Migrating a research data warehouse to a public cloud: challenges and opportunities.
Clinical research data warehouses (RDWs) linked to genomic pipelines and open data archives are being created to support innovative, complex data-driven discoveries. The computing and storage needs of these research environments may quickly exceed the capacity of on-premises systems. New RDWs are migrating to cloud platforms for the scalability and flexibility needed to meet these challenges. We describe our experience in migrating a multi-institutional RDW to a public cloud. This study is descriptive. Primary materials included internal and public presentations before and after the transition, analysis documents, and actual billing records. Findings were aggregated into topical categories. Eight categories of migration issues were identified. Unanticipated challenges included legacy system limitations; network, computing, and storage architectures that realize performance and cost benefits in the face of hyper-innovation, complex security reviews and approvals, and limited cloud consulting expertise. Cloud architectures enable previously unavailable capabilities, but numerous pitfalls can impede realizing the full benefits of a cloud environment. Rapid changes in cloud capabilities can quickly obsolete existing architectures and associated institutional policies. Touchpoints with on-premise networks and systems can add unforeseen complexity. Governance, resource management, and cost oversight are critical to allow rapid innovation while minimizing wasted resources and unnecessary costs. Migrating our RDW to the cloud has enabled capabilities and innovations that would not have been possible with an on-premises environment. Notwithstanding the challenges of managing cloud resources, the resulting RDW capabilities have been highly positive to our institution, research community, and partners.


Anterior cruciate ligament reconstruction. Bone-patella tendon-bone versus semitendinosus anatomic reconstruction.
In this article, the long term (2-10 years; mean, 4.8 years) followup results of two reconstructive procedures for the anterior cruciate ligament are compared. The bone-patella tendon-bone (with interference fit fixation) was performed on 69 knees, and the semitendinosus anatomic reconstruction was performed on 68 knees, in a population of 76 men and 52 women (age range, 15-60 years; average, 31 years). The patients in the two groups showed no difference in subjective results or activity level and no significant difference to manual testing. The semitendinosus procedure group had a slightly higher KT manual maximum failure rate than the patella tendon group (17% versus 11%). Arthrometric stability did not show deterioration, but patient satisfaction decreased in those patients who had meniscectomies. Both procedures showed satisfactory results during the long term followup. However, if the secondary restraints are compromised, the stiffer bone-patella tendon-bone construct is preferred for reconstruction of the chronic anterior cruciate ligament deficient knee.


Lemildipine Merck and Co Inc.
Lemildipine is a 1,4-dihydropyridine calcium channel blocker which is under phase III development by Banyu (Merck and Co), in Japan, for its potential to treat hypertension and cerebrovascular ischemia. In one study, involving five patients with essential hypertension accompanied by cerebrovascular disorder, lemildipine, administered orally at doses of 5 to 20 mg/day, significantly lowered blood pressure and increased cerebral blood flow [256721]. Another study in 31 patients with essential hypertension demonstrated that lemildipine has significant pressure lowering effects without affecting serum lipids [256722]. Worldwide rights to market the drug have been assigned to Kowa in Japan.


Toward personalized treatment in multiple myeloma based on molecular characteristics.
To date, the choice of therapy for an individual multiple myeloma patient has been based on clinical factors such as age and comorbidities. The widespread evolution, validation, and clinical utilization of molecular technologies, such as fluorescence in situ hybridization and next-generation sequencing has enabled the identification of a number of prognostic and predictive biomarkers for progression-free survival, overall survival, and treatment response. In this review, we argue that in order to continue to improve myeloma patient outcomes incorporating such biomarkers into the routine diagnostic workup of patients will allow for the use of personalized, biologically based treatments.


One-way valve bottle contamination rates in the immediate post-functional endoscopic sinus surgery period.
Sinonasal saline irrigation has become an accepted practice in the immediate postoperative management of functional endoscopic sinus surgery (FESS) patients. Recent studies have found that valveless delivery systems of sinonasal irrigation are colonized with bacteria. An alternative delivery system uses a one-way valve to reduce saline backflow and may limit bottle contamination. Our sole objective was to determine whether this system in post-FESS patients eliminates microbial bottle contamination. Eight patients undergoing FESS were given one-way valve irrigation bottles to use immediately after surgery. Bottles were collected after 1 week of use and another set of bottles after an additional week. Endoscopic-directed cultures of the middle meatus were performed at the time of surgery. Returned used bottles were swabbed for bacteria and the valve system of the bottle was analyzed under scanning electron microscopy (SEM) for the presence of bacteria. All sinus swabs collected at the time of surgery grew bacteria with Staphylococcus sp. present in all samples. After the 1st week of use, 5/8 bottles grew bacterial cultures and showed bacterial presence on the valves by SEM. After the 2nd week, 4/5 bottles had positive culture results and also showed bacterial presence on the valves by SEM. Despite commercial claims that the use of valves and limit of backflow into the bottle will eliminate contamination, our study showed that one-way valve delivery systems become contaminated with bacteria after 1 week of use. We also showed that the bottle valves themselves harbor bacteria after 1 week of use.


Tissue changes around loose prostheses. A canine model to investigate the effects of an antiinflammatory agent.
The aseptically loosened prosthesis provided a means for investigating the in vivo and in vitro activity of the cells associated with the loosening process in seven dogs. The cells were isolated and maintained in culture for sufficient periods of time so that their biologic activity could be studied as well as the effect of different agents added to the cells in vivo or in vitro. The biologic response as determined by interleukin-1 and prostaglandin E2 activity paralleled the roentgenographic appearance of loosening and the technetium images and observations made at the time of revision surgery. The correlation between clinical, roentgenographic, histologic, and biochemical loosening indicates that the canine model is suitable for investigating the mechanisms of prosthetic failure. A canine model permits the study of possible nonsurgical therapeutic interventions with the ultimate hope of stopping or slowing the loosening process.


Mechanical strain of alveolar type II cells in culture: changes in the transcellular cytokeratin network and adaptations.
Mechanical forces exert multiple effects in cells, ranging from altered protein expression patterns to cell damage and death. Despite undisputable biological importance, little is known about structural changes in cells subjected to strain ex vivo. Here, we undertake the first transmission electron microscopy investigation combined with fluorescence imaging on pulmonary alveolar type II cells that are subjected to equibiaxial strain. When cells are investigated immediately after stretch, we demonstrate that curved cytokeratin (CK) fibers are straightened out at 10% increase in cell surface area (CSA) and that this is accompanied by a widened extracellular gap of desmosomes-the insertion points of CK fibers. Surprisingly, a CSA increase by 20% led to higher fiber curvatures of CK fibers and a concurrent return of the desmosomal gap to normal values. Since 20% CSA increase also induced a significant phosphorylation of CK8-ser431, we suggest CK phosphorylation might lower the tensile force of the transcellular CK network, which could explain the morphological observations. Stretch durations of 5 min caused membrane injury in up to 24% of the cells stretched by 30%, but the CK network remained surprisingly intact even in dead cells. We conclude that CK and desmosomes constitute a strong transcellular scaffold that survives cell death and hypothesize that phosphorylation of CK fibers is a mechano-induced adaptive mechanism to maintain epithelial overall integrity.


Health and well-being of children with congenital cardiac malformations, and their families, following open-heart surgery.
Infants who survive open-heart surgery are at risk for developmental disability, which may impact on the well-being not only of the child, but also the family. The objective of our prospective study, therefore, was to determine the long-term health-related quality of life of children with congenital cardiac malformations following open-heart surgery, and to describe the persisting level of stress in their families. To this end, 49 parents completed the Child Health Questionnaire, the Parenting Stress Index, and the Child Behaviour Checklist as part of a developmental follow-up protocol when their child was 5 years of age. Mean scores on the Child Health Questionnaire were in the normal range, with physical well-being equal to 53.5, psychosocial well-being 50.9, with only 6.4 percent and 8.5 percent of subjects, respectively, falling within the suboptimal range of less than 40. The distribution of scores on the Parenting Stress Index, however, were more variable, with over one-quarter of parents indicating a high level of stress, with almost one-fifth having low levels of stress, and just over half scoring in the normal range, with the group mean being 52.6 plus or minus 32.3. An abnormal neurologic examination before surgery was associated with lower physical health (beta equal to -5.5, p equal to 0.02, r2 equal to 0.18), whereas lower arterial saturations of oxygen, less than 85 percent preoperatively, was associated with lower psychosocial health (beta equal to -6.6, p equal to 0.01, and r(2) equal to 0.14). The internalizing and externalizing behaviours of the child were significantly correlated with psychosocial well being, with r ranging from -0.32 to -0.52, and p less than 0.05. Parental stress also correlated with psychosocial health (r equal to -0.48 and p equal to 0.0009). Overall, the perception by the parents of the health-related quality of life of their child is favourable 5 years following open-heart surgery during infancy. Many parents, nonetheless, continue to feel either stressed or defensive about their child, particularly if their child exhibits behavioural difficulties. Our findings suggest that strategies need to be considered to enhance family well-being in the planning and delivery of health services to this population at high risk.


Human T cell activation. III. Rapid induction of a phosphorylated 28 kD/32 kD disulfide-linked early activation antigen (EA 1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens.
With human T cells activated by 12-o-tetradecanoyl phorbol-13-acetate (TPA) as immunogen, an IgG2a mAb, early activation antigen 1 (EA 1), was generated against a 60-kD protein with disulfide-linked 28-kD and 32-kD subunits. Both subunits were phosphorylated. The antigen, EA 1, was readily detected on approximately 60% of isolated and cryopreserved thymocytes, as determined by indirect immunofluorescence. A low level of EA 1 expression was detectable on 6-7% of blood lymphocytes. TPA-activated T cells expressed EA 1 as early as 30 min after activation. By 1 h, 85-90% of the T cells stained with mAb EA 1. By 3-4 h, the expression of EA 1 was detected in greater than 95% of the T cells. Although the percentages of EA 1+ T cells did not change, the intensity of staining increased slightly. After 18-24 h, both the percentage of EA 1+ cells and the intensity of staining decreased gradually. TPA-induced EA 1 expression was independent of monocytes. EA 1 expression was slightly delayed in T cells that were isolated without the rosette selection and treated with TPA. Nevertheless, greater than 85% of these T cells expressed EA 1 within 1 h, and the maximal number of EA 1+ T cells was also detected at 3-4 h. In T cell populations with 1-2% monocytes, about 50-90% of the PHA- or Con A-activated T cells expressed EA 1 with a slower kinetics. EA 1 expression preceded that of IL-2-R in these activation processes. Similarly, T cells activated by soluble antigens (tetanus toxoid and PPD) and alloantigens in MLR also expressed EA 1 after a longer incubation. Approximately 20% of the T cells stained for EA 1 at day 6. EA 1 expression was not limited to activated T cells. B cells activated by TPA or anti-IgM antibody plus B cell growth factor expressed EA 1. The kinetics of EA 1 expression was markedly slower and the staining was less intense. Repeated attempts to detect EA 1 on resting and TPA-activated monocytes and granulocytes have not been successful. However, the detection of EA 1 in nonlymphoid cell lines would indicate that EA 1 may have a broader cell distribution. EA 1 expression was due to de novo synthesis, as the induction of EA 1 was blocked by cycloheximide and actinomycin D.(ABSTRACT TRUNCATED AT 400 WORDS)


Peer and parent influences on youth skateboarding and factors that affect their decision to return to the sport after injury.
Skateboarding is an increasingly popular sport among youth, despite the fact that they are a high-risk group for injuries during this activity. The purpose of this study was twofold: to explore youths' perceptions about the influences that peers and parents have on their skateboarding; and to identify factors that affect their decisions about returning to the sport after injury. Virtual semi-structured interviews were conducted with 26 youth, 14-17 years of age, who had experienced a medically-treated injury while skateboarding during the past year. Applying thematic analyses, major findings indicated that sharing the activity with peers fosters psychological well-being, companionship, and a valued sense of community that motivates return to the sport even after serious injury and sometimes before they are fully physically ready to do so safely. Parental concerns about physical injury (vulnerability, severity) were acknowledged but not influential, with youth feeling that parents do not appreciate the valued mental health benefits that they experience from the skateboarding community. Youth reported withholding injury information from parents, hiding injuries and downplaying their severity, and not always disclosing returning to the sport. Youths' decisions to return to the sport after injury was motivated by their feelings that skateboarding enhances their sense of identity, promotes their mental health, and provides respite because it allows them to escape from reality temporarily. Recommendations for reducing risk of injury to youth skateboarders at skateparks are provided.


Diazotrophy under continuous light in a marine unicellular diazotrophic cyanobacterium, Gloeothece sp. 68DGA.
Nitrogenase is extremely sensitive to molecular oxygen (O(2)), and unicellular diazotrophic cyanobacteria separate nitrogen (N(2))-fixation and photosynthesis to protect nitrogenase from O(2) produced by photosynthesis. When grown under 12 h light/12 h dark cycles (LD), the marine unicellular diazotrophic cyanobacterium Gloeothece sp. 68DGA expressed the nitrogenase protein and its activity (acetylene reduction activity) only during the dark phase. However, this strain was able to grow diazotrophically under continuous light (CL). To determine whether nitrogenase synthesis and N(2)-fixation are temporally separated from photosynthesis in the Gloeothece cells that have fully acclimated to CL, the proportion of cells containing nitrogenase (the Fe-protein of nitrogenase) in the culture was measured using an immunocytochemical technique. Cells were grown in a continuous-culture device to maintain constant cell density. Under LD, the cells showed diurnal oscillation of nitrogenase activity, photosynthesis, respiration and the expression and the abundance of the Fe-protein. The oscillation was gradually reduced after the transfer of the cells to CL, and was lost after 23-25 days of cultivation under CL. In CL-acclimated cultures, the Fe-protein was always detected in about 94 % of the cells, although the nitrogenase activity was about one-third of the maximum activity in LD-acclimated cultures. These results suggest that synthesis of nitrogenase proceeds without diurnal oscillation in the CL-acclimated cells of Gloeothece sp. 68DGA. As the respiration rate in CL-acclimated culture was as high as the maximum rate observed in LD-acclimated culture, O(2)-uptake mechanism(s) may have been upregulated to maintain low intracellular pO(2).


There Is No Significant Difference in Fretting and Corrosion at the Trunnion of Metal and Ceramic Heads.
No study has compared the prevalence of fretting and corrosion at the trunnion of cobalt-chrome (Co-Cr) and zirconia ceramic heads in the same patients. The authors sought to compare the prevalence of fretting and corrosion at the trunnion after total hip arthroplasty with a 32-mm Co-Cr or a 32-mm zirconia ceramic head-on-polyethylene bearing. Isolated revision of the ace-tabular components was performed in 78 patients (156 hips) for polyethylene wear and osteolysis of the acetabulum. Seventy-eight Co-Cr head-titanium alloy stem pairs were compared with 78 zirconia ceramic head-titanium alloy stem pairs in the same patients. Using a visual scoring technique, the 156 head-stem pairs were analyzed for the prevalence of fretting and/or corrosion at the trunnion of the stem and the prevalence of metal transfer to the inner taper of the femoral head. Mean patient age was 48 years, and there were 65 men and 13 women. There was no trunnionosis in either group. Prevalence of fretting (81% vs 83%) and corrosion (4% vs 3%) at the trunnion was not significantly different (P=.518 vs .612, respectively) between the 2 groups. The median fretting scores (1.4±1.1 vs 1.2±1.4 points) and corrosion scores (1.2±0.8 vs 1.3±0.9 points) at the trunnion were not significantly different (P=.893 vs .781, respectively) between the 2 groups. Prevalence of metal transfer to the inner taper of the femoral head (8% vs 10%) and the median metal transfer scores (1.2±0.9 vs 1.4±1.1 points) were not significantly different (P=.213 vs .729, respectively) between the 2 groups. [Orthopedics. 2019; 42(1):e99-e103.].


Strategy of Daiichi Sankyo discovery research in oncology.
We would like to introduce Daiichi Sankyo's approach to developing cancer targeted medicines with special reference to the drug discovery strategy, global discovery activities and external research collaboration leading to generation of innovative drugs for cancer patients. We are developing 14 clinical projects for cancer treatment and three of them have been previously approved. These are mostly targeted for growth and survival signals of cancer cells. To overcome the drug resistance mechanism derived from the heterogeneous nature of cancer, we are developing selective inhibitors in three major clusters of signal pathways which may allow future rational combinations of oncology products. In addition to the main research facility in Japan, research sites in the EU and the USA provide us with different technical expertise and diversified ideas of drug discovery. To access novel drug targets, we are facilitating research collaboration with leading academia and successful cancer research scientists. In conclusion, we intend to focus more on developing innovative personalized medicines for better treatment of cancer.


Distinct MEG correlates of conscious experience, perceptual reversals and stabilization during binocular rivalry.
During binocular rivalry, visual perception alternates spontaneously between two different monocular images. Such perceptual reversals are slowed or halted if stimuli are presented intermittently with inter-stimulus intervals larger than ~400 ms--a phenomenon called stabilization. Often, the neural correlates of reversal and stabilization are studied separately, and both phenomena in turn are studied separately from the neural correlates of conscious perception. To distinguish the neural correlates of perceptual content, stabilization and reversal, we recorded MEG signals associated with each in the same group of healthy humans observing repeated trials of intermittent presentation of a dichoptic stimulus. Perceptual content correlated mainly with modulation of stimulus-specific activity in occipital/temporal areas 150-270 ms after stimulus onset, possibly reflecting inhibition of the neural populations representing the suppressed image. Stability of perception reflected a gradual build-up of this modulation across at least 10 trials and was also, to some extent, associated with parietal activity 40-90 ms and 220-270 ms after stimulus onset. Perceptual reversals, in contrast, were associated with parietal (150-270 ms) and temporal (150-210 ms) activity on the trial before the reversal and a gradual change in perception-specific activity in occipital (150-270 ms) and temporal (220-420 ms) areas across at least 10 trials leading up to a reversal. Mechanistically, these findings suggest that stability of perception during rivalry is maintained by modulation of activity related to the two monocular images, and gradual adaptation of neuronal populations leads to instability that is eventually resolved by signals from parietal and late sensory cortices.


Lactose metabolism by Staphylococcus aureus: characterization of lacABCD, the structural genes of the tagatose 6-phosphate pathway.
The nucleotide and deduced amino acid sequences of the lacA and lacB genes of the Staphylococcus aureus lactose operon (lacABCDFEG) are presented. The primary translation products are polypeptides of 142 (Mr = 15,425) and 171 (Mr = 18,953) amino acids, respectively. The lacABCD loci were shown to encode enzymes of the tagatose 6-phosphate pathway through both in vitro studies and complementation analysis in Escherichia coli. A serum aldolase assay, modified to allow detection of the tagatose 6-phosphate pathway enzymes utilizing galactose 6-phosphate or fructose phosphate analogs as substrate, is described. Expression of both lacA and lacB was required for galactose 6-phosphate isomerase activity. LacC (34 kDa) demonstrated tagatose 6-phosphate kinase activity and was found to share significant homology with LacC from Lactococcus lactis and with both the minor 6-phosphofructokinase (PfkB) and 1-phosphofructokinase (FruK) from E. coli. Detection of tagatose 1,6-bisphosphate aldolase activity was dependent on expression of the 36-kDa protein specified by lacD. The LacD protein is highly homologous with LacD of L. lactis. Thus, the lacABCD genes comprise the tagatose 6-phosphate pathway and are cotranscribed with genes lacFEG, which specify proteins for transport and cleavage of lactose in S. aureus.


Working memory for meaningless manual gestures.
Effects on working memory performance relating to item similarity have been linked to prior categorisation of representations in long-term memory. However, there is evidence from gesture processing that this link may not be obligatory. The present study investigated whether working memory for incidentally generated meaningless manual gestures is influenced by formational similarity and whether this effect is modulated by working-memory load. Results showed that formational similarity did lower performance, demonstrating that similarity effects are not dependent on prior categorisation. However, this effect was only found when working-memory load was low, supporting a flexible resource allocation model according to which it is the quality rather than quantity of working memory representations that determines performance. This interpretation is in line with proposals suggesting language modality specific allocation of resources in working memory.


GrouseFlocks: steerable exploration of graph hierarchy space.
Several previous systems allow users to interactively explore a large input graph through cuts of a superimposed hierarchy. This hierarchy is often created using clustering algorithms or topological features present in the graph. However, many graphs have domain-specific attributes associated with the nodes and edges, which could be used to create many possible hierarchies providing unique views of the input graph. GrouseFlocks is a system for the exploration of this graph hierarchy space. By allowing users to see several different possible hierarchies on the same graph, the system helps users investigate graph hierarchy space instead of a single fixed hierarchy. GrouseFlocks provides a simple set of operations so that users can create and modify their graph hierarchies based on selections. These selections can be made manually or based on patterns in the attribute data provided with the graph. It provides feedback to the user within seconds, allowing interactive exploration of this space.


Accounting for Selectivity Bias and Correlation Across the Sequence From Elevated Blood Pressure to Hypertension Diagnosis and Treatment.
It is unknown whether efforts to reduce hypertension burden in countries with very high prevalence, would be more effective if directed at hypertension diagnosis vs. treatment. Most analyses do not address bias and correlation across the sequence from elevated blood pressure (BP) to hypertension diagnosis and treatment, leading to potentially misleading findings. Using data spanning 18 years of the China Health and Nutrition Survey (n = 18,926; ages 18-75 years), we used an innovative 3-step, integrated system of equations to predict the sequence from: (i) elevated BP (systolic/diastolic BP ≥ 140/90 mm Hg) to (ii) diagnosed hypertension conditional on elevated BP, and to (iii) treatment (medication use) conditional on diagnosis, accounting for measured and unmeasured individual- and community-level confounders at each of the 3 steps. We compared results to separate traditional logistic regression models without control for unmeasured confounding. Using our 3-step model, elevated BP increased from 12.6% and 8.5% (1991) to 36.8% and 29% (2009) in men and women, respectively, but diagnosis remained under 50%. We found widening disparities in hypertension diagnosis (higher hypertension at lower vs. higher education (difference of 2% in 1991 that widened to 5% in 2009)) and narrowing disparities in education (difference of 6% in 1991 to 4% in 2009) and insurance status (difference of 7% in 1991 to 2% in 2009) for treatment. Our 3-step model improved model fit over traditionally used models. Our findings highlight serious barriers to hypertension diagnosis in Chinese adults, particularly among men and individuals of low attained education.


Optimising the design of preliminary toxicity studies for pharmaceutical safety testing in the dog.
A working party, comprising two animal welfare organisations and some 12 pharmaceutical companies in Europe, was established to minimise the use of the dog in safety testing. As first step, the participants defined the major objectives of preliminary dose-range finding/MTD toxicity studies in non-rodents, defined the principles and requirements for this study type and agreed on a proposal for an optimised study design, based on collective experience of conducting such studies in industry, involving an evaluation of 100 individual study data sets. The suggested study design is explained and described, and reflects current best practice in the pharmaceutical industry in Europe. The implementation of such an optimised design is believed to result in a reduction in the overall numbers of animals used for this purpose, without jeopardising the scientific rationale and usefulness of the studies for informing the conduct of later regulatory studies.


[A device for feminine urinary incontinence].
Urinary incontinence is grave health problem which causes severe repercussions in the quality of life of those patients which suffer it and it is a serious risk factor in the development of pressure sores or ulcers. Urinary collecting sacks provide an option to deal with this problem even though up to present time these collecting sacks were only available for male patients. In this instrument usage article, the authors introduce a new device, VILUC, commercialized by Lauclar Laboratories in Spain, for feminine urinary incontinence as a possible alternate treatment for women affected by this problem who are incapable of maintaining a progressive and complete vesicle reeducation. The authors inform about how to install this device, its different components, how to care for it and the indications for its use in females who suffer from incontinence.


Ultrasound assessment of uterine disorders.
Around the time of menopause many women develop disorders of the uterus that may cause abnormal bleeding and other troublesome symptoms. Some of these disorders, such as uterine polyps, are typically benign and easily correctable. Others, such as endometrial cancer, are potentially more serious. This article discusses the etiology, diagnosis and treatment of some common uterine disorders, with special emphasis on their sonographic appearance.


Indicator Layers Based on Ethylene-Vinyl Acetate Copolymer (EVA) and Dicyanovinyl Azobenzene Dyes for Fast and Selective Evaluation of Vaporous Biogenic Amines.
The article presents naked-eye methods for fast, sensitive, and selective detection of isopentylamine and cadaverine vapours based on 4-N,N-dioctylamino-4'-dicyanovinylazobenzene (CR-528) and 4-N,N-dioctylamino-2'-nitro-4'-dicyanovinylazobenzene (CR-555) dyes immobilized in ethylene-vinyl acetate copolymer (EVA). The reaction of CR-528/EVA and CR-555/EVA indicator layers with isopentylamine vapours caused a vivid colour change from pink/purple to yellow/orange-yellow. Additionally, CR-555/EVA showed colour changes upon exposure to cadaverine. The colour changes were analysed by ultraviolet⁻visible (UV/VIS) molecular absorption spectroscopy for amine quantification, and the method was partially validated for the detection limit, sensitivity, and linear concentration range. The lowest detection limits were reached with CR-555/EVA indicator layers (0.41 ppm for isopentylamine and 1.80 ppm for cadaverine). The indicator layers based on EVA and dicyanovinyl azobenzene dyes complement the existing library of colorimetric probes for the detection of biogenic amines and show great potential for food quality control.


Quality-of-life and body image impairments in patients with lymphedema.
The psychological and social consequences of chronic lymphedema are still often overlooked, as is the frequency with which they occur. Secondary lymphedema after mastectomy or breast-conservation procedures following the diagnosis of breast cancer is especially common and represents a substantial problem for those affected. The aim of this study was to investigate differences in body image and quality of life (QOL) between female lymphedema patients and trauma patients and to further monitor the changes in female lymphedema patients during three weeks of rehabilitation. This survey was conducted on 80 female patients at the State Hospital of Wolfsberg/Carinthia, Austria, 40 were trauma patients and the other 40 patients had some type of lymphedema, 20 of these patients were located in the general lymphedema ward and 20 in rehabilitation. The Frankfurt Body Image Questionnaire was used to determine body image, and the German version of the Short Form-36 Health Survey was used to determine QOL. The results indicate that female lymphedema patients are greatly affected in various areas of body image and QOL. Lymphedema patients show significantly lower body image scores in seven of nine areas compared to trauma patients. Female lymphedema patients also describe their QOL as being lower in the areas of general health perception, vitality and mental well-being. After rehabilitation, there were improvements in the evaluation of physical functioning and an increased acceptance of the body. Patients also showed a significant increase in health perception, vitality and mental health.


Income Timing and Liquidity Constraints: Evidence from a Randomized Field Experiment.
People in developing countries sometimes desire deferred income streams, which replace more-frequent income flows with a single, later lump sum. We study the effects of short-term wage deferral using a randomized experiment with participants in a temporary cash-for-work program. Workers who are assigned to lump-sum payments are five percentage points more likely to purchase a high-return investment. We discuss the role of both barriers to saving and credit constraints in explaining our results. While stated preferences for deferred payments suggest a role for savings constraints, the evidence is also consistent with a simpler model of credit constraints alone.


Two-dimensional structure of the light-harvesting chlorophyll a/b complex by cryoelectron microscopy.
The light-harvesting chlorophyll a/b complex (LHC-II) found in green plants has at least three functions: it absorbs light energy for transfer to the reaction centers, it is involved in keeping the photosynthetic membranes stacked, and it regulates energy distribution between the two photosystems. We have developed a procedure to produce large vesicles consisting almost exclusively of two-dimensional crystalline domains of LHC-II in which LHC-II is biochemically and structurally intact, as shown by SDS-PAGE, response to cations, and 77K fluorescence excitation spectra. The vesicles were examined by cryoelectron microscopy and analyzed, in projection, to a resolution of 17 A. Their surface lattice consists of trimers arranged in interlocking circles; the two-sided plane group is p321 (unit cell dimension, a = 124 A) with two, oppositely facing trimers/unit cell. Individual trimers consist of matter arranged in a ring, around a central cavity, an appearance similar to that obtained in some conditions using negative stain (Li, J., 1985. Proc. Natl. Acad. Sci. USA. 82:386-390). The monomer (approximately 45 x 20 A) is seen as two domains of slightly different size at this resolution. The thickness of single layers is approximately 48 A, measured from edge-on views of the frozen vesicles. Based on these dimensions, the molecular mass of the monomer is approximately 30 kD. Therefore, each monomer appears to be composed of a single polypeptide and its associated pigments.


The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease.
Macronutrient and micronutrient deficiencies are very common in the general population and may be even more common in patients with hypertension and cardiovascular disease due to genetic, environmental causes and prescription drug use. The Hypertension Institute in Nashville, TN, has evaluated micronutrient deficiencies and oxidation status, in a group of hypertensive versus normotensive patients. There are significant differences in numerous intracellular micronutrients and oxidation status between these two groups. Replacement of the micronutrient deficiencies, as well as high-dose therapy of selected nutraceuticals in combination with optimal diet, exercise and weight management resulted in control of blood pressure to goal levels in 62% of the hypertensive population (as defined by JNC 7) over a period of 6 months with complete tapering and discontinuation of antihypertensive drugs. These deficiencies will have an enormous impact on present and future cardiovascular health and outcomes such as hypertension, myocardial infarction, stroke and renal disease and overall health costs. It is estimated that the annual savings in drug costs alone for the treatment of hypertension could be as much as US$10 billion. Diagnosis and treatment of these nutrient deficiencies and improvement in oxidation status using functional intracellular assessments will reduce blood pressure, improve vascular health, endothelial dysfunction, vascular biology and cardiovascular events. Vascular biology assumes a pivotal role in the initiation and perpetuation of hypertension and target organ damage sequelae. Endothelial activation, oxidative stress, inflammation and vascular smooth muscle dysfunction are initial events that start hypertension. Nutrient-gene interactions determine a broad array of phenotypic consequences such as vascular problems and hypertension. Optimal nutrition, nutraceuticals, vitamins, antioxidants, minerals, weight loss, exercise, smoking cessation and moderate restriction of alcohol and caffeine in addition to other lifestyle modifications can prevent and control hypertension in many patients. An integrative approach combining these lifestyle suggestions with the correct pharmacologic treatment will best achieve new goal blood pressure levels, reduce cardiovascular risk factors, improve vascular biology and vascular health, reduce cardiovascular target organ damage and reduce healthcare expenditure. The expanded scientific roles for nutraceutical supplements are discussed in relation to the prevention and treatment of essential hypertension and cardiovascular diseases with emphasis on mechanisms of action and clinical integration with drug therapy with hypertension guidelines. It is the purpose of this paper to review only the hypertension clinical trials that have evaluated the clinical use and efficacy of nutrition, weight loss, exercise and selected nutritional supplements, vitamins, minerals and antioxidants. Numerous clinical trials have evaluated the use of nutritional supplements such as beta carotene, selenium, vitamin C and vitamin E in the prevention of coronary heart disease and stroke yielding conflicting results (positive, neutral and negative). In many of these clinical trials there are enormous clinical design problems, methodologic flaws, varied patient population, variable dose and type of vitamin use, improper selection of vitamin used and many other issues that make the studies difficult to interpret. It is beyond the scope of this paper to review these trials. The reader is referred to the vast literature on this subject.


Reducing hepatic endoplasmic reticulum stress ameliorates the impairment in insulin signaling induced by high levels of β-hydroxybutyrate in bovine hepatocytes.
Ketotic dairy cows exhibit a state of negative energy balance (NEB) characterized by elevated circulating levels of β-hydroxybutyrate (BHB) and fatty acids. Impaired hepatic insulin signaling in dairy cows occurs frequently during the transition into lactation, but its role on liver function during this period is not well known. In nonruminants, endoplasmic reticulum (ER) stress is a causal factor contributing to impaired insulin signaling in the liver. Thus, the aim of this study was to investigate the status of hepatic insulin and ER stress signaling and whether ER stress contributes to impaired insulin signaling in dairy cows with ketosis. Healthy (control cows, n = 10, BHB ≤0.6 mM) and ketotic (ketotic cows, n = 10, BHB ≥1.2 mM) cows at 3 to 10 d in milk were selected for liver biopsy and blood sampling before feeding. In vitro experiments were conducted with isolated hepatocytes from 5 healthy calves (1 d old, fasted female, 30-40 kg of body weight). Treatments included BHB (0, 0.9, 1.8, 3.6 mM), tauroursodeoxycholic acid (TUDCA, a canonical inhibitor of ER stress), and different incubation times (0.5, 1, 2, 3, 5, 7, 9, or 12 h). Ketotic cows had lower daily milk yield (median: 29.50 vs. 23.00 kg), higher plasma nonesterified fatty acid (NEFA) (median: 0.33 vs. 1.17 mM), BHB (median: 0.43 vs. 3.22 mM), aspartate aminotransferase (median: 70.58 vs. 155.70 U/L), alanine aminotransferase (median: 18.31 vs. 37.90 U/L), lower plasma glucose (median: 4.32 vs. 2.37 mg/dL), and revised quantitative insulin sensitivity check index (median: 0.39 vs. 0.37) compared with healthy cows. Increased abundance of phosphorylated insulin receptor substrate-1 (IRS1) and decreased abundance of phosphorylated protein kinase B (AKT) and glycogen synthase kinase-3β (GSK3β) in ketotic cows indicated a state of insulin resistance. In addition, abundance of phosphorylated protein kinase RNA-like ER kinase (PERK) and inositol requiring protein-1α (IRE1α), and cleavage of activating transcription factor-6 (ATF6) were greater in the liver of ketotic cows. In vitro, at the early stages of incubation, treatment with BHB upregulated abundance of phosphorylated of IRE1α, PERK, and the cleavage of ATF6, as well as several unfolded protein response genes [X-box-binding protein-1 (XBP1), 78 kDa glucose-regulated protein (GRP78), and C/EBP homologous protein (CHOP)]. Furthermore, in response to increasing doses of BHB, the phosphorylation level of PERK, IRE1α, and the cleavage of ATF6, and the abundance of XBP1, GRP78, and CHOP increased. In addition, BHB treatment increased phosphorylation of IRS1 and decreased phosphorylation of AKT and GSK3β, and upregulated abundance of gluconeogenic genes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase). Importantly, these changes were reversed by inhibiting ER stress with TUDCA treatment. Overall, the present study indicated that reversing ER stress during ketosis might help alleviate hepatic insulin resistance. Targeting ER stress may represent a potential therapeutic target for controlling the negative aspects of ketosis on liver function.


Extraordinary Diversity in the Origins of Sex Chromosomes in Anurans Inferred from Comparative Gene Mapping.
Sex determination in frogs (anurans) is genetic and includes both male and female heterogamety. However, the origins of the sex chromosomes and their differentiation processes are poorly known. To investigate diversity in the origins of anuran sex chromosomes, we compared the chromosomal locations of sex-linked genes in 4 species: the African clawed frog (Xenopus laevis), the Western clawed frog (Silurana/X. tropicalis), the Japanese bell-ring frog (Buergeria buergeri), and the Japanese wrinkled frog (Rana rugosa). Comparative mapping data revealed that the sex chromosomes of X. laevis, X. tropicalis and R. rugosa are different chromosome pairs; however, the sex chromosomes of X. tropicalis and B. buergeri are homologous, although this may represent distinct evolutionary origins. We also examined the status of sex chromosomal differentiation in B. buergeri, which possesses heteromorphic ZW sex chromosomes, using comparative genomic hybridization and chromosome painting with DNA probes from the microdissected W chromosome. At least 3 rearrangement events have occurred in the proto-W chromosome: deletion of the nucleolus organizer region and a paracentric inversion followed by amplification of non-W-specific repetitive sequences.


Idiopathic thrombocytopenic purpura presenting in a high school football player: a case report.
To alert athletic trainers to the signs and symptoms of idiopathic thrombocytopenic purpura and its clinical presentation in order to facilitate immediate intervention. Idiopathic thrombocytopenic purpura (ITP), also known as immune thrombocytopenic purpura, is a hemorrhagic disorder that is primarily immunologic in origin but is sometimes triggered by viral infection in children. It has also been associated with heroin and quinine drug use. A reduced platelet count can result in mucosal or deep tissue bleeding, or both, and most importantly, intracranial bleeding. Because football is a collision sport, it is imperative that any player presenting with ITP-type symptoms be removed immediately from all contact and referred to a physician. Leukemia, aplastic anemia, drug side effects, vitamin deficiency, kidney failure, infection, multiple contusions. The traditional first-line treatment consists of corticosteroid medication and time and removal from all physical activities until the blood platelet count is normal and controlled. In quinine-induced ITP, discontinuation of the drug and bedrest are recommended to reduce the risk of major hemorrhage for a 12-to 14-hour period in order to allow the quinine to clear the system and the platelet count to return to normal. ITP's presentation needs to be differentiated from other disorders. Incorrect diagnosis could seriously jeopardize the athlete, who could develop intracranial and internal bleeding. Recognition of the signs and symptoms associated with ITP is essential to prevent further participation by the athlete. Immediate intervention is needed to determine the severity and to institute appropriate treatment.


Prenatal vitamin B12 status and cognitive functioning in children at 4 years of age: The ECLIPSES Study.
Maternal vitamin B12 deficiency has been associated with disturbed cognitive functioning in offspring at different ages during childhood. However, this association has not been explored in pre-school-age children. The objective of this study was to examine the association between maternal vitamin B12 levels at the beginning and end of pregnancy and cognitive functioning in their children at 4 years of age. This longitudinal prospective study included a subsample of pregnant women and their children aged 4 years (n = 249) who participated in the ECLIPSES Study conducted in the province of Tarragona, Spain, from 2013 to 2017. Maternal vitamin B12 concentrations were determined in the first and third trimesters, and sociodemographic, nutritional and psychological data were collected. The children's cognitive functioning was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) and subtests of the Neuropsychological Assessment of Development (NEPSY-II). The multivariable models showed a significant relationship between vitamin B12 and the working memory index in the first trimester of the pregnancy but not in the third trimester. Children of mothers in the second vitamin B12 level tertile (314-413 pg/mL) (β = 6.468, 95% confidence interval [CI]: = 2.054, 10.882, p = 0.004) and third vitamin B12 level tertile (≥414 pg/mL) (β = 4.703, 95% CI: = 0.292, 9.114, p = 0.037) scored higher in the working memory index of the WPPSI-IV than the children of mothers with vitamin B12 levels in the first tertile (<314 pg/mL). Maintaining an adequate level of maternal vitamin B12 during early pregnancy contributes to improved performance in childhood working memory at 4 years of age.


Implications of COVID-19 in Neurological Disorders.
The coronavirus disease 2019 (COVID-19) pandemic affected healthcare at different levels and almost all medical specialties are impacted one way or the other. In this review we try to discuss the impact of COVID-19 on neurology in particular and suggest changes that can be adopted in different neurologic diseases for navigating this pandemic without compromising the healthcare delivery to this specific patient population.


Total hip arthroplasty in patients 50 years and younger.
Because the young patient with a total hip arthroplasty is presumed to place increased demands on a reconstruction for a longer period than the average patient with a hip replacement, long-term results are expected to be inferior. To determine the efficacy of total hip replacements in this population, the current authors reviewed the long-term results of patients who were 50 years and younger who had cementless total hip arthroplasties at their institution, and reviewed the literature on total hip arthroplasty in younger patients. The results from the study population and the literature were encouraging. At the author's institute, during the past 20 years, 561 hip replacements were done on 488 patients in this age group, using extensively porous-coated cobalt-chromium stems matched with beaded, press-fit acetabular components of cobalt-chrome or titanium. Using the Kaplan-Meier technique, the survival rates for femoral and acetabular components, using any revision as an end point, were 89% at 10-year followup and 60% at 15-year followup. A subset of the authors' patients who were 40 years and younger (256 hips, 223 patients) had slightly inferior results, with 85% 10-year survivorship and 54% 15-year survivorship, using any revision as an end point. A comprehensive literature review also showed that long-term success can be achieved with cemented or cementless total hip arthroplasties in young patients. Because some reconstructions exhibited inferior results in younger patients, the authors recommend that surgeons be much more critical of the components used in these patients and allow long-term data to guide their decisions.


Midterm procedural and clinical outcomes of percutaneous paravalvular leak closure with the Occlutech Paravalvular Leak Device.
The aim of this study was to assess the efficacy and safety of the Occlutech Paravalvular Leak Device (PLD) for the percutaneous closure of paravalvular leaks (PVL). Patients with PVL were enrolled at 21 sites from nine countries. Indications for PVL closure were heart failure and/or haemolytic anaemia. Endpoint measures were changes in PV regurgitation grade, NYHA class and requirement for haemolysis-related transfusion. One-hundred and thirty-six patients with mitral (67.6%) or aortic (32.4%) leaks were included (mean age 66.7 years, 58% male); 31% had multiple PVLs. The proportion of patients with NYHA Class III/IV decreased from 77.3% at baseline to 16.9% at latest follow-up. The proportion of patients with need for haemolysis-related blood transfusion decreased from 36.8% to 5.9% and from 8.3% to 0% for ML patients and AL patients, respectively. All-cause mortality was 7.4%. Complications included interference with valve leaflets (0.7%), transient device embolisation (percutaneously solved) (0.7%), late device embolisation (0.7%), recurrent haemolytic anaemia (2.2%), new-onset haemolytic anaemia (0.7%), valve surgery (2.2%), need for repeat closure (0.7%), complications at femoral puncture site (0.7%) and arrhythmias requiring treatment (4.4%). PVL closure with the Occlutech PLD demonstrated a high success rate associated with significant clinical improvement and a relatively low rate of serious complications. Visual summary. PVL characteristics, leak approach, device types and midterm procedural and clinical outcomes of percutaneous paravalvular leak closure with the Occlutech® PLD. Transcatheter PVL closure with the specifically designed PLD was demonstrated to be effective with a relatively low rate of major complications. Procedural success for ML and AL closure was high with a low rate of residual or recurrent leaks. Significant improvement of NYHA class, and reduction of haemolytic anaemia and transfusion dependency were achieved.


Fifteen-Year Audit of Anterior Cruciate Ligament Reconstructions in the Australian Football League From 1999 to 2013: Return to Play and Subsequent ACL Injury.
Anterior cruciate ligament (ACL) injury has been a major cause of missed game time among Australian Football League (AFL) players. Return to play after ACL reconstruction is not always achieved, even among elite athletes. The rate of subsequent ACL injury in the AFL from 1990 to 2000 was high as compared with that of other elite sports. To determine the rates of return to play and subsequent ACL injury after ACL reconstruction among AFL players from 1999 to 2013 and to explore factors associated with differing rates of return to play and subsequent ACL injury. Case series; Level of evidence, 4. A total of 158 AFL players who underwent ACL reconstruction were identified from a prospectively maintained registry of AFL player injuries. Further data were gathered from official playing statistics, surgical records, and structured phone interviews. The rate of return to play after an initial ACL injury was 77% (121 of 158 players). Greater preinjury playing experience and earlier selection in the AFL draft were associated with higher rates of return to play. The rate of subsequent ACL injury to either knee was 30% (48 of 158 players) and was especially high among players aged <21 years (23 of 46 players, 50%). After subsequent ACL injury, 34 of 48 players (71%) returned to play. In primary ACL reconstruction, the use of Ligament Augmentation and Reconstruction System grafts resulted in a faster return to play ( P = .001) but had a higher risk of subsequent revision reconstruction (risk ratio = 2.8, P = .048). Family history of ACL injury was associated with an increased risk of subsequent contralateral ACL injury (risk ratio = 3.8, P = .002). Most AFL players who underwent ACL reconstruction returned to play at least 1 AFL match. The high rate of subsequent ACL injury among AFL players demonstrates the highly demanding nature of Australian football, particularly at the elite level. The risk factors for subsequent ACL injury should be considered carefully when treatment and rehabilitation decisions are made for these high-demand athletes.


A probable primary HIV infection associated with acute non-specific myocarditis causing severe dilated cardiomyopathy.
A patient with a probable primary HIV infection and a biopsy proven non-specific myocarditis is reported. The patient developed a severe dilated cardiomyopathy and initially presented with global heartfailure and fever. The left ventricular function partially recovered. One week after discharge the patient was readmitted in a septic shock and died. Current hypotheses concerning the etiology of left ventricular dysfunction in HIV infection are discussed.


Temporary Mechanical Circulatory Support in Sepsis-Associated Cardiogenic Shock With and Without Acute Myocardial Infarction.
To describe the current use and outcomes of temporary mechanical circulatory support (MCS) in patients with sepsis-associated cardiogenic shocks with and without acute myocardial infarction (AMI) in the United States. Retrospective cohort study. The National Inpatient Sample database from 2017 to 2019. Adult patients with sepsis-associated cardiogenic shock with and without AMI. Temporary MCSs, including intra-aortic balloon pump (IABP), percutaneous left ventricular assist device (pLVAD), and extracorporeal membrane oxygenation (ECMO). Multivariate logistic regression analyses adjusting for patient characteristics, organ failures, and socioeconomic status. Although the uses of IABP and pLVAD were associated with significantly lower odds of in-hospital mortality in patients with sepsis-associated cardiogenic shock (IABP: adjusted odds ratio [aOR] 0.57, 95% CI 0.44-0.73, p < .001; pLVAD: aOR 0.66, 95% CI 0.45-0.98, p = .037), ECMO was not (aOR 1.51, 95% CI 0.93-2.45, p = 0.096). In the subgroup with AMI, temporary MCSs were not associated with significantly lower or higher odds of in-hospital mortality. In the subgroup without AMI, IABP was associated with significantly lower odds of in-hospital mortality (aOR 0.43, 95% CI 0.28-0.65, p < 0.001). Although temporary MCS is deemed to be a feasible option in sepsis-associated cardiogenic shock, the selection of the right patients whose shock is driven mainly by cardiogenic shock rather than septic shock, as represented by low cardiac output and high systemic vascular resistance, plays a critical role in the feasibility of this approach in the absence of clinical trials.


Protease Inhibitors Do Not Affect Antibody Responses to Pneumococcal Vaccination.
HIV(+) subjects on optimal antiretroviral therapy have persistently impaired antibody responses to pneumococcal vaccination. We explored the possibility that this effect may be due to HIV protease inhibitors (PIs). We found that in humans and mice, PIs do not affect antibody production in response to pneumococcal vaccination.


Granular Flow Graph, Adaptive Rule Generation and Tracking.
A new method of adaptive rule generation in granular computing framework is described based on rough rule base and granular flow graph, and applied for video tracking. In the process, several new concepts and operations are introduced, and methodologies formulated with superior performance. The flow graph enables in defining an intelligent technique for rule base adaptation where its characteristics in mapping the relevance of attributes and rules in decision-making system are exploited. Two new features, namely, expected flow graph and mutual dependency between flow graphs are defined to make the flow graph applicable in the tasks of both training and validation. All these techniques are performed in neighborhood granular level. A way of forming spatio-temporal 3-D granules of arbitrary shape and size is introduced. The rough flow graph-based adaptive granular rule-based system, thus produced for unsupervised video tracking, is capable of handling the uncertainties and incompleteness in frames, able to overcome the incompleteness in information that arises without initial manual interactions and in providing superior performance and gaining in computation time. The cases of partial overlapping and detecting the unpredictable changes are handled efficiently. It is shown that the neighborhood granulation provides a balanced tradeoff between speed and accuracy as compared to pixel level computation. The quantitative indices used for evaluating the performance of tracking do not require any information on ground truth as in the other methods. Superiority of the algorithm to nonadaptive and other recent ones is demonstrated extensively.


The reliability of an instrumented start block analysis system.
The swimming start is highly influential to overall competition performance. Therefore, it is paramount to develop reliable methods to perform accurate biomechanical analysis of start performance for training and research. The Wetplate Analysis System is a custom-made force plate system developed by the Australian Institute of Sport--Aquatic Testing, Training and Research Unit (AIS ATTRU). This sophisticated system combines both force data and 2D digitization to measure a number of kinetic and kinematic parameter values in an attempt to evaluate start performance. Fourteen elite swimmers performed two maximal effort dives (performance was defined as time from start signal to 15 m) over two separate testing sessions. Intraclass correlation coefficients (ICC) were used to determine each parameter's reliability. The kinetic parameters all had ICC greater than 0.9 except the time of peak vertical force (0.742). This may have been due to variations in movement initiation after the starting signal between trials. The kinematic and time parameters also had ICC greater than 0.9 apart from for the time of maximum depth (0.719). This parameter was lower due to the swimmers varying their depth between trials. Based on the high ICC scores for all parameters, the Wetplate Analysis System is suitable for biomechanical analysis of swimming starts.


The role of self-antigen in the development of autoimmunity in Obese strain chickens with spontaneous autoallergic thyroiditis.
Neonatal thyroidectomy of Obese strain (OS) chickens showed that the spontaneous development of thyroid autoimmunity in these animals was fully dependent upon the presence of autoantigen, and could not be ascribed essentially to antigen-independent mechanisms such as polyclonal lymphocyte activation or innate distortions within the idiotype network. Similarly, removal of the gland in animals with established thyroiditis demonstrated the need for antigen to maintain the autoimmune response. Thyroglobulin from normal chickens induced autoantibodies in neonatally thyroidectomized OS birds, suggesting that an abnormality in the structure of this protein is not a prerequisite for the development of autoimmunity. This contention is supported by the finding that OS and normal thyroglobulin were immunochemically indistinguishable, whether compared using OS autoantibodies or rabbit anti-chicken thyroglobulin sera.


Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.


Quality of life as an independent predictor for cardiac events and death in patients with heart failure.
Little is known about health-related quality of life (QOL) in Japanese patients with heart failure. The purpose of this study was to identify factors related to QOL using a disease-specific QOL instrument, and to clarify whether QOL independently predicts clinical outcomes among Japanese patients with heart failure. A total of 114 outpatients with heart failure were enrolled (mean age 64.7 ± 15.8 years; 73.7% males). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) to assess patient's QOL was used. At baseline, depressive symptoms and chronic kidney disease were significantly associated with worse QOL in multiple regression analysis. During a 2-year follow up, patients with a MLHFQ score ≥ 26, indicating worse QOL, had a higher incidence of the combined endpoint of cardiac death or hospitalization for heart failure, and a higher all-cause mortality than those with a score < 26 (25.3% vs. 7.5%, P = 0.011; 18.5% vs. 6.4%, P = 0.018; respectively). Multivariate Cox proportional hazard models demonstrated that a higher MLHFQ score was significantly associated with increased risks of cardiac events (hazard ratio, 1.02, 95% confidential interval, 1.001-1.05, P = 0.038) and of all-cause death (hazard ratio, 1.04, 95% confidential interval, 1.02-1.07, P = 0.001). Depressive symptoms and chronic kidney disease are major determinants of impaired QOL, and the MLHFQ score is an independent predictor of both cardiac events and death among Japanese patients with heart failure.


Analysis of pyridyloxobutyl DNA adducts in F344 rats chronically treated with (R)- and (S)-N'-nitrosonornicotine.
NNN (1) is an esophageal carcinogen in rats. 2'-Hydroxylation of NNN is believed to be the major bioactivation pathway for NNN tumorigenicity. (S)-NNN is preferentially metabolized by 2'-hydroxylation in cultured rat esophagus, whereas there is no preference for 2'-hydroxylation versus 5'-hydroxylation in the metabolism of (R)-NNN. 2'-Hydroxylation of NNN generates the reactive intermediate 4-oxo-4-(3-pyridyl)butanediazohydroxide (8), resulting in the formation of pyridyloxobutyl (POB)-DNA adducts. On the basis of these observations, we hypothesized that (S)-NNN treatment would produce higher levels of POB-DNA adducts than that by (R)-NNN in the rat esophagus. We tested this hypothesis by treating male F344 rats with 10 ppm of (R)-NNN or (S)-NNN in drinking water. After 1, 2, 5, 10, 16, or 20 weeks of treatment, POB-DNA adducts in esophageal, liver, and lung DNA were quantified by HPLC-ESI-MS/MS. In the rat esophagus, (S)-NNN treatment generated levels of POB-DNA adducts 3-5 times higher than (R)-NNN treatment, which supports our hypothesis. 7-[4-(3-Pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua, 14) was the major adduct detected, followed by O2-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O2-POB-dThd, 11) and O2-[4-(3-pyridyl)-4-oxobut-1-yl]cytosine (POB-Cyt, 15). O6-[4-(3-Pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O6-POB-dGuo, 10) was not detected. The total POB-DNA adduct levels in the esophagus were 3-11 times higher than those in the liver for (R)-NNN and 2-6 times higher than those for (S)-NNN. In contrast to the esophagus and liver, (R)-NNN treatment produced more POB-DNA adducts than (S)-NNN treatment in the rat lung, which suggested an important role for cytochrome P450 2A3 in NNN metabolism in the rat lung. In both the liver and lung, O2-POB-dThd was the predominant adduct and accumulated during the experiment. The results of this study demonstrate that individual POB-DNA adducts form and persist in the esophagi, livers, and lungs of rats chronically treated with NNN enantiomers and demonstrate that (S)-NNN produces higher levels of POB-DNA adducts in the esophagus than (R)-NNN, suggesting that (S)-NNN is more tumorigenic than (R)-NNN to the rat esophagus.


Quantitative analysis of dual-purpose, patient-specific craniofacial implants for correction of temporal deformity.
The development of computer-assisted design, virtual modeling, and computed tomography has allowed precise customization of implants for patients who undergo neurosurgical or craniofacial surgery procedures. However, such techniques and implant designs have not adequately addressed temporal asymmetry due to postoperative bone resorption, temporalis muscle malposition/foreshortening, and/or temporal fat pad atrophy. We hypothesized that an alteration in customized craniofacial implant (CCI) design with a strategic extension inferolaterally and excessive material bulking would provide simultaneous reconstruction of coexisting temporal skull defects and therefore reduce the effect of soft tissue deformities. A single-surgeon, single-institution retrospective cohort study was performed to include 10 consecutive subjects who underwent cranioplasty reconstruction with modified implants during a 3-year period. Implants were placed with the use of our previously described pericranial-onlay technique. With the use of a computed tomography-based, computer-assisted design/manufacturing methodology, novel dual-purpose implants were designed to prevent and/or correct persistent temporal hollowing. The efficacy of the new CCI shape and design for cranial restoration of temporal symmetry was analyzed in both 2 and 3 dimensions. In 2-dimensional analyses, the modified implant provided enhanced lateral projection (21%; 1.06 cm(3)) in areas closest to the temporal arch. Three-dimensional volumetric analyses demonstrated that additional bulking totaled 24 ± 11 cm(3) (range, 9-43 cm), which essentially replaced 40 ± 13.7% (range, 26%-60%) of the absent temporal volume contributing to persistent temporal hollowing. Computer-designed, dual-purpose CCIs can be safely created with unprecedented shape to prevent and/or eradicate postoperative temporal deformity.


The inspection of anisotropic single-crystal components using a 2-D ultrasonic array.
Single-crystal metal alloys are used extensively in the manufacture of jet engine components for their excellent mechanical properties at elevated temperatures. The inspection of these components using 2-D ultrasonic arrays potentially allows the detection of subsurface defects in threedimensions from one inspection location. Such methods are not currently suitable for the inspection of single-crystal components because the high elastic anisotropy of single-crystal materials causes directional variation in ultrasonic waves. In this paper, a model of wave propagation in anisotropic material is used to correct an ultrasonic imaging algorithm and is applied to a single-crystal test specimen. For this correctedalgorithm, the orientation of the crystal in a specimen must be known before the inspection. Using the same ultrasonic array to measure the orientation and perform the defect inspection offers the most practical solution. Therefore, potential crystallographic orientation methods using 2-D ultrasonic arrays are also developed and evaluated.


Microfluidic baker's transformation device for three-dimensional rapid mixing.
We developed a new passive-type micromixer based on the baker's transformation and realized a fast mixing of a protein solution, which has lower diffusion constant. The baker's transformation is an ideal mixing method, but there is no report on the microfluidic baker's transformation (MBT), since it is required to fabricate the complicated three-dimensional (3D) structure to realize the MBT device. In this note, we successfully fabricate the MBT device by using precision diamond cutting of an oxygen-free copper substrate for the mould fabrication and PDMS replication. The MBT device with 10.4 mm mixing length enables us to achieve complete mixing of a FITC solution (D = 2.6 × 10(-10) m(2) s(-1)) within 51 ms and an IgG solution (D = 4.6 × 10(-11) m(2) s(-1)) within 306 ms. Its mixing speed is 70-fold higher for a FITC solution and 900-fold higher for an IgG solution than the mixing speed by the microchannel without MBT structures. The Péclet number to attain complete mixing in the MBT device is estimated to be 6.9 × 10(4).


The 5' noncoding sequences from a less virulent Theiler's virus dramatically attenuate GDVII neurovirulence.
RNA transcripts derived from recombinant chimeras between the highly virulent GDVII virus and the less virulent BeAn virus were constructed to study the molecular pathogenesis of Theiler's murine encephalomyelitis virus infection. The presence of the BeAn 5' noncoding sequences in chimera 2 (BeAn 5' noncoding sequences joined with the GDVII nucleotides encoding the polyprotein and present in the 3' end) resulted in dramatic attenuation of GDVII neurovirulence and development of poliomyelitis in mice. This reduced neurovirulence was associated with slower virus growth and lower peak titers in the brain and spinal cord than with parental GDVII virus replication. On the other hand, the sites of replication following chimera 2 infection were the same as those seen in GDVII-infected mice; the distribution of virus antigen and histopathological changes indicated that chimera 2 replicates in neurons in the brain, e.g., in the neocortex, hippocampus, caudate putamen, and brain stem, as well as in anterior-horn cells in the spinal cord. Chimera 2 was efficiently cleared from the mouse central nervous system by day 30 postinfection, in marked contrast to the persistence of the BeAn parent in the central nervous system. This suggests that elements in the BeAn sequences that encode the polyprotein or are present in the 3' noncoding region are necessary for viral persistence. It is of interest that chimera 2-infected mice developed localized inflammatory, demyelinating lesions which were detected at day 28 postinfection but these lesions did not become larger with time. Thus, virus persistence appears to be required for maintenance and progression of immune-mediated demyelination. If the demyelinating lesions become sufficiently large, clinical signs and disease may develop.


Older nurses' experiences of providing direct care in hospital nursing units: a qualitative systematic review.
Most developed countries throughout the world are experiencing an aging nursing workforce as their population ages. Older nurses often experience different challenges then their younger nurse counterparts. With the increase in older nurses relative to younger nurses potentially available to work in hospitals, it is important to understand the experience of older nurses on high paced hospital nursing units. This understanding will lend knowledge to ways of lessening the loss of these highly skilled experienced workers and improve patient outcomes. To identify, evaluate and synthesize the existing qualitative evidence on older nurses' experiences of providing direct care to patients in hospital nursing units. The review considered studies which included registered nurses 45 years and over who work as direct caregivers in any type of in-patient hospital nursing unit. The phenomenon of interest was the experience of older nurses in providing direct nursing care in any type of in-patient hospital nursing unit (i.e. including but not limited to medical/surgical units, intensive care units, critical care units, perioperative units, palliative care units, obstetrical units, emergency departments and rehabilitative care units). The review excluded studies focussing entirely on enrolled nurses, licensed practical nurses and licensed vocational nurses. Qualitative data including, but not limited to the following methodologies: phenomenology, grounded theory, ethnography, action research and feminist research. The databases CINAHL, PubMed, PsycINFO, Embase, AgeLine, Sociological Abstracts and SocINDEX were searched from inception; the search was conducted on October 13, 2017; no date limiters or language limiters were applied. Each paper was assessed by two independent reviewers for methodological quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Qualitative Research. Any disagreements that arose between the reviewers were resolved through discussion. Data extraction was conducted by two independent reviewers using the standardized qualitative data extraction tool from JBI. The qualitative research findings were pooled using JBI methodology. The JBI process of meta-aggregation was used to identify categories and synthesized findings. Twelve papers were included in the review. Three synthesized findings were extracted from 12 categories and 75 findings. The three synthesized findings extracted from the papers were: (1) Love of nursing: It's who I am and I love it; (2) It's a rewarding but challenging and changing job; it's a different job and it can be challenging; (3) It's a challenging job; can I keep up? Older nurses love nursing and have created an identity around their profession. They view their profession positively and believe their job to be unlike any other, yet they identify many ongoing challenges and changes. Despite their desire to continue in their role they are often faced with hardships that threaten their ability to stay at the bedside. A key role of hospital administrators to keep older nurses in the workplace is to develop programs to prevent work related illness and to promote health. Given the low ConQual scores in the current systematic review, additional research is recommended to understand the older nurses' experience in providing direct care in hospital nursing units as well as predicting health age of retirement and length of bedside nursing.


The oxygen-binding modulation of hemocyanin from the Southern spiny lobster Palinurus gilchristi.
Arthropod hemocyanins transport and store oxygen and are composed of six subunits, or multiples thereof depending on the species. Palinurus gilchristi hemocyanin is found only as 1 x 6-mers, as normally occurs in spiny lobsters. An alkaline pH and removal of calcium ions induce a wholly reversible dissociation into monomers. The oxygen-binding properties of 1 x 6-meric hemocyanin from P. gilchristi were investigated with respect to pH and modulating effect exerted by calcium, lactate and urate. The oxygen affinity was highly affected by pH in the presence of calcium ions, while in its absence the Bohr coefficient became 60% lower. The protein is insensitive to lactate, but affected by urate which markedly increased hemocyanin-oxygen affinity, acting as the physiological major positive effector. Calcium ions decrease oxygen affinity at low concentration range (0-1 mM), while as concentration becomes higher than 100 mM, the oxygen affinity increases, indicating the presence of two independent types of calcium-binding sites with high and low affinity, respectively. The previous hypothesis, that the presence of high-affinity binding sites in addition to low affinity ones could be a characteristic feature of Palinuran hemocyanins, has been tested by analyzing, with respect to calcium-hemocyanin interaction, three other species belonging to Palinura.


Simulating calcium influx and free calcium concentrations in yeast.
Yeast can proliferate in environments containing very high Ca(2+) primarily due to the activity of vacuolar Ca(2+) transporters Pmc1 and Vcx1. Yeast mutants lacking these transporters fail to grow in high Ca(2+) environments, but growth can be restored by small increases in environmental Mg(2+). Low extracellular Mg(2+) appeared to competitively inhibit novel Ca(2+) influx pathways and to diminish the concentration of free Ca(2+) in the cytoplasm, as judged from the luminescence of the photoprotein aequorin. These Mg(2+)-sensitive Ca(2+) influx pathways persisted in yvc1 cch1 double mutants. Based on mathematical models of the aequorin luminescence traces, we propose the existence in yeast of at least two Ca(2+) transporters that undergo rapid feedback inhibition in response to elevated cytosolic free Ca(2+) concentration. Finally, we show that Vcx1 helps return cytosolic Ca(2+) toward resting levels after shock with high extracellular Ca(2+) much more effectively than Pmc1 and that calcineurin, a protein phosphatase regulator of Vcx1 and Pmc1, had no detectable effects on these factors within the first few minutes of its activation. Therefore, computational modeling of Ca(2+) transport and signaling in yeast can provide important insights into the dynamics of this complex system.


Supporting patients with unlicensed medicine use: Analysing the script schemas for prescribing, pharmaceutical assessment and supply.
Unlicensed medicines (ULMs) are those which have not received authorisation from a regulator, as such they do not have the same reassurances around safety and efficacy as licensed medicines. This study aimed to explore the use of ULMs from the perspectives of prescribers, pharmacists and patients within the UK National Health Service (NHS) setting. Grounded theory was used as a framework, conducting 28 semi-structured qualitative interviews with prescribers, pharmacists and patients across both primary and secondary care settings. Participants were identified from their known use of ULMs where possible and a theoretical sampling approach was used to support recruitment of participants based on the emergent analysis. Analysis followed a constructivist inductive approach, using constant comparison to develop initial themes. This was followed by two focus groups, one with patients and one with professionals where initial analytic findings were presented to participants to further support the development of themes. All interviews were audio recorded and transcribed verbatim. Three sequential schema scripts were identified and used as a framework to explain our findings: ULM prescribing, pharmaceutical assessment of an ULM and ULM supply. Common and divergent events within these scripts were identified and analysed in an attempt to explain similarities and differences across primary and secondary care and between actors. The analysis identified issues around healthcare professional awareness of using ULMs, perceptions of ULM safety, challenges around what information should be provided to patients and by whom and adds to the debate around the place of ULMs in treatment pathways. This study highlights the need for a multidisciplinary conversation about how ULMs should be used in the NHS.


Differential mRNA expression of inflammasome genes NLRP1 and NLRP3 in abdominal aneurysmal and occlusive aortic disease.
NLRP1 and NLRP3 inflammasomes might differentially mediate the chronic inflammatory response in abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD). We measure differential relative gene expression of NLRP1 and NLRP3 inflammasomes in aortic tissues from 30 patients undergoing AAA open repair compared to aortic biopsies from 30 patients undergoing surgery to treat AOD. Aortic wall samples from autopsy without aortic disease were used as controls. NLRP3 was overexpressed in patients with AAA and AOD (RQ 1.185 ± 0.15, and 1.098 ± 0.05, respectively) compared to donors (RQ 1.001 ± 0.08) (OR 2.8, 95% CI 1.2-4.3, p < 0.05 for AAA and OR 2.1, 95% CI 1.1-3.8, p < 0.05 for AOD). NLRP1 gene expression was significantly upregulated in patients with AOD (RQ 1.197 ± 0.09). Meanwhile, NLRP1 was normal expressed in AAA (RQ 1.003 ± 0.07) as well as in autopsy aortic specimens (RQ 1.005 ± 0.11). Enhanced NLRP1 expression in AOD was even significant when compared to AAA (OR 2.3, 95% CI 1.2-3.3, p < 0.05) or controls (OR 2.2, 95% CI 1.1-3.1, p < 0.05). According to our findings, NLRP3 could be involved in the common etiology of AAA and AOD, whereas NLRP1 appears to have a specific role in AOD development.


Facilitation among plants in alpine environments in the face of climate change.
While there is a large consensus that plant-plant interactions are a crucial component of the response of plant communities to the effects of climate change, available data remain scarce, particularly in alpine systems. This represents an important obstacle to making consistent predictions about the future of plant communities. Here, we review current knowledge on the effects of climate change on facilitation among alpine plant communities and propose directions for future research. In established alpine communities, while warming seemingly generates a net facilitation release