Adherence to the traditional mediterranean diet is inversely associated with body mass index and obesity in a spanish population.
The Mediterranean diet is a healthy eating pattern with protective effects on chronic diseases. The purpose of this study was to assess the relation between BMI and obesity and the level of adherence to the traditional Mediterranean diet. The subjects were Spanish men (n = 1547) and women (n = 1615) aged 25-74 y who were examined in 1999-2000, in a population-based, cross-sectional survey in the northeast of Spain (Girona). Dietary intake was assessed using a FFQ. A Mediterranean diet score, including foods considered to be characteristic components of the traditional Mediterranean diet (vegetables, fruits, pulses, nuts, fish, meat, cereals, olive oil, and wine) was created. An increase of 5 U in the dietary score was associated with a change in the BMI of 0.43 (P = 0.030) and 0.68 (P = 0.007), after controlling for potential confounders, in men and women, respectively. The obesity risk decreased in men (P = 0.010) and women (P = 0.013) with increasing adherence to the traditional Mediterranean dietary pattern. The population in the top tertile of this score were less likely to be obese in both genders [odds ratio (OR) and (95% CI): 0.61 (0.40-0.92) in men; 0.61 (0.40-0.93) in women] after adjusting for potential confounders. These data suggest that the traditional Mediterranean dietary pattern is inversely associated with BMI and obesity. This finding may be useful in the development of dietary approaches for dietary counseling and the prevention of obesity.


Developmental outcomes of children with myelomeningocele: prenatal predictors.
The purpose of the current investigation was to determine cognitive developmental outcomes for a cohort of children with prenatally detected myelomeningocele and to determine whether the variables of (1) severity of ventriculomegaly and (2) anatomic level of lesion were predictive of cognitive development. Prenatal ultrasonographic examinations were reviewed by a single perinatologist to determine the degree of ventriculomegaly and the anatomic level of the lesion. Ventriculomegaly was defined as a lateral ventricular atrial width > 10 mm. Anatomic level of lesion was defined as (1) thoracic, (2) high lumbar, (3) midlumbar, (4) low lumbar-high sacral, or (5) sacral. Cognitive developmental quotients for surviving children were determined by one of two developmental pediatricians with use of a modified version of the Clinical Adaptive Test/Clinical Linguistic Auditory Milestone Scale, a measure of visual-motor and language abilities. The mean cognitive developmental quotient for subjects with absent to mild ventriculomegaly was 90.3 (range 54 to 120, SD 17.4), whereas the mean cognitive developmental quotient for those with moderate to severe ventriculomegaly was 74.0 (range 65 to 100, SD 17.1) (p < 0.01). There was a negative correlation between the degree of ventriculomegaly and the cognitive developmental quotient (r = -0.43, p < 0.025) and a positive correlation between the level of the lesion and the cognitive developmental quotient (r = 0.50, p < 0.01). The degree of ventriculomegaly determined on high-resolution prenatal ultrasonography is predictive of early cognitive development in children with myelomeningocele, with worsening ventriculomegaly being associated with lower cognitive developmental quotients. The anatomic level of the lesion also has predictive value, with lower level lesions being associated with more favorable cognitive outcomes. However, because of the high degree of variance in developmental quotients within the two ventriculomegaly groups, we advise clinicians to use caution in the interpretation and use of our data.


Phosphorylation and activation of smooth muscle myosin light chain kinase by MAP kinase and cyclin-dependent kinase-1.
Smooth muscle myosin light chain kinase (MLCK) features several consensus sites of phosphorylation by proline-directed protein serine/threonine kinases. The phosphorylation of MLCK by two proline-directed kinases isolated from sea star oocytes, i.e., p44mpk (Mpk, a mitogen-activated protein kinase homologue) and cyclin-dependent kinase-1 (CDK1, also known as p34cdc2), was investigated. Chicken gizzard MLCK was phosphorylated on seryl and threonyl residues by both Mpk and CDK1. Phosphorylation of MLCK to 0.6 mol Pi/mol by Mpk increased the Vmax of phosphotransferase activity towards a synthetic peptide corresponding to residues 11-23 of the 20-kDa light chain of myosin by 1.6-fold. Phosphorylation of MLCK to 1.0 mol Pi/mol by CDK1 increased the Vmax by 2.3-fold. Phosphorylation by either kinase had no significant effect on the concentration of calmodulin required for half-maximal activation of MLCK. Analysis of the phosphorylation of synthetic peptides containing consensus phosphorylation sites for Mpk and CDK1 indicated that the major site of phosphorylation in MLCK by Mpk was Ser-834, and by CDK1 was Thr-283. Both of these sites are located outside the calmodulin-binding site (residues 796-815), consistent with the observation that phosphorylation by Mpk or CDK1 was unaffected by the presence of bound Ca2+/calmodulin. These results indicate that MLCK activity may be regulated by phosphorylation catalyzed by proline-directed kinases, possibly directed at Thr-40 and Thr-43 at the amino terminus of MLCK.


A Synthesis of the Sustainability of Remedial Reading Intervention Effects for Struggling Adolescent Readers.
A majority of reading-related intervention studies aiming to remediate struggling readers' reading outcomes assess student performance immediately following the conclusion of an intervention to determine intervention effects. Few studies collect follow-up data to measure the long-term sustainability of treatment effects. Hence, the aim of the current synthesis was to examine follow-up intervention effects of reading interventions involving adolescent struggling readers in Grades 6 to 12. Our literature search yielded only 10 studies that reported follow-up data for intervention participants, which highlights the dearth of intervention research that examines sustainability of intervention effects. Of the 10 included studies, the weighted mean effect size for all reading outcome measures was gw = 0.78 at immediate posttest and gw = 0.27 at follow-up, in favor of treatment group students. Although the magnitude of difference between treatment and control groups diminished at follow-up time, a comparison of treatment group students' immediate posttest and follow-up scores showed that students mostly maintained gains made during intervention at follow-up time points.


How do probiotics and prebiotics function at distant sites?
The realisation that microbes regarded as beneficial to the host can impart effects at sites distant from their habitat, has raised many possibilities for treatment of diseases. The objective of a workshop hosted in Turku, Finland, by the International Scientific Association for Probiotics and Prebiotics, was to assess the evidence for these effects and the extent to which early life microbiome programming influences how the gut microbiota communicates with distant sites. In addition, we examined how probiotics and prebiotics might affect the skin, airways, heart, brain and metabolism. The growing levels of scientific and clinical evidence showing how microbes influence the physiology of many body sites, leads us to call for more funding to advance a potentially exciting avenue for novel therapies for many chronic diseases.


Zingiber roseum Rosc. rhizome: A rich source of hepatoprotective polyphenols.
Zingiber roseum is native to Bangladesh and widely used in folk medicine. This present study was designed to assess the ameliorative potential of Zingiber roseum rhizome extract in carbon tetrachloride (CCl4) induced hepatotoxicity in mice model. Seven phenolic compounds were identified and quantified by HPLC analysis in the plant extract, including quercetin, myricetin, catechin hydrate, trans-ferulic acid, trans-cinnamic acid, (-) epicatechin, and rosmarinic acid. Hepatotoxicity was induced by administrating a single intraperitoneal injection of CCl4 (10 mL/kg) on 7th day of treatment. The results revealed that plant extract at all doses (100, 200 and 400 mg/kg) significantly reduced (p < 0.05) the elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) concentrations, and these effects were comparable to that of standard drug silymarin. Histopathological examination also revealed the evidence of recovery from CCL4 induced cellular damage when pretreated with Z. roseum rhizome extract. The in-vivo hepatoprotective effects were further investigated by the in-silico study of the aforementioned compounds with liver-protective enzymes such as superoxide dismutase (SOD), peroxiredoxin, and catalase. The strong binding affinities (ranging from -7.3359 to -9.111 KCal/mol) between the phenolic compounds (except trans-cinnamic acid) and oxidative stress enzymes inhibit ROS production during metabolism. The compounds were also found non-toxic in computational prediction, and a series of biological activities like antioxidant, anticarcinogen, cardio-protectant, hepato-protectant have been detected.


Preparation of dendritic graft copolymer consisting of poly-(L-lysine) and arabinogalactan as a hepatocyte specific DNA carrier.
The dendriTIc graft copolymers (PAX) consisting of a poly(L-lysine) (PLL) main chain and grafts of arabinogalactan (AG) were prepared as a liver cell-specific DNA carrier. The copolymers were successfully prepared by reductive amination reaction between a reductive end of AG and epsilon-amino groups of PLL using NaBH3CN as a catalyst. The fractionation of a low molecular weight fraction (Mn = 25 kDa) from a crude AG (Mn = 33 kDa) was essential for the reaction to proceed. The resulting copolymers were isolated by ultrafiltration from unreacted AG and characterized by 1H NMR and gel permeation chromatography equipped with a multiangle laser light scattering detector (GPC-MALLS). The binding and internalization of DNA to hepatoma cells, HepG2, were considerably enhanced by complexing DNA with PAX copolymers. The interactions between PAX/DNA complexes and HepG2 cells were thoroughly inhibited in the presence of a competitor to asialoglycoprotein receptors (ASGP-R), indicating high specificity of the complex to ASGP-R. Furthermore, the PAX copolymers allowed the expression of the reporter gene. Our results reveal that the PAX copolymers may provide a new research tool for cell-specific gene delivery and eventually enhance gene-therapy technology.


[Criteria for assessment of endogenous intoxication in patients with pelvic peritonitis].
The time course of changes in the serum levels of average mass molecules and malondialdehyde in patients with pelvic peritonitis was studied within two weeks after surgery. The values of the above indices of endogenous intoxication (EI) were found to be 1.3-2.9 times higher than the normal values almost throughout the follow-up (p < 0.05). An integral EI coefficient (EIC) including relative (as compared with the normal values) EI indices was proposed to evaluate the magnitude of EI. In patients with pelvic peritonitis, EIC was established to be 2.9-4.8 times greater than the normal values (p < 0.05) in all follow-up periods. Thus, the application of EIC enhances the sensitivity of EI diagnosis in patients with pelvic peritonitis as compared with that in the determination of individual EI indices.


