation. Since electron transfer is suggested to be rate limiting, redox mediators are being considered to improve dye reduction kinetics. This study evaluates the use of riboflavin, the redox active moiety of common occurring enzyme cofactors, as a redox mediator to accelerate the reduction of the azo dye, mordant yellow 10 (MY10). Dye reduction was found to follow zero order kinetics, the total rate constant (Vtotal) could be separated into two components: the rate of reduction due to direct contact between enzymes in the sludge with the dye (Vdirect); and the rate of reduction mediated by riboflavin (Vmediated). Riboflavin increased the Vtotal by 61% at extremely sub-stoichiometric concentrations of 9.1 micromol l(-1), which corresponded to a molar riboflavin:dye ratio of 1:60. The accelerating effect of riboflavin displayed saturation kinetics at higher concentrations, with a maximum increase of Vtotal of approximately 2-fold. A model is presented which assumes that Vmediated depends on the activity of riboflavin reductase (RR) and thus follows Michaelis-Menton kinetics with respect to the riboflavin concentration. The half-velocity constant (Km) was very low (6.3 micromol l(-1)), indicating a high affinity of the sludge RR for riboflavin. Both Vdirect and Vmediated were found to be proportional to the assay sludge concentration. The results taken as a whole indicate that vitamin levels of riboflavin can be utilized to improve the kinetics of azo dye reduction during anaerobic treatment.


Trauma exposure and posttraumatic stress disorder in adolescents: a national survey in Switzerland.
There are a limited number of epidemiological studies that have focused on trauma exposure and prevalence of posttraumatic stress disorder (PTSD) in representative general population samples of adolescents, especially outside of the United States. We therefore aimed to assess the lifetime prevalence of traumatic events (TEs) and current prevalence of PTSD, and to examine demographic risk factors for TEs and PTSD in a representative sample of adolescents. Data were collected by a school survey among a sample of 6,787 9th-grade students in Switzerland. Roughly 56% of the adolescents (females 56.6%; males 55.7%) reported having experienced at least 1 TE. Non-Swiss nationality (OR = 1.80), not living with both biological parents (OR = 1.64), and lower parental education (OR = 1.18) were associated with a higher risk of trauma exposure. The current prevalence of PTSD according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) criteria was 4.2% (females 6.2%; males 2.4%). Female gender (OR = 2.70), not living with both biological parents (OR = 1.47), lower parental education (OR = 1.51), and exposure to multiple TEs (OR = 9.56) were significant risk factors for PTSD. Results suggest considerably high rates of TEs and PTSD among adolescents. Intervention efforts must be intensified to reduce trauma exposure and treat PTSD.


BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells.
BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here, B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Coimmunoprecipitation studies revealed a multifaceted role for Bcl-2 in binding proapoptotic partners including Bax, Bak, Bik, and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199, with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall, our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines that have been evaluated previously. Furthermore, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL.


The CMA Code of Ethics: more room for reflection.
Codes of ethics stand as a promise to society about the integrity of a profession in return for the power and authority given to that profession by society. The revised CMA Code of Ethics (see pages 1176A to 1176B) is timely and significant and should be applauded and supported by all physicians. It speaks clearly to competence, high standards of practice and communication, and the importance of informed patient choice. Nonetheless, the code provides no systematic justification for the principles it asserts. Although these principles are helpful tools, they are insufficient to resolve major ethical dilemmas. The code provides no means of ordering ethical priorities and fails to address issues such as peer review and conflict of interest. It is deafeningly silent on both abortion and euthanasia. In view of these limitations, the code must be seen as an important but unfinished reflection on the essence of being a good physician.


Detection of mitral ring abscess by two-dimensional echocardiography.
M-mode and two-dimensional echocardiographic features of mitral ring abscess are described. A round, dense echo mass between the posterior mitral leaflet and left ventricular posterior wall was demonstrated in long- and short-axis views of the left ventricle. The diagnosis of mitral ring abscess was confirmed at surgery. The superiority of two-dimensional echocardiography over M-mode echocardiography for evaluating patients with mitral ring abscess is also discussed.


Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies.
Non-metastatic castration resistant prostate cancer (M0CRPC) is a heterogenous disease state affecting an estimated 100,000 men in the United States. Development of more sensitive modalities for detection of metastasis has altered the landscape of advanced prostate cancer, but M0CRPC has remained a condition that previously lacked FDA-approved treatment. The emerging data on new generation Androgen Receptor (AR) pathway inhibitors should address this gap in the management of such patients. We reviewed and summarized the current literature for the definition, diagnosis and treatment of M0CRPC. We highlight the results of recent Phase III trials that show significant impact on the outcomes of M0CRPC. Androgen deprivation therapy remains the foundation of therapy for M0CRPC. Recently published Phase III trials provided data on improved progression free survival when ADT is augmented with newer AR pathway inhibitors. The SPARTAN trial showed that metastasis-free survival (MFS) for patients treated with apalutamide plus ADT is 40.5 months compared to 16.2 months for patients who received standard ADT plus placebo, a 72% reduction in the risk of distant metastasis or death in apalutamide plus ADT compared to ADT plus placebo. The PROSPER trial demonstrated that MFS for patients treated with enzalutamide plus ADT was 36.6 months compared to 14.7 months for patients who received standard ADT only indicating a 71% reduction in the risk of developing metastatic CRPC or death compared to ADT alone. The ARAMIS trial on darolutamide, another AR pathway inhibitor, is also ongoing, and can potentially be another fitting option for M0CRPC. The recent Phase III trials SPARTAN and PROPSER demonstrate effective treatment options for the M0CRPC disease state that has historically lacked treatment from high level evidence. In particular, an FDA-approved treatment, Apalutamide, can finally be offered for M0CRPC patients. The newer AR pathway inhibitors should provide a basis for further investigation into treatments for M0CRPC.


Damage to cobalt-chromium surfaces during arthroscopy of total knee replacements.
It has been stated that care must be taken not to scratch the metal components during total knee arthroscopy; however, this concern has not been studied. Clinical observation during arthroscopy of total knee replacements suggested the possibility of damage to the femoral component by the arthroscopic cannula; therefore, a bench test was performed to study this potential risk. Cobalt-chromium femoral components were tested to determine the surface damage that resulted from moving a stainless-steel arthroscopic cannula and a plastic arthroscopic cannula across the components under a variety of applied loads. Scanning electron microscopy and surface-roughness measurements of the prosthetic surface were used to evaluate the damage. The stainless-steel cannula produced observable alterations to the surface of the femoral component at loads as small as 8 N. The majority of these alterations were deposits of stainless steel from the cannula onto the component. The plastic cannula did not appear to produce alterations on the component surface. Surface roughness increased with increasing loading of the stainless-steel cannula, but there was no noticeable change with increasing loading of the plastic cannula. These forces did, however, severely damage some parts of the plastic cannula. Alterations to the surface of cobalt-chromium femoral components can occur during arthroscopy with stainless-steel cannulae but not with plastic cannulae. The results of this study support a recommendation to use plastic cannulae during arthroscopy of total knee replacements. Arthroscopy of total knee replacements is increasing in the clinical setting, and damage to the prosthesis should be avoided whenever possible. This study provides evidence that damage to the femoral component is possible with a stainless-steel cannula and that use of a plastic cannula may reduce this risk.


Candida albicans Enhances the Progression of Oral Squamous Cell Carcinoma In Vitro and In Vivo.
Oral squamous cell carcinoma (OSCC) is associated with oral Candida albicans infection, although it is unclear whether the fungus promotes the genesis and progression of OSCC or whether cancer facilitates fungal growth. In this study, we investigated whether C. albicans can potentiate OSCC tumor development and progression. In vitro, the presence of live C. albicans, but not Candida parapsilosis, enhanced the progression of OSCC by stimulating the production of matrix metalloproteinases, oncometabolites, protumor signaling pathways, and overexpression of prognostic marker genes associated with metastatic events. C. albicans also upregulated oncogenes in nonmalignant cells. Using a newly established xenograft in vivo mouse model to investigate OSCC-C. albicans interactions, oral candidiasis enhanced the progression of OSCC through inflammation and induced the overexpression of metastatic genes and significant changes in markers of the epithelial-mesenchymal transition. Finally, using the 4-nitroquinoline 1-oxide (4NQO) murine model, we directly correlate these in vitro and short-term in vivo findings with the progression of oncogenesis over the long term. Taken together, these data indicate that C. albicans upregulates oncogenes, potentiates a premalignant phenotype, and is involved in early and late stages of malignant promotion and progression of oral cancer. IMPORTANCE Oral squamous cell carcinoma (OSCC) is a serious health issue worldwide that accounts for 2% to 4% of all cancer cases. Previous studies have revealed a higher yeast carriage and diversity in oral cancer patients than in healthy individuals. Furthermore, fungal colonization in the oral cavity bearing OSCC is higher on the neoplastic epithelial surface than on adjacent healthy surfaces, indicating a positive association between oral yeast carriage and epithelial carcinoma. In addition to this, there is strong evidence supporting the idea that Candida contributes to carcinogenesis events in the oral cavity. Here, we show that an increase in Candida albicans burden promotes an oncogenic phenotype in the oral cavity.


Differential roles for the low-affinity phosphate transporters Pho87 and Pho90 in Saccharomyces cerevisiae.
When starved of P(i), yeast cells activate the PHO signalling pathway, wherein the Pho4 transcription factor mediates expression of genes involved in P(i) acquisition, such as PHO84, encoding the high-affinity H(+)/P(i) symporter. In contrast, transcription of PHO87 and PHO90, encoding the low-affinity H(+)/P(i) transport system, is independent of phosphate status. In the present work, we reveal that, upon P(i) starvation, these low-affinity P(i) transporters are endocytosed and targeted to the vacuole. For Pho87, this process strictly depends on SPL2, another Pho4-dependent gene that encodes a protein known to interact with the N-terminal SPX domain of the transporter. In contrast, the vacuolar targeting of Pho90 upon Pi starvation is independent of both Pho4 and Spl2, although it still requires its SPX domain. Furthermore, both Pho87 and Pho90 are also targeted to the vacuole upon carbon-source starvation or upon treatment with rapamycin, which mimics nitrogen starvation, but although these responses are independent of PHO pathway signalling, they again require the N-terminal SPX domain of the transporters. These observations suggest that other SPX-interacting proteins must be involved. In addition, we show that Pho90 is the most important P(i) transporter under high P(i) conditions in the absence of a high-affinity P(i)-transport system. Taken together, our results illustrate that Pho87 and Pho90 represent non-redundant P(i) transporters, which are tuned by the integration of multiple nutrient signalling mechanisms in order to adjust P(i)-transport capacity to the general nutritional status of the environment.


Rotational thrombelastometry: a step forward to safer patient care?
The study by Hincker and colleagues indicated that the perioperative use of rotational thrombelastometry (ROTEM™) could predict thromboembolic events in 90% of the cases in non-cardiac surgery. Viscoelastic tests (VETs)--ROTEM™ and thrombelastography (TEG™)--are used mainly to predict bleeding complications. Most conventional coagulation tests, like prothrombin time and activated partial thromboplastin time, can identify a disturbance in plasmatic hemostasis. However, the relevance of these assays is limited to the initiation phase of coagulation, whereas VETs are designed to assess the whole clotting kinetics and strength of the whole blood clot and reflect more the interaction between procoagulants, anticoagulants, and platelets. The first reports about VET and hypercoagulable state were published more than 25 years ago. Since then, several studies with different quality and sample size have been published, sometimes with conflicting results. A systematic review about hypercoagulable state and TEG™ indicated that further studies are needed to recommend VETs as a screening tool to predict postoperative thrombosis.


Is there a clinical benefit with a smooth compensator design compared with a plunged compensator design for passive scattered protons?
In proton therapy, passive scattered proton plans use compensators to conform the dose to the distal surface of the planning volume. These devices are custom made from acrylic or wax for each treatment field using either a plunge-drilled or smooth-milled compensator design. The purpose of this study was to investigate if there is a clinical benefit of generating passive scattered proton radiation treatment plans with the smooth compensator design. We generated 4 plans with different techniques using the smooth compensators. We chose 5 sites and 5 patients for each site for the range of dosimetric effects to show adequate sample. The plans were compared and evaluated using multicriteria (MCA) plan quality metrics for plan assessment and comparison using the Quality Reports [EMR] technology by Canis Lupus LLC. The average absolute difference for dosimetric metrics from the plunged-depth plan ranged from -4.7 to +3.0 and the average absolute performance results ranged from -6.6% to +3%. The manually edited smooth compensator plan yielded the best dosimetric metric, +3.0, and performance, + 3.0% compared to the plunged-depth plan. It was also superior to the other smooth compensator plans. Our results indicate that there are multiple approaches to achieve plans with smooth compensators similar to the plunged-depth plans. The smooth compensators with manual compensator edits yielded equal or better target coverage and normal tissue (NT) doses compared with the other smooth compensator techniques. Further studies are under investigation to evaluate the robustness of the smooth compensator design.


Genetic association of aromatic hydrocarbon receptor and its repressor gene polymorphisms with risk of rheumatoid arthritis in Han Chinese populations.
The goal of this study was to evaluate the potential relationship among polymorphisms of aromatic hydrocarbon receptor, aromatic hydrocarbon receptor repressor, and rheumatoid arthritis (RA) susceptibility as well as the association among the polymorphisms of aromatic hydrocarbon receptor, aromatic hydrocarbon receptor repressor, and their expression.We performed a hospital-based, case-control study of 400 patients with RA and 726 healthy controls in Han Chinese populations. Two single-nucleotide polymorphisms were selected for genotyping including aromatic hydrocarbon receptor (rs2066853) and aromatic hydrocarbon receptor repressor (rs2292596).To single-nucleotide polymorphism rs2292596, a statistically significantly increased risk of RA was found to be associated with the G allele of rs2292596; the odds ratio was 2.170 (95% confidence interval: 1.820-2.587). Unfortunately, no significant differences exhibited in the allelic and the genotype frequencies of rs2066853 between 2 groups. We failed to find any association between rs2066853, rs2292596 genotypes and their expression of patients, respectively. No statistical relationship was found between aromatic hydrocarbon receptor, aromatic hydrocarbon receptor repressor at messenger Ribonucleic acid levels and clinical data, either.This study demonstrated that the polymorphisms of rs2292596 was significant with genetic susceptibility to RA patients; furthermore, it suggests the G allele of rs2292596 might be associated with a dangerous effect on RA in Han Chinese populations.