Electronic health records approaches and challenges: a comparison between Malaysia and four East Asian countries.
An integrated Lifetime Health Record (LHR) is fundamental for achieving seamless and continuous access to patient medical information and for the continuum of care. However, the aim has not yet been fully realised. The efforts are actively progressing around the globe. Every stage of the development of the LHR initiatives had presented peculiar challenges. The best lessons in life are those of someone else's experiences. This paper presents an overview of the development approaches undertaken by four East Asian countries in implementing a national Electronic Health Record (EHR) in the public health system. The major challenges elicited from the review including integration efforts, process reengineering, funding, people, and law and regulation will be presented, compared, discussed and used as lessons learned for the further development of the Malaysian integrated LHR.


Siblings caring for siblings with Intellectual Disabilities: Naming and negotiating emotional tensions.
Extended longevity among adults with Intellectual Disabilities (ID) and increasing rates of diagnosis of Autism Spectrum Disorders (ASD) mean that parents are unlikely to remain primary carers throughout the lifecourse of adults with ID and ASD. In the context of decreased funding for disability services and policy moves toward de-congregated living, non-disabled (ND) siblings of people with ID/ASD are increasingly likely to be drawn into support and care roles for their siblings. Drawing on literature on moral emotions and the ethics of care, and on narratives collected from 25 ND siblings in Ireland in 2015/6, this paper explores the emotional dynamics entwined in the care and support roles ND siblings engage in. Findings indicate that relationships forged in childhood underpinned the moral ethic to care exhibited by many participants and that their caregiving was experienced as moral practice and emotional engagement, shaped by and constitutive of biography and moral identity. When making care choices, siblings undertook evaluative judgement of their own behaviours, which was informed by perceptions about obligations to care and about what constitutes good care. Decisions about care had emotional resonance, with guilt, other-oriented empathy and righteous-anger emerging as the key emotions in the narratives. Dilemmas between autonomy and relatedness caused siblings to grapple with feelings of resentment and guilt, and many struggled to exercise self-compassion in the face of perceived moral failings. Others experienced conflict characterised by a struggle to reconcile competing care and nurturing expectations within their intimate relationships. Through ongoing self-evaluation of their care behaviours siblings' moral identities were continually reconstituted. It is imperative that service providers and professionals understand and acknowledge such moral and emotional dynamics when working with people with ID/ASD and their families.


Polycomb group genes are targets of aberrant DNA methylation in renal cell carcinoma.
The combined effects of genetic and epigenetic aberrations are well recognized as causal in tumorigenesis. Here, we defined profiles of DNA methylation in primary renal cell carcinomas (RCC) and assessed the association of these profiles with the expression of genes required for the establishment and maintenance of epigenetic marks. A bead-based methylation array platform was used to measure methylation of 1,413 CpG loci in ~800 cancer-associated genes and three methylation classes were derived by unsupervised clustering of tumors using recursively partitioned mixture modeling (RPMM). Quantitative RT-PCR was performed on all tumor samples to determine the expression of DNMT1, DNMT3B, VEZF1 and EZH2. Additionally, methylation at LINE-1 and AluYb8 repetitive elements was measured using bisulfite pyrosequencing. Associations between methylation class and tumor stage (p = 0.05), LINE-1 (p < 0.0001) and AluYb8 (p < 0.0001) methylation, as well as EZH2 expression (p < 0.0001) were noted following univariate analyses. A multinomial logistic regression model controlling for potential confounders revealed that AluYb8 (p < 0.003) methylation and EZH2 expression (p < 0.008) were significantly associated with methylation class membership. Because EZH2 is a member of the Polycomb repressive complex 2 (PRC2), we next analyzed the distribution of Polycomb group (PcG) targets among methylation classes derived by clustering the 1,413 array CpG loci using RPMM. PcG target genes were significantly enriched (p < 0.0001) in methylation classes with greater differential methylation between RCC and non-diseased kidney tissue. This work contributes to our understanding of how repressive marks on DNA and chromatin are dysregulated in carcinogenesis, knowledge that might aid the development of therapies or preventive strategies for human malignancies.


Sexuality education in Russia: defining pleasure and danger for a fledgling democratic society.
Public health indicators have plummeted throughout Russia since the collapse of the Soviet Union, with exponential increases in sexually transmitted diseases reported among this society's young adults. Newly developing sexuality education programs provide insights into the ways local health providers interpret such public health challenges and conceptualize the educational needs of Russian youth. Moreover, these initiatives reveal the impact of both Soviet-era discourses and more recent, international anti-abortion activism on contemporary thinking about sexual health matters. This article explores the implicit and sometimes explicit ways that sex education lectures are being driven by debates over the significance of the Soviet past and anxieties over the perceived chaos of current transformations. Drawing on material from lectures, fieldwork, and interviews with sex educators, I argue that sexuality education efforts reveal a persistent ambivalence between the hope to promote individual autonomy from state interests and the presumed need to control sexual expression and reproductive practices within an emerging moral economy of post-Soviet Russia.


The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter.
The expression of bone morphogenetic proteins (BMPs) was analysed in 47 osteosarcomas to determine differences in the expression of BMP subtypes and to correlate expression with response to chemotherapy, in addition to the disease free and overall survival of patients. The expression of BMPs was examined immunohistochemically in 47 biopsy specimens of osteosarcoma using commercially available antibodies against different subtypes (BMP-2/4 (A-20), BMP-3 (N-19), BMP-4 (N-19), BMP-5 (N-19), BMP-6 (N-19), BMP-7 (N-19), BMP-8 (N-19)). The avidin-biotin-immunoperoxidase method was used for all antibodies. The expression of BMP subtypes varied considerably: 28 of the 47 tumours expressed BMP-2/4, 24 expressed BMP-3, 41 expressed BMP-5, 31 expressed BMP-6, 43 expressed BMP-7, and 42 expressed BMP-8. High expression of BMP-6 was found in those parts of the osteosarcoma with a chondroid differentiation (p = 0.016, Mann-Whitney test). No correlation was observed between the response to chemotherapy and the expression of BMPs (p > 0.05, Mann-Whitney test). Univariate analysis showed no correlation between overall survival or progression free survival and the expression of BMPs (p > 0.05, log rank test). BMP-7 and BMP-8 are highly expressed in osteosarcoma. Moreover, high expression of BMP-6 correlates with a chondroid differentiation. In contrast to conclusions derived from previous studies in which small numbers of tumours were investigated, these results indicate that the expression of BMPs does not help to predict the outcome of patients.


High-Pressure Brillouin Studies and Elastic Properties of Single-Crystal H2S Grown in a Diamond Cell.
High-pressure Brillouin spectra of crystalline hydrogen sulfide (H(2)S) have been measured at up to 7 gigapascals at room temperature. The best fit of the angular dependence of Brillouin acoustic velocities between experimental values and calculations based on Every's expression for elastic waves of an arbitrary direction yielded the orientation of an H(2)S cubic crystal grown in the diamond-anvil high-pressure cell. In situ determinations of sound velocities, as a function of pressure, could be made for any direction, the refractive index, the density, and the elastic constants. This method provides a means for the systematic study of elastic properties and phase transitions of condensed gases under ultrahigh pressures.


Analyzing fuzzy boundary value problems: a study on the influence of mitochondria and ER fluxes on calcium ions in neuron cells.
Cytosolic-free calcium ions play an important role in various physical and physiological processes. A vital component of neural signaling is the free calcium ion concentration often known as the second messenger. There are many parameters that effect the cytosolic free calcium concentration like buffer, voltage-gated ion channels, Endoplasmic reticulum, Mitochondria, etc. Mitochondria are small organelles located within the nervous system that are involved in processes within cells such as calcium homeostasis management, energy generation, response to stress, and cell demise pathways. In this work, a mathematical model with fuzzy boundary values has been developed to study the effect of Mitochondria and ER fluxes on free Calcium ions. The intended findings are displayed utilizing the physiological understanding that amyloid beta plaques and tangles of neurofibrillary fibers have been identified as the two main causes of AD. The key conclusion of the work is the investigation of [Formula: see text] for healthy cells and cells affected by Alzheimer's disease, which may aid in the study of such processes for computational scientists and medical practitioners. Also, it has been shown that when a unique solution is found for a specific precise problem, it also successfully deals with any underlying ambiguity within the problem by utilizing a technique based on the principles of linear transformation. Furthermore, the comparison between the analytical approach and the generalized hukuhara derivative approach is shown here, which illustrates the benefits of the analytical approach. The simulation is carried out in MATLAB.


Utilization of eye care services by Victorians likely to benefit from eye care.
To assess the utilization of eye care services by Australians most likely to benefit from eye assessment. The Melbourne Visual Impairment Project was a population-based study that collected demographic, health and vision-related information including use of eye care services. A standardized detailed ophthalmic examination was performed. Utilization of eye care services by those who might most benefit from eye care was assessed and compared to the general population. These participants include those with undiagnosed glaucoma, unoperated visually significant cataract, undercorrected refractive error, diabetes mellitus, age-related macular degeneration and visual acuity < 6/12. Sociodemographic characteristics were assessed for their influence on eye care utilization among these participants. A total of 4744 urban and rural residents participated (86% of those eligible) and 4612 (83% of total eligible) of these had a complete data set for the use of eye care services and were included. There were 933 participants (20.2%) who did not report eye assessment in the previous 5 years, and 891 participants (19.3%) had one or more aforementioned conditions potentially benefiting from eye care. Of these, between 34.4% and 59.4% reported no examination in the previous year and between 9% and 25% reported no examination within the previous 5 years. These participants were more likely to seek eye care within the short term (1 year) if they had a family history of eye disease, otherwise a noticed change in vision was the main influence in the longer term (2-5 years). Male participants, younger participants and those whose main spoken language was not English were less likely to seek eye care in the longer term. In Victoria 19% of those >40 years of age have potentially unmanaged eye disease including glaucoma, unoperated visually significant cataract, undercorrected refractive error, age-related macular degeneration, diabetes mellitus or visual acuity < 6/12. A substantial proportion of these report no eye assessment in the previous 1, 2 or 5 years or ever before. Younger age, male sex and main language other than English make assessment less likely. Many may have these conditions despite having had a recent eye assessment.


The Painful Face - Pain Expression Recognition Using Active Appearance Models.
Pain is typically assessed by patient self-report. Self-reported pain, however, is difficult to interpret and may be impaired or in some circumstances (i.e., young children and the severely ill) not even possible. To circumvent these problems behavioral scientists have identified reliable and valid facial indicators of pain. Hitherto, these methods have required manual measurement by highly skilled human observers. In this paper we explore an approach for automatically recognizing acute pain without the need for human observers. Specifically, our study was restricted to automatically detecting pain in adult patients with rotator cuff injuries. The system employed video input of the patients as they moved their affected and unaffected shoulder. Two types of ground truth were considered. Sequence-level ground truth consisted of Likert-type ratings by skilled observers. Frame-level ground truth was calculated from presence/absence and intensity of facial actions previously associated with pain. Active appearance models (AAM) were used to decouple shape and appearance in the digitized face images. Support vector machines (SVM) were compared for several representations from the AAM and of ground truth of varying granularity. We explored two questions pertinent to the construction, design and development of automatic pain detection systems. First, at what level (i.e., sequence- or frame-level) should datasets be labeled in order to obtain satisfactory automatic pain detection performance? Second, how important is it, at both levels of labeling, that we non-rigidly register the face?


Angle-to-Angle Mandibular Defect Reconstruction With Fibula Flap by Using a Mandibular Fixation Device and Surgical Navigation.
Although free fibula flaps are widely used for mandibular reconstruction, 3-dimensional (3D) position is difficult to control in angle-to-angle mandibular defects. The present study describes a revised approach for angle-to-angle mandibular reconstruction with fibula flaps by using mandibular fixation device and surgical navigation. Preoperative maxillofacial and fibular computed tomography (CT) scans were acquired, and CT data were imported into ProPlan CMF software. Virtual mandibulectomy was performed, and 3D fibula image was superimposed on the mandibular defect. The fibula flap was shaped according to virtual parameters and the stereo model. Surgical navigation was used to check and correct shaped segments. Position of the osteotomy lines and relevant parameters regarding the shape of the fibula flap were provided to the surgeon. A mandibular fixation device (Cibei, China) was fixed to bilateral mandibular ramus before mandibulectomy, which maintained normal mandibular width. Under computer navigation guidance, the fibula flap was accurately positioned in 3D direction, and the defect could be precisely reconstructed despite the lack of stable occlusal relationship after osteotomy. Postoperative CT and 3D error analysis revealed that osteotomy lines and reconstruction contour matched well with preoperative planning. Using our method, we precisely recovered the original configuration of the mandible. Bilateral condyles were located in the temporomandibular joint fossae, and normal mandibular width was maintained. Compared with preoperative positions, the average shift on the remaining mandible was 0.803 ± 0.502 mm (largest, 1.886 mm). Average shift in the reconstructed mandible was 0.281 ± 0.300 mm, largest being 2.441 mm. We describe a novel method for angle-to-angle mandibular reconstruction with free fibula flap. A mandibular fixation device combined with computer-assisted techniques involving surgical navigation improved clinical outcomes of this procedure.


Incidence and Prognostic Significance of the Segond Fracture in Patients Undergoing Anterior Cruciate Ligament Reconstruction.
The Segond fracture is an avulsion of the anterolateral tibia that can be found in patients with an anterior cruciate ligament (ACL) tear. It is currently unclear if the Segond fracture needs treatment or if it heals spontaneously and if it is associated with an increased risk of failure after ACL reconstruction. To identify the incidence and spontaneous healing rate of Segond fractures in a consecutive cohort of patients undergoing ACL reconstruction and to examine the predictive value of the Segond fracture on the risk of undergoing revision surgery. Cohort study; Level of evidence, 3. A retrospective review of a cohort undergoing isolated ACL reconstruction between 2002 and 2016 was performed. Radiographs from the time of injury and preoperative radiographs were evaluated for Segond fractures and healed Segond fractures. Descriptive data were extracted from an internal quality database. Statistical analyses were performed to investigate risk of revision surgery and to compare across subgroups of patients. A total of 1364 patients were included in the study. The incidence of Segond fractures was 7.4%. In addition, 10.4% of patients displayed signs of healed Segond fractures. In total, 15.2% of patients had either 1 or both findings. The overall healing response of the fracture was 35.6%. Those with Segond fractures were older (P = .014) and had a shorter interval from injury to surgery (P = .003) as compared with the rest of the cohort. The incidence of Segond fractures was significantly higher in those injured during downhill skiing as compared with other injury mechanisms (P = .04). The Segond fracture did not represent an increased risk of undergoing revision when compared with the control group (not significant). The incidence of conventional Segond fractures in patients with ACL injury was found to be in accordance with former studies. Accounting for the high incidence of healed Segond fractures, a much higher incidence (15%) was seen. Although the spontaneous healing rate from initial radiographs to preoperative imaging was only 36%, the presence of Segond fractures did not represent a higher risk of undergoing revision surgery.


Structure of rabbit liver fructose 1,6-bisphosphatase at 2.3 A resolution.
The three-dimensional structure of the R form of rabbit liver fructose 1,6-bisphosphatase (Fru-1,6-Pase; E.C. 220.127.116.11) has been determined by a combination of heavy-atom and molecular-replacement methods. A model, which includes 2394 protein atoms and 86 water molecules, has been refined at 2.3 A resolution to a crystallographic R factor of 0.177. The root-mean-square deviations of bond distances and angles from standard geometry are 0.012 A and 1.7 degrees, respectively. This structural result, in conjunction with recently redetermined amino-acid sequence data, unequivocally establishes that the rabbit liver enzyme is not an aberrant bisphosphatase as once believed, but is indeed homologous to other Fru-1,6-Pases. The root-mean-square deviation of the Calpha atoms in the rabbit liver structure from the homologous atoms in the pig kidney structure complexed with the product, fructose 6-phosphate, is 0.7 A. Fru-1,6-Pases are homotetramers, and the rabbit liver protein crystallizes in space group I222 with one monomer in the asymmetric unit. The structure contains a single endogenous Mg2+ ion coordinated by Glu97, Asp118, Asp121 and Glu280 at the site designated metal site 1 in pig kidney Fru-1,6-Pase R-form complexes. In addition, two sulfate ions, which are found at the positions normally occupied by the 6-phosphate group of the substrate, as well as the phosphate of the allosteric inhibitor AMP appear to provide stability. Met177, which has hydrophobic contacts with the adenine moiety of AMP in pig kidney T-form complexes, is replaced by glycine. Binding of a non-hydrolyzable substrate analog, beta-methyl-fructose 1,6-bisphosphate, at the catalytic site is also examined.


Maintenance of cerebral circulation during hemorrhagic hypotension in newborn pigs: role of prostanoids.
The possibility that the prostanoid system contributes to the capability of the newborn piglet to maintain cerebral blood flow and cerebral metabolic rate during hypotension was investigated. The effect of hemorrhage on net (arterial-to-venous) cerebral prostacyclin production and the effects of indomethacin on cerebral hemodynamic response to hemorrhage and on the cerebral oxygen utilization following hemorrhage were determined in chronically instrumented, unanesthetized newborn pigs. Hemorrhage decreased arterial pressure about 35% but did not affect cerebral blood flow or cerebral O2 consumption. Hemorrhage was accompanied by an increase in net cerebral 6-keto-PGF1 alpha production from 4.0 +/- 1.1 to 15.3 +/- 4.9 ng/100g X min (mean +/- SEM). Indomethacin treatment of piglets following hemorrhage inhibited the net cerebral production of 6-keto-PGF1 alpha and caused a decrease in blood flow (approximately equal to 40%) to all brain regions within 20 minutes. The decrease in cerebral blood flow was the result of an increase in cerebral vascular resistance of 57 and 180%, 20 and 40 minutes post treatment, respectively. Cerebral O2 consumption was reduced from 2.5 +/- 0.3 ml/100 g X min to 1.5 +/- 0.3 ml/100 g X min 20 minutes following treatment of hemorrhaged piglets with indomethacin and to 1.1 +/- 0.3 ml/100 g X min 40 minutes after treatment. Six of 8 piglets for whom the data were recorded that were administered indomethacin following hemorrhage became comatose with cerebral O2 consumption of 0.4 +/- 0.1 ml O2/100 g X min by 40 minutes after treatment. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn.


Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing.
Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.


Biotechnology and the soybean.
Glyphosate-tolerant soybeans (GTSs), the first biotechnologically improved soybeans to be marketed, became available commercially in 1996. The safety of GTSs was assessed in 2 ways: study of the introduced protein and of the soybean seed and selected processing fractions. Because soybeans are a major source of protein in most farm animals' diets, animal feeding studies in wholesomeness were done to complement the analyses. Analysis of the expressed protein in GTSs [3-phosphoshikimate 1-carboxyvinyltransferase (EC 126.96.36.199)] showed it to be readily digestible and to possess no allergenic concerns. In addition, comparison of the composition of seeds and selected processing fractions from 2 GTS lines with the parental line showed that the lines are equivalent. Feeding studies in various animal species confirmed that the feeding value of GTS lines is comparable with that of the parental line. These studies support the conclusion that GTSs are as safe and nutritious as traditional soybeans marketed currently and can be incorporated safely into feed and food products in the near future.


Age of Natural Menopause and Related Factors among the Tabari Cohort.
The age of menopause is affected by several factors. In this study we aimed to identify the age of natural menopause and its related factors in a large-scale population-based cohort in Iran. In this study, a subset of data collected during the enrollment phase of the Tabari cohort study was utilized. Reproductive history and other related data were collected using a structured questionnaire. Blood samples were obtained from all participants. Data were analyzed using chi-square test, independent t test, and ANOVA as well as a multivariate linear regression model. Among participants of the Tabari cohort, 2,753 were menopausal women. The mean age of natural and induced menopause was 49.2 ± 4.7 and 43.2 ± 6.4 years, respectively (P = 0.001). The number of pregnancies, duration of breastfeeding, level of education, residency, presence of thyroid disease, and body mass index affected the age of menopause. After adjustments for confounding variables, the number of pregnancies remained significantly associated with late menopause. The age of natural menopause in this study was similar to that in other studies, and the number of pregnancies was positively associated with the age of menopause after adjustments for confounding variables.


Human HELQ regulates DNA end resection at DNA double-strand breaks and stalled replication forks.
Following a DNA double strand break (DSB), several nucleases and helicases coordinate to generate single-stranded DNA (ssDNA) with 3' free ends, facilitating precise DNA repair by homologous recombination (HR). The same nucleases can act on stalled replication forks, promoting nascent DNA degradation and fork instability. Interestingly, some HR factors, such as CtIP and BRCA1, have opposite regulatory effects on the two processes, promoting end resection at DSB but inhibiting the degradation of nascent DNA on stalled forks. However, the reason why nuclease actions are regulated by different mechanisms in two DNA metabolism is poorly understood. We show that human HELQ acts as a DNA end resection regulator, with opposing activities on DNA end resection at DSBs and on stalled forks as seen for other regulators. Mechanistically, HELQ helicase activity is required for EXO1-mediated DSB end resection, while ssDNA-binding capacity of HELQ is required for its recruitment to stalled forks, facilitating fork protection and preventing chromosome aberrations caused by replication stress. Here, HELQ synergizes with CtIP but not BRCA1 or BRCA2 to protect stalled forks. These findings reveal an unanticipated role of HELQ in regulating DNA end resection at DSB and stalled forks, which is important for maintaining genome stability.


Right ventricular functional recovery after acute myocardial infarction: relation with left ventricular function and interventricular septum motion. GISSI-3 echo substudy.
To evaluate the pattern of right ventricular (RV) functional recovery and its relation with left ventricular (LV) function and interventricular septal (IVS) motion in low risk patients after acute myocardial infarction (AMI). Multicentre clinical trial carried out in 47 Italian coronary care units. 500 patients from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico) -3 echo substudy, who underwent serial echocardiograms 24-48 hours after symptom onset and at discharge, six weeks, and six months after AMI. Tricuspid annular plane systolic excursion (TAPSE) increased significantly during follow up (mean (SD) 1.79 (0.46) cm at 24-48 hours to 1.92 (0.46) cm at six months, p < 0.001) and the increase was already significant at discharge (1.88 (0.47) cm, p < 0.001). LV ejection fraction (LVEF) was the best correlate of TAPSE at 24-48 hours (r = 0.15, p = 0.001). TAPSE increased significantly in patients both with reduced (< 45%) and with preserved (> or = 45%) LVEF, but the magnitude of increase was higher in patients with lower initial LVEF (p = 0.001). Improvement in IVS wall motion score index (IVS-WMSI) was the only independent predictor of TAPSE changes during follow up (r = -0.12, p = 0.007). In low risk patients after AMI, RV function recovered throughout six months of follow up and was already significant at discharge. TAPSE was significantly related to LVEF at 24-48 hours. The magnitude of RV functional recovery was higher in patients with lower initial LVEF. RV functional recovery is best related to IVS-WMSI improvement, suggesting that IVS motion has an important role in RV functional improvement in this setting.


Associations between caregiver mental health and young children's behaviour in a rural Kenyan sample.
Background: Research shows that caregiver mental health problems have direct, significant effects on child behaviour. While these risks are amplified in low-resource settings, limited evidence exists from these places, especially sub-Saharan Africa. Objective: We measured associations between caregiver mental health and child behaviour in a rural Kenyan sample, hypothesizing that higher rates of caregiver mental health would be associated with increased child behavioural problems. We also sought to provide an overview of caregiver mental health symptoms in our sample. Method: Cross-sectional data were collected from caregivers of children ages 4-5 years old enrolled in a community-based early child development programme in western Kenya. 465 caregivers were recruited and assessed at baseline, and answered questions about child behaviour, mental health symptoms (depression, anxiety, stress), and help-seeking. A multivariate linear regression model was used to assess significance of each mental health factor. Results: Caregiver anxiety (p = 0.01) and parenting stress (p < 0.001) were significantly associated with child behavioural problems. 245 caregivers (52.9%) had high levels of symptoms of depression, anxiety, or both; furthermore, 101 caregivers (21.7%) scored above the cut-off for both of these scales. A high proportion of our sample (60.6%) reported seeking some formal or informal psychosocial support services; however, less than one-third of these caregivers were symptomatic (30.9%). Conclusion: Anxiety and stress were associated with poorer child behavioural outcomes. Our sample reflected a higher prevalence of caregiving adults with mental health symptomology than previous estimates from Kenya, with few high-symptom caregivers seeking support. We discuss further implications for programming and health services delivery.


Hox10 genes function in kidney development in the differentiation and integration of the cortical stroma.
Organogenesis requires the differentiation and integration of distinct populations of cells to form a functional organ. In the kidney, reciprocal interactions between the ureter and the nephrogenic mesenchyme are required for organ formation. Additionally, the differentiation and integration of stromal cells are also necessary for the proper development of this organ. Much remains to be understood regarding the origin of cortical stromal cells and the pathways involved in their formation and function. By generating triple mutants in the Hox10 paralogous group genes, we demonstrate that Hox10 genes play a critical role in the developing kidney. Careful examination of control kidneys show that Foxd1-expressing stromal precursor cells are first observed in a cap-like pattern anterior to the metanephric mesenchyme and these cells subsequently integrate posteriorly into the kidney periphery as development proceeds. While the initial cap-like pattern of Foxd1-expressing cortical stromal cells is unaffected in Hox10 mutants, these cells fail to become properly integrated into the kidney, and do not differentiate to form the kidney capsule. Consistent with loss of cortical stromal cell function, Hox10 mutant kidneys display reduced and aberrant ureter branching, decreased nephrogenesis. These data therefore provide critical novel insights into the cellular and genetic mechanisms governing cortical cell development during kidney organogenesis. These results, combined with previous evidence demonstrating that Hox11 genes are necessary for patterning the metanephric mesenchyme, support a model whereby distinct populations in the nephrogenic cord are regulated by unique Hox codes, and that differential Hox function along the AP axis of the nephrogenic cord is critical for the differentiation and integration of these cell types during kidney organogenesis.


Singular knot bundle in light.
As the size of an optical vortex knot, imprinted in a coherent light beam, is decreased, nonparaxial effects alter the structure of the knotted optical singularity. For knot structures approaching the scale of wavelength, longitudinal polarization effects become non-negligible, and the electric and magnetic fields differ, leading to intertwined knotted nodal structures in the transverse and longitudinal polarization components, which we call a knot bundle of polarization singularities. We analyze their structure using polynomial beam approximations and numerical diffraction theory. The analysis reveals features of spin-orbit effects and polarization topology in tightly focused geometry, and we propose an experiment to measure this phenomenon.


Identification of fluoropyrogallols as new intermediates in biotransformation of monofluorophenols in Rhodococcus opacus 1cp.
The transformation of monofluorophenols by whole cells of Rhodococcus opacus 1cp was investigated, with special emphasis on the nature of hydroxylated intermediates formed. Thin-layer chromatography, mass spectrum analysis, and (19)F nuclear magnetic resonance demonstrated the formation of fluorocatechol and trihydroxyfluorobenzene derivatives from each of three monofluorophenols. The (19)F chemical shifts and proton-coupled splitting patterns of the fluorine resonances of the trihydroxyfluorobenzene products established that the trihydroxylated aromatic metabolites contained hydroxyl substituents on three adjacent carbon atoms. Thus, formation of 1,2, 3-trihydroxy-4-fluorobenzene (4-fluoropyrogallol) from 2-fluorophenol and formation of 1,2,3-trihydroxy-5-fluorobenzene (5-fluoropyrogallol) from 3-fluorophenol and 4-fluorophenol were observed. These results indicate the involvement of fluoropyrogallols as previously unidentified metabolites in the biotransformation of monofluorophenols in R. opacus 1cp.


Manganese in residential drinking water from a community-initiated case study in Massachusetts.
Manganese (Mn) is a metal commonly found in drinking water, but the level that is safe for consumption is unknown. In the United States (U.S.), Mn is not regulated in drinking water and data on water Mn concentrations are temporally and spatially sparse. Examine temporal and spatial variability of Mn concentrations in repeated tap water samples in a case study of Holliston, Massachusetts (MA), U.S., where drinking water is pumped from shallow aquifers that are vulnerable to Mn contamination. We collected 79 residential tap water samples from 21 households between September 2018 and December 2019. Mn concentrations were measured using inductively coupled plasma mass spectrometry. We calculated descriptive statistics and percent of samples exceeding aesthetic (secondary maximum containment level; SMCL) and lifetime health advisory (LHA) guidelines of 50 µg/L and 300 µg/L, respectively. We compared these concentrations to concurrent and historic water Mn concentrations from publicly available data across MA. The median Mn concentration in Holliston residential tap water was 2.3 µg/L and levels were highly variable (range: 0.03-5,301.8 µg/L). Mn concentrations exceeded the SMCL and LHA in 14% and 12% of samples, respectively. Based on publicly available data across MA from 1994-2022, median Mn concentration was 17.0 µg/L (N = 37,210; range: 1-159,000 µg/L). On average 40% of samples each year exceeded the SMCL and 9% exceeded the LHA. Samples from publicly available data were not evenly distributed between MA towns or across sampling years. This study is one of the first to examine Mn concentrations in drinking water both spatially and temporally in the U.S. Findings suggest that concentrations of Mn in drinking water frequently exceed current guidelines and occur at concentrations shown to be associated with adverse health outcomes, especially for vulnerable and susceptible subpopulations like children. Future studies that comprehensively examine exposure to Mn in drinking water and its associations with children's health are needed to protect public health.


Which starting style is faster in sprint running--standing or crouch start?
The purpose of this study was to further understand the biomechanical differences between the standing and crouch starting methods, and to investigate whether one of the starting styles provides better acceleration and proves to be faster. Six university track team sprinters performed 2 x 3 x 50 m trials. Digitised video, photocell timing, and velocity data revealed that during the first steps of the performance the standing start produced higher body centre of mass horizontal velocity than the crouch start. This may be due to the longer distance between the feet in the standing start, which caused longer push-off phases, and the work against gravity in the crouch start. However, this advantage in horizontal velocity disappeared by the 10 m mark, where similar velocities were recorded with both start styles. Further, there was no statistically significant difference between the two starting styles in horizontal velocity at the 25 m mark, nor in the time to reach the 25 m or 50 m mark. Regarding relay running, where athletes need to decide to adopt either a crouch start without starting blocks or a standing start, there seems to be no specific reason for outgoing athletes to use a crouch start, although this area warrants further investigation.


The associations between interoceptive awareness, emotion regulation, acceptance, and well-being in patients receiving multicomponent treatment: a dynamic panel network model.
Mechanisms of change represent the cornerstone of the therapeutic process. This study aimed to investigate how network models could be used to test mechanisms of change at a group level. A secondary aim was to investigate which of the several hypothesized mechanisms (emotion regulation, interoceptive awareness, and acceptance) are related to changes in psychological well-being. The sample comprised adult patients suffering from psychological disorders (N=444; 70% women) from 7 clinical sites in the Czech Republic who were undergoing groupbased multicomponent treatment composed mainly of psychodynamic psychotherapy (lasting from 4 to 12 weeks depending on the clinical site). Data were collected weekly using the multidimensional assessment of interoceptive awareness, emotion regulation skills questionnaire, chronic pain acceptance questionnaire-symptoms and outcome rating scale. A lag-1 longitudinal network model was employed for exploratory analysis of the panel data. The pruned final model demonstrated a satisfactory fit. Three networks were computed, i.e., temporal, contemporaneous, and between-person networks. The most central node was the modification of negative emotions. Mechanisms that were positively associated with well-being included modification, readiness to confront negative emotions, activity engagement, and trust in bodily signals. Acceptance of negative emotions showed a negative association with well-being. Moreover, noticing bodily sensations, not worrying, and self-regulation contributed indirectly to changes in well-being. In conclusion, the use of network methodology to model panel data helped generate novel hypotheses for future research and practice; for instance, well-being could be actively contributing to other mechanisms, not just a passive outcome.


Maternal lactocrine programming of porcine reproductive tract development.
The lactocrine hypothesis for maternal programming of female reproductive tract development is based on the idea that non-nutritive, milk-borne bioactive factors (MbFs), delivered from mother to offspring during nursing, play a role in determining the trajectory of development with long-term consequences in the adult. Porcine female reproductive tract development is completed postnatally, and the period during which maternal support of neonatal growth derives exclusively from colostrum/milk defines a window of opportunity for lactocrine programming of reproductive tissues. Beyond nutrition, milk serves as a delivery system for a variety of bioactive factors. Porcine relaxin is a prototypical MbF. Present in colostrum at highest concentrations at birth, relaxin is transmitted into the circulation of nursing piglets where it can act on Relaxin receptors found in neonatal female reproductive tract tissues. This process is facilitated by the physiology of the maternal-neonatal dyad and the fact that the neonatal gastrointestinal tract is open to absorb macromolecules for a period of time postnatally. Age at first nursing and duration of nursing from birth are also important for porcine female reproductive tract development. These parameters affect both the quality and quantity of colostrum consumed. Disruption of lactocrine signaling by feeding milk replacer from birth altered porcine uterine, cervical, and testicular development by postnatal Day 2. Moreover, insufficient colostrum consumption in nursing piglets can impair uterine capacity to support viable litters of optimal size in adulthood. In the pig, lactocrine signaling supports neonatal organizational events associated with normal reproductive development and may program adult uterine capacity.


A possible mechanism for ezrin to establish epithelial cell polarity.
Ezrin is an important membrane/actin cytoskeleton linker protein, especially in epithelia. Ezrin has two important binding domains: an NH(2)-terminal region that binds to plasma membrane and a COOH-terminal region that binds to F-actin only after a conformational activation by phosphorylation at Thr567 of ezrin. The present experiments were undertaken to investigate the detailed cellular changes in the time course of expression of ezrin-T567 mutants (nonphosphorylatable T567A and permanent phospho-mimic T567D) in parietal cells and to assess ezrin distribution and its influence on the elaborate membrane recruitment processes of these cells. T567A mutant and wild-type (WT) ezrin were consistently localized to the apical plasma membrane, even with overexpression. On the other hand, T567D went first to apical membrane at early times and low expression levels, then accumulated mainly at the basal surface after 24 h. Overexpression of WT or T567A led to incorporation of internal membranes to apical vacuoles, while overexpression of T567D led to large incorporation of apical and intracellular membranes (including H-K-ATPase) to the basal surface. Differences in polar distribution of ezrin suggest a role for the linker protein in promoting formation and plasticity of membrane surface projections, forming the basis for a novel theory for ezrin as an organizer and regulator of membrane recruitment. A model simulating the cellular distribution of ezrin and its associated membrane- and F-actin-binding forms is given to predict redistributions observed with phosphorylation and mutant overexpression, and it can easily be modified as more specific information regarding binding constants and specific sites becomes available.


SMARCAD1-mediated active replication fork stability maintains genome integrity.
The stalled fork protection pathway mediated by breast cancer 1/2 (BRCA1/2) proteins is critical for replication fork stability. However, it is unclear whether additional mechanisms are required to maintain replication fork stability. We describe a hitherto unknown mechanism, by which the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily-A containing DEAD/H box-1 (SMARCAD1) stabilizes active replication forks, that is essential to maintaining resistance towards replication poisons. We find that SMARCAD1 prevents accumulation of 53BP1-associated nucleosomes to preclude toxic enrichment of 53BP1 at the forks. In the absence of SMARCAD1, 53BP1 mediates untimely dissociation of PCNA via the PCNA-unloader ATAD5, causing frequent fork stalling, inefficient fork restart, and accumulation of single-stranded DNA. Although loss of 53BP1 in SMARCAD1 mutants rescues these defects and restores genome stability, this rescued stabilization also requires BRCA1-mediated fork protection. Notably, fork protection-challenged BRCA1-deficient naïve- or chemoresistant tumors require SMARCAD1-mediated active fork stabilization to maintain unperturbed fork progression and cellular proliferation.


Phase II trial of the Sigma-1 receptor agonist cutamesine (SA4503) for recovery enhancement after acute ischemic stroke.
The σ-1 receptor (Sig-1R) agonist cutamesine (SA4503) enhanced functional recovery after experimental stroke with a treatment initiation window of 48 hours and chronic treatment for 28 days. We conducted a phase 2 clinical trial exploring the safety, tolerability, dose range, and functional effects of cutamesine in patients with ischemic stroke. Subjects were randomized between 48 and 72 hours after stroke to receive cutamesine 1 mg/d, 3 mg/d, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (day 28), and at end of follow-up (day 56). In 60 patients, treatment with both cutamesine dosages was safe and well tolerated without significant differences in numbers of treatment emergent or serious adverse events. No significant effect was observed on the primary efficacy measure (change in National Institutes of Health Stroke Scale from baseline to day 56) or modified Rankin Scale and Barthel Index scores. Post hoc analysis of moderately and severely affected patients (baseline National Institutes of Health Stroke Scale, ≥7 and ≥10) showed greater National Institutes of Health Stroke Scale improvements in the 3 mg/d cutamesine group when compared with placebo (P=0.034 and P=0.038, respectively). A trend toward a higher proportion being able to complete a 10m timed walk was observed for cutamesine-treated subjects. Cutamesine was safe and well tolerated at both dosage levels. Although no significant effects on functional end points were seen in the population as a whole, greater improvement in National Institutes of Health Stroke Scale scores among patients with greater pretreatment deficits seen in post hoc analysis warrants further investigation. Additional studies should focus on the patient population with moderate-to-severe stroke. http://www.clinicaltrials.gov/show/NCT00639249. Unique identifier: NCT00639249. The EudraCT number is 2007-004840-60 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004840-60/GB).


Phylogenetic analysis and rapid identification of Candida dubliniensis based on analysis of ACT1 intron and exon sequences.
The phylogenetic position of Candida dubliniensis has previously been established on the basis of the sequence of rRNA genes. In order to confirm the relationship between C. dubliniensis and other yeast species, particularly Candida albicans, using non-rRNA gene sequences the ACT1 gene was chosen for analysis. Three overlapping fragments that together span the entire C. dubliniensis ACT1 gene (CdACT1) were amplified from a recombinant phage isolated from a genomic DNA lambda library using PCR. These were cloned and used to determine the contiguous sequence of the gene. Analysis of the sequence data revealed the presence of a 1131 bp ORF interrupted by a single 632 bp intron at the 5' extremity of the gene. Comparison of the CdACT1 sequence with the C. albicans homologue (CaACT1) revealed that although the exons are 97.9% identical the introns are only 83.4% identical. Phylogenetic trees generated using ACT1 exon and intron sequences from a range of yeast species unequivocally confirmed the phylogenetic position of C. dubliniensis as a unique taxon within the genus Candida. Analysis of the ACT1-associated intron sequences from 10 epidemiologically unrelated C. dubliniensis isolates from disparate geographical locations showed a very low level of intraspecies sequence variation. In order to develop an accurate and rapid method to identify C. dubliniensis from primary isolation plates the significant divergence between the C. dubliniensis and C. albicans ACT1 intron sequences was exploited by designing C. dubliniensis-specific PCR primers. Using a rapid boiling method to produce template DNA directly from colonies from primary isolation plates in 10 min, these primers were used in a blind test with 122 isolates of C. dubliniensis, 53 isolates of C. albicans, 10 isolates of C. stellatoidea and representative isolates of other clinically relevant Candida and other yeast species. Only the C. dubliniensis isolates yielded the C. dubliniensis-specific 288 bp amplimer. Use of this technique on colonies suspected to be C. dubliniensis allows their correct identification as C. dubliniensis in as little as 4 h.


Exact and approximate area-proportional circular Venn and Euler diagrams.
Scientists conducting microarray and other experiments use circular Venn and Euler diagrams to analyze and illustrate their results. As one solution to this problem, this paper introduces a statistical model for fitting area-proportional Venn and Euler diagrams to observed data. The statistical model outlined in this paper includes a statistical loss function and a minimization procedure that enables formal estimation of the Venn/Euler area-proportional model for the first time. A significance test of the null hypothesis is computed for the solution. Residuals from the model are available for inspection. As a result, this algorithm can be used for both exploration and inference on real data sets. A Java program implementing this algorithm is available under the Mozilla Public License. An R function venneuler() is available as a package in CRAN and a plugin is available in Cytoscape.


Epidemiology of Meningitis and Encephalitis in Infants and Children in the United States, 2011-2014.
Large epidemiologic studies evaluating the etiologies, management decisions and outcomes of infants and children with meningitis and encephalitis in the United States are lacking. Children 0-17 years of age with meningitis or encephalitis as assessed by International Classification of Diseases, Ninth Revision, codes available in the Premier Healthcare Database during 2011-2014 were analyzed. Six thousand six hundred sixty-five patients with meningitis or encephalitis were identified; 3030 (45.5%) were younger than 1 year of age, 295 (4.4%) were 1-2 years of age, 1460 (21.9%) were 3-9 years of age, and 1880 (28.2%) were 10-17 years of age. Etiologies included enterovirus (58.4%), unknown (23.7%), bacterial (13.0%), noninfectious (3.1%), herpes simplex virus (1.5%), other viruses (0.7%), arboviruses (0.5%) and fungal (0.04%). The majority of patients were male [3847 (57.7%)] and healthy [6094 (91.4%)] with no reported underlying conditions. Most underwent a lumbar puncture in the emergency department [5363 (80%)] and were admitted to the hospital [5363 (83.1%)]. Antibiotic therapy was frequent (92.2%) with children younger than 1 year of age with the highest rates (97.7%). Antiviral therapy was less common (31.1%). Only 539 (8.1%) of 6665 of patients received steroids. Early administration of adjunctive steroids was not associated with a reduction in mortality (P = 0.266). The overall median length of stay was 2 days. Overall mortality rate (0.5%) and readmission rates (<1%) was low for both groups. Meningitis and encephalitis in infants and children in the United States are more commonly caused by viruses and are treated empirically with antibiotic therapy and antiviral therapy in a significant proportion of cases. Adjunctive steroids are used infrequently and are not associated with a benefit in mortality.


Reframing cognition: getting down to biological basics.
The premise of this two-part theme issue is simple: the cognitive sciences should join the rest of the life sciences in how they approach the quarry within their research domain. Specifically, understanding how organisms on the lower branches of the phylogenetic tree become familiar with, value and exploit elements of an ecological niche while avoiding harm can be expected to aid understanding of how organisms that evolved later (including Homo sapiens) do the same or similar things. We call this approach basal cognition. In this introductory essay, we explain what the approach involves. Because no definition of cognition exists that reflects its biological basis, we advance a working definition that can be operationalized; introduce a behaviour-generating toolkit of capacities that comprise the function (e.g. sensing/perception, memory, valence, learning, decision making, communication), each element of which can be studied relatively independently; and identify a (necessarily incomplete) suite of common biophysical mechanisms found throughout the domains of life involved in implementing the toolkit. The articles in this collection illuminate different aspects of basal cognition across different forms of biological organization, from prokaryotes and single-celled eukaryotes-the focus of Part 1-to plants and finally to animals, without and with nervous systems, the focus of Part 2. By showcasing work in diverse, currently disconnected fields, we hope to sketch the outline of a new multidisciplinary approach for comprehending cognition, arguably the most fascinating and hard-to-fathom evolved function on this planet. Doing so has the potential to shed light on problems in a wide variety of research domains, including microbiology, immunology, zoology, biophysics, botany, developmental biology, neurobiology/science, regenerative medicine, computational biology, artificial life and synthetic bioengineering. This article is part of the theme issue 'Basal cognition: conceptual tools and the view from the single cell'.


An FMRI Stroop task study of ventromedial prefrontal cortical function in pathological gamblers.
Function of the ventromedial prefrontal cortex has been implicated in impulse control. The authors used the Stroop paradigm to test attention and response inhibition during the presentation of congruent and incongruent stimuli in male pathological gamblers and a group of comparison subjects. Event-related functional magnetic resonance imaging was used to examine ventromedial prefrontal cortex function during Stroop performance. In response to infrequent incongruent stimuli, pathological gamblers demonstrated decreased activity in the left ventromedial prefrontal cortex relative to the comparison subjects. Both groups demonstrated similar activity changes in multiple brain regions, including activation of the dorsal anterior cingulate and dorsolateral frontal cortex. Pathological gamblers share many neural correlates of Stroop task performance with healthy subjects but differ in a brain region previously implicated in disorders characterized by poor impulse control.


Improved stove interventions to reduce household air pollution in low and middle income countries: a descriptive systematic review.
Household air pollution (HAP) resulting from the use of solid fuels presents a major public health hazard. Improved stoves have been offered as a potential tool to reduce exposure to HAP and improve health outcomes. Systematic information on stove interventions is limited. We conducted a systematic review of the current evidence of improved stove interventions aimed at reducing HAP in real life settings. An extensive search of ten databases commenced in April 2014. In addition, we searched clinical trial registers and websites for unpublished studies and grey literature. Studies were included if they reported on an improved stove intervention aimed at reducing HAP resulting from solid fuel use in a low or middle-income country. The review identified 5,243 records. Of these, 258 abstracts and 57 full texts were reviewed and 36 studies identified which met the inclusion criteria. When well-designed, implemented and monitored, stove interventions can have positive effects. However, the impacts are unlikely to reduce pollutant levels to World Health Organization recommended levels. Additionally, many participants in the included studies continued to use traditional stoves either instead of, or in additional to, new improved options. Current evidence suggests improved stove interventions can reduce exposure to HAP resulting from solid fuel smoke. Studies with longer follow-up periods are required to assess if pollutant reductions reported in the current literature are sustained over time. Adoption of new technologies is challenging and interventions must be tailored to the needs and preferences of the households of interest. Future studies require greater process evaluation to improve knowledge of implementation barriers and facilitators. The review was registered on Prospero (registration number CRD42014009796).


Thalamic Shape Abnormalities Differentially Relate to Cognitive Performance in Early-Onset and Adult-Onset Schizophrenia.
Early-onset schizophrenia (EOS) shares many biological and clinical features with adult-onset schizophrenia (AOS), but may represent a unique subgroup with greater susceptibility for disease onset and worsened symptomatology and progression, which could potentially derive from exaggerated neurodevelopmental abnormalities. Neurobiological explanations of schizophrenia have emphasized the involvement of deep-brain structures, particularly alterations of the thalamus, which have been linked to core features of the disorder. The aim of this study was to compare thalamic shape abnormalities between EOS and AOS subjects and determine whether unique behavioral profiles related to these differences. It was hypothesized abnormal thalamic shape would be observed in anterior, mediodorsal and pulvinar regions in both schizophrenia groups relative to control subjects, but exacerbated in EOS. Magnetic resonance T1-weighted images were collected from adult individuals with EOS (n = 28), AOS (n = 33), and healthy control subjects (n = 60), as well as collection of clinical and cognitive measures. Large deformation high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. General linear models were used to compare groups on surface shape features, and Pearson correlations were used to examine relationships between thalamic shape and behavioral measures. Results revealed both EOS and AOS groups demonstrated significant abnormal shape of anterior, lateral and pulvinar thalamic regions relative to CON (all p < 0.007). Relative to AOS, EOS exhibited exacerbated abnormalities in posterior lateral, mediodorsal and lateral geniculate thalamic regions (p = 0.003). Thalamic abnormalities related to worse episodic memory in EOS (p = 0.03) and worse working memory (p = 0.047) and executive functioning (p = 0003) in AOS. Overall, findings suggest thalamic abnormalities are a prominent feature in both early- and late-onset schizophrenia, but exaggerated in EOS and have different brain-behavior profiles for each. The persistence of these abnormalities in adult EOS patients suggests they may represent markers of disrupted neurodevelopment that uniquely relate to the clinical and cognitive aspects of the illness.


Development of a Transgender and Gender Nonconforming Language Self-Efficacy Scale for Social Service Providers Working With Older Adults.
There is consensus that providers who work with transgender and gender nonconforming (TGNC) older adults should use the language preferred by the older adult; however, assessment tools to document professional training efforts are lacking. This study presents data on a new TGNC Language Self-Efficacy Scale, using responses collected from employees and volunteers of area agencies on aging (AAA) across the United States (N = 155). Exploratory factor analysis supports a two-factor model: Interactions and Information subscales significantly correlated with knowledge of TGNC terminology, genderism and transphobia, gender role beliefs, beliefs about gender and gender identity, and attitudes toward lesbians and gay men. Future directions include additional measurement development work and replication of these findings outside of AAAs.


Detection of two distinct malignant B cell clones in a single patient using anti-idiotype monoclonal antibodies and immunoglobulin gene rearrangement.
Immunoglobulin gene rearrangement analysis and somatic cell hybridization techniques were used to examine the malignant cell population in an unusual patient with hairy cell leukemia and macroglobulinemia (N Engl J Med 296:92, 1977). Although previous investigations suggested that the IgM macroglobulin was secreted by the circulating leukemia cells, anti-idiotype monoclonal antibodies raised to the IgM macroglobulin failed to react with the malignant cells in the circulation and bone marrow. In contrast, approximately 50% of the mononuclear cells from an enlarged inguinal lymph node reacted strongly with the anti-idiotype antibodies. Subsequent reanalysis of all cell populations demonstrated that whereas the circulating and bone marrow cells were IgM kappa-bearing, the macroglobulin was IgM gamma-bearing and the lymph node cells were evenly divided among IgM kappa-bearing and IgM gamma-bearing. Immunofluorescence flow cytometry indicated that those lymph node cells that reacted strictly with the anti-idiotype antibody were IgM gamma-bearing, demonstrating that they were the source of macroglobulin. An analysis of immunoglobulin gene DNA confirmed the coexistence of two distinct malignant B cell populations in the lymph node and indicated that the IgM kappa-bearing lymph node cells were identical to the circulating and bone marrow leukemic cells.


Usefulness of subtraction of 3D T2WI-DRIVE from contrast-enhanced 3D T1WI: preoperative evaluations of the neurovascular anatomy of patients with neurovascular compression syndrome.
High-resolution 3D MR cisternography techniques such as 3D T2WI-driven equilibrium radiofrequency reset pulse (DRIVE) are used preoperatively to assess neurovascular anatomy in patients with neurovascular compression syndrome, but contrast between vessels and cranial nerves at the point of neurovascular contact is limited. The postprocessing technique subtraction of 3D T2WI-driven equilibrium radiofrequency reset pulse from contrast-enhanced 3D T1WI (sDRICE) provides both high spatial resolution and excellent contrast in depicting the neurovascular contact. We evaluated the usefulness of sDRICE compared with 3D T2WI-DRIVE. Twelve patients who underwent microvascular decompression for hemifacial spasm or trigeminal neuralgia were examined preoperatively with 3D T2WI-DRIVE and sDRICE. Two neuroradiologists retrospectively analyzed and scored lesion conspicuity, defined as the ease of discrimination between offending vessels and compressed nerves or the brain stem at the neurovascular contact. They also quantitatively analyzed the contrast and contrast-to-noise ratio at the neurovascular contact. The lesion conspicuity scores of sDRICE images were significantly higher than those of 3D T2WI-DRIVE for all 12 patients (P = .006) and the 6 cases of hemifacial spasm (P = .023) but were not significantly higher in the 6 trigeminal neuralgia cases alone (P = .102). For all 12 patients, the contrast-to-noise ratio between the offending vessels and the brain stem and between the vessels and nerves on sDRICE images was significantly higher than that on 3D T2WI-DRIVE (P = .003 and P = .007, respectively). Among these structures, the contrast values were also significantly higher on the sDRICE than on the 3D T2WI-DRIVE (P < .001) images. The postprocessing technique sDRICE is useful to evaluate neurovascular anatomy and to improve contrast and the contrast-to-noise ratio in patients with neurovascular compression syndrome.


Prognostic value of MIP-1 alpha, TGF-beta 2, sELAM-1, and sVCAM-1 in patients with gram-positive sepsis.
The aim of the present study was to evaluate the potential prognostic value of MIP-1 alpha, TGF-beta 2, sELAM-1, and sVCAM-1 in patients with gram-positive sepsis. Twenty-eight patients with gram-positive sepsis were compared to 11 patients with gram-negative sepsis and 15 healthy volunteers. Sepsis was defined by the criteria of Bone et al. (Crit. Care Med. 21, 5447-5463, 1993) and by isolation of at least two positive blood cultures with gram-positive/gram-negative bacteria. Plasma samples for determination of the immunological parameters were collected daily. Analysis of cytokines and adhesion molecules was performed on days 0 (day of sepsis criteria fulfillment), 4, and 7 (or 1 day before death). In the gram-positive group 10 of 28 patients died; in the gram-negative group 4 of 11 died. Only sELAM-1 plasma concentrations were found to be a useful early parameter in predicting patients' outcome in gram-positive sepsis. sELAM-1 concentrations at the onset of the study (day 0) were significantly higher in the nonsurviving patients than those in the survivors. MIP-1 alpha levels were significantly higher only on days 4 and 7. With regard to the measured plasma concentrations we believe that MIP-1 alpha is not a useful parameter for predicting patients' prognosis. The increase of sVCAM-1 might play a role in the pathogenesis of gram-positive sepsis; however, it could not be relied upon as an early prognostic parameter. The potential role of TGF-beta 2 in the development of gram-positive sepsis could not evaluated in the present study, whereas routine measurements of TGF-beta 2 offered no additional prognostic information.


Serological investigation on cattle vaccinated with a killed Brucella abortus strain 45/20 adjuvant vaccine.
Serum antibody reactions were monitored for a period of 18 months in 18 heifers which had been vaccinated with Brucella abortus Killed 45/20 adjuvant vaccine, using four standard serological procedures: the Rose Bengal, Serum agglutination, Complement fixation and Coombs antibovine globulin tests. The Rose Bengal and Serum agglutination tests were persistently negative during the experiment. Titres to the complement fixation test rose sharply for only four weeks after the second dose of the vaccine. Thereafter the titres fluctuated to positive levels at unpredictable intervals. One out of 14 heifers tested 12 months after vaccination was strongly positive to the complement fixation test but all the animals were absolutely negative at the end of the experiment. The Coombs test became strongly positive after the second dose of the vaccine for up to 34 weeks after primary vaccination. The animals were negative to the test at the end of the experimental period but some still retained suspicious titres. It was concluded that the Brucella abortus killed 45/20 adjuvant vaccine did not interfer stall with the Rose Bengal and Serum agglutination tests, that the fluctuations of the Complement fixation titres to positive levels at unpredictable intervals were undesirable and that the Coombs test showed little promise as an assay which would be used to differentiate antibody titres due to Brucella abortus Killed 45/20 adjuvant vaccine from those of natural infection. It would appear that the Complement fixation test and the Coombs antibovine globulin test could be safely used 12 and 18 months respectively, after immunization of cattle with the vaccine.


An investigation of the trade-off between the count level and image quality in myocardial perfusion SPECT using simulated images: the effects of statistical noise and object variability on defect detectability.
Quantum noise as well as anatomic and uptake variability in patient populations limits observer performance on a defect detection task in myocardial perfusion SPECT (MPS). The goal of this study was to investigate the relative importance of these two effects by varying acquisition time, which determines the count level, and assessing the change in performance on a myocardial perfusion (MP) defect detection task using both mathematical and human observers. We generated ten sets of projections of a simulated patient population with count levels ranging from 1/128 to around 15 times a typical clinical count level to simulate different levels of quantum noise. For the simulated population we modeled variations in patient, heart and defect size, heart orientation and shape, defect location, organ uptake ratio, etc. The projection data were reconstructed using the OS-EM algorithm with no compensation or with attenuation, detector response and scatter compensation (ADS). The images were then post-filtered and reoriented to generate short-axis slices. A channelized Hotelling observer (CHO) was applied to the short-axis images, and the area under the receiver operating characteristics (ROC) curve (AUC) was computed. For each noise level and reconstruction method, we optimized the number of iterations and cutoff frequencies of the Butterworth filter to maximize the AUC. Using the images obtained with the optimal iteration and cutoff frequency and ADS compensation, we performed human observer studies for four count levels to validate the CHO results. Both CHO and human observer studies demonstrated that observer performance was dependent on the relative magnitude of the quantum noise and the patient variation. When the count level was high, the patient variation dominated, and the AUC increased very slowly with changes in the count level for the same level of anatomic variability. When the count level was low, however, quantum noise dominated, and changes in the count level resulted in large changes in the AUC. This behavior agreed with a theoretical expression for the AUC as a function of quantum and anatomical noise levels. The results of this study demonstrate the importance of the tradeoff between anatomical and quantum noise in determining observer performance. For myocardial perfusion imaging, it indicates that, at current clinical count levels, there is some room to reduce acquisition time or injected activity without substantially degrading performance on myocardial perfusion defect detection.


Serum CCL-18 level is a risk factor for COPD exacerbations requiring hospitalization.
Chemokine (C-C motif) ligand 18 (CCL-18) has been shown to be elevated in chronic obstructive pulmonary disease (COPD) patients. This study primarily aimed to evaluate whether the serum CCL-18 level differentiates the frequent exacerbator COPD phenotype from infrequent exacerbators. The secondary aim was to investigate whether serum CCL-18 level is a risk factor for exacerbations requiring hospitalization. Clinically stable COPD patients and participants with smoking history but normal spirometry (NSp) were recruited for the study. Modified Medical Research Council Dyspnea Scale, COPD Assessment Test, spirometry, and 6-min walking test were performed. Serum CCL-18 levels were measured with a commercial ELISA Kit. Sixty COPD patients and 20 NSp patients were recruited. Serum CCL-18 levels were higher in COPD patients than those in NSp patients (169 vs 94 ng/mL, P<0.0001). CCL-18 level was significantly correlated with the number of exacerbations (r=0.30, P=0.026), although a difference in CCL-18 values between infrequent and frequent exacerbator COPD (168 vs 196 ng/mL) subgroups did not achieve statistical significance (P=0.09). Serum CCL-18 levels were significantly higher in COPD patients who had experienced at least one exacerbation during the previous 12 months. Overall, ROC analysis revealed that a serum CCL-18 level of 181.71 ng/mL could differentiate COPD patients with hospitalized exacerbations from those who were not hospitalized with a 88% sensitivity and 88.2% specificity (area under curve: 0.92). Serum CCL-18 level had a strong correlation with the frequency of exacerbations requiring hospitalization (r=0.68, P<0.0001) and was found to be an independent risk factor for hospitalized exacerbations in the multivariable analysis. CCL-18 is a promising biomarker in COPD, as it is associated with frequency of exacerbations, particularly with severe COPD exacerbations requiring hospitalization, as well as with functional parameters and symptom scores.


Food taxes and subsidies to protect health: relevance to Aotearoa New Zealand.
The hazardous and obesogenic food environment are major contributors to health loss in Aotearoa New Zealand. Here we consider the potential use of food taxes and subsidies to protect health in this country. We find that each one of the 14 recent systematic reviews on the tax and/or subsidy topic since 2015 in the scientific literature report that such interventions have favourable impacts from a health perspective. The New Zealand evidence we considered (n=12 studies since January 2010) is less definitive, but the pattern of results is consistent with the international evidence. Given this overall picture, the New Zealand Government should seriously consider such tax/subsidy interventions, potentially starting with a UK-style sugary drinks industry levy.


Central placenta praevia accreta with focal bladder percretism. Conservative management.
Placenta praevia is a condition when placenta is inserted in an abnormal position near or over the internal cervical orifice (ICO). Abnormal placental attachment (placenta accreta, increta, percreta) is a wide spectrum disorder ranging from abnormal adherence to deeply invasive placental tissue. We report a very rare case of central placenta praevia accreta and focal bladder percretism in a 29 years old pregnant woman with an obstetrical history of one previous vaginal delivery and four curettages following miscarriage. She was taken in charge by Catania S. Marco' university-hospital at 20 weeks with diagnosis of Central Placenta Praevia and Accreta (CPPA) detected by means of ultrasounds (US). At 31 weeks Magnetic Resonance Imaging (MRI) confirmed CPPA with focal bladder percretism. After alerting multidisciplinary team and obtaining blood units available, a Caesarean Section (CS) at 34 weeks was planned, when by means of US a detachment area with bleeding was observed. An adequate informed consent was completed, where the pregnant woman and her husband accepted the risk of possible hysterectomy and blood transfusions. A Pfannestiel's laparotomy with transversal corporal uterine incision, bilateral uterine ligation, packed tamponage, removal of placental tissue separated during fetal extraction and leaving a portion of placenta only in the place of percretism, allowed conservative intervention (uterus preservation) ending in good results for both mother and fetus. KEY WORDS: Caesarean section, Curettage, Placenta praevia, Placenta accreta, Preterm birth.


Statistical reflections on finding atypical cells.
In practice, the presence of atypical cells among leukocytes will only be recognized with reasonable certainty (greater than 95%) in a 100-cell differential if the percentage is five or more. With automated flow cytochemistry, the corresponding limit will usually be approximately 2.3%.


Examining response process validity of script concordance testing: a think-aloud approach.
This study investigated whether medical student responses to Script Concordance Testing (SCT) items represent valid clinical reasoning. Using a think-aloud approach students provided written explanations of the reasoning that underpinned their responses, and these were reviewed for concordance with an expert reference panel. A set of 12, 11 and 15 SCT items were administered online to Year 3 (2018), Year 4 (2018) and Year 3 (2019) medical students respectively. Students' free-text descriptions of the reasoning supporting each item response were analysed, and compared with those of the expert panel. Response process validity was quantified as the rate of true positives (percentage of full and partial credit responses derived through correct clinical reasoning); and true negatives (percentage of responses with no credit derived through faulty clinical reasoning). Two hundred and nine students completed the online tests (response rate = 68.3%). The majority of students who had chosen the response which attracted full or partial credit also provided justifications which were concordant with the experts (true positive rate of 99.6% for full credit; 99.4% for partial credit responses). Most responses that attracted no credit were based on faulty clinical reasoning (true negative of 99.0%). The findings provide support for the response process validity of SCT scores in the setting of undergraduate medicine. The additional written think-aloud component, to assess clinical reasoning, provided useful information to inform student learning. However, SCT scores should be validated on each testing occasion, and in other contexts.


Robust organic nanoparticles for noninvasive long-term fluorescence imaging.
Fluorescence imaging is a non-invasive imaging technique, which facilitates the visualization of sub-cellular components in cells with high sensitivity and selectivity. Up to now, only indocyanine green (ICG) has been approved as a diagnostic reagent for intravenous application. But the intrinsic disadvantage of ICG has spurred more research attention to exploit new fluorescent materials in imaging fields. In the last decade, many materials, including inorganic and organic materials, have been developed for fluorescence imaging. There are some reviews about fluorescence bioimaging. In this review, we will summarize and highlight the reported organic nanoparticles for noninvasive long-term bioimaging. According to the emitting mechanism, fluorescent nanoparticles obtained from fluorophores with aggregation-caused quenching and aggregation-induced emission features are discussed respectively. Finally, we come up with some key issues and challenges in the future and clinical translation.


Soft landings: dissolving a physician network.
Many healthcare organizations established physician networks to strengthen their competitive position in the marketplace. Many of these networks, however, have been unprofitable. As a result, some healthcare organizations are dissolving their networks. Healthcare organizations should plan the dissolution carefully and help the physicians establish an infrastructure for their new practices. By easing the physicians' transition to independent practice, healthcare organizations ensure the likelihood of a continued business relationship with the physicians in the future.


Hypophosphatemia Associated with Intravenous Iron Therapies for Iron Deficiency Anemia: A Systematic Literature Review.
Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia. The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US). A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs. The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as "asymptomatic" or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities. Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.


Mosquito Exposure and Chikungunya and Dengue Infection Among Travelers During the Chikungunya Outbreak in the Americas.
AbstractTravelers are at risk for arbovirus infection. We prospectively enrolled 267 Department of Defense beneficiaries traveling to chikungunya-outbreak regions in the Americas between December 2013 and May 2015 and assessed travel characteristics and serologic exposure to chikungunya virus (CHIKV) and dengue virus (DENV). Ten ill-returning travelers were also assessed retrospectively. Self-reported mosquito exposure was common (64% of 198 evaluable travelers saw mosquitoes; 53% of 201 reported ≥ 1 bite). Increased exposure was associated with active-duty travelers (odds ratio [OR] = 2.6 [1.3-5.4] for seeing mosquitoes) or travelers visiting friends and relatives (VFR) (OR = 3.5 [1.0-10.0] for high-intensity bite exposure). Arbovirus infection was defined as seroconversion on plaque reduction neutralization testing (PRNT) of pre- and posttravel sera. For ill subjects enrolled posttravel, infection was defined by a positive convalescent PRNT and/or a positive reverse transcription polymerase chain reaction for CHIKV or DENV. We identified seven cases of arbovirus infection: four with CHIKV, five with DENV, and two with both. The composite attack rate for CHIKV and DENV infection was 3.7% of 108 evaluable, immunologically naïve, prospectively assessed travelers; there was serologic and/or polymerase chain reaction evidence of arbovirus infection in three of four evaluable (three of 10 total) ill-returning travelers. We identified both symptomatic and asymptomatic cases. Military purpose of travel and VFR travel accounted for five of seven cases. Pretravel counseling is important and should target higher risk groups. Given a shared vector between CHIKV, DENV, and Zika virus (ZIKV), this study can also help guide counseling for travelers to ZIKV-outbreak regions.


Structure-solubility relationships in fluoride-containing phosphate based bioactive glasses.
The dissolution of fluoride-containing bioactive glasses critically affects their biomedical applications. Most commercial fluoride-releasing bioactive glasses have been designed in the soda-lime-silica system. However, their relatively slow chemical dissolution and the adverse effect of fluoride on their bioactivity are stimulating the study of alternative biodegradable materials with higher biodegradability, such as biodegradable phosphate-based bioactive glasses, which can be a good candidate for applications where a fast release of active ions is sought. In order to design new biomaterials with controlled degradability and high bioactivity, it is essential to understand the connection between chemical composition, molecular structure, and solubility in physiological fluids. Accordingly, in this work we have combined the strengths of various experimental techniques with Molecular Dynamics (MD) simulations, to elucidate the impact of fluoride ions on the structure and chemical dissolution of bioactive phosphate glasses in the system: 10Na2O-(45 -x)CaO-45P2O5-xCaF2, where x varies between 0-10 mol%. NMR and MD data reveal that the medium-range atomic-scale structure of these glasses is dominated by Q2 phosphate units followed by Q1 units, and the MD simulations further show that fluoride tends to associate with network modifier cations to form alkali/alkaline-earth rich ionic aggregates. The impact of fluoride on chemical dissolution of glasses has been studied in deionized water, acidic (pH = 3.0), neutral (pH = 7.4) and basic (pH = 9.0) buffer solutions, while the bioactivity and cytotoxicity of glasses has been studied in vitro through their apatite-forming ability in simulated body fluid (SBF) and cell culture tests on mesenchymal stem cells (MSCs), respectively. The macroscopic trends observed from various chemical dissolution and bioactivity studies are discussed on the basis of the effect of fluoride on the atomistic structure of glasses, such as F-induced phosphate network re-polymerization, in an attempt to establish composition-structure-property relationships for these biomaterials.


Evolution of Metastasis Study Models toward Metastasis-On-A-Chip: The Ultimate Model?
For decades, several attempts have been made to obtain a mimetic model for the study of metastasis, the reason of most of deaths caused by cancer, in order to solve the unknown phenomena surrounding this disease. To better understand this cellular dissemination process, more realistic models are needed that are capable of faithfully recreating the entire and essential tumor microenvironment (TME). Thus, new tools known as tumor-on-a-chip and metastasis-on-a-chip have been recently proposed. These tools incorporate microfluidic systems and small culture chambers where TME can be faithfully modeled thanks to 3D bioprinting. In this work, a literature review has been developed about the different phases of metastasis, the remaining unknowns and the use of new models to study this disease. The aim is to provide a global vision of the current panorama and the great potential that these systems have for in vitro translational research on the molecular basis of the pathology. In addition, these models will allow progress toward a personalized medicine, generating chips from patient samples that mimic the original tumor and the metastatic process to perform a precise pharmacological screening by establishing the most appropriate treatment protocol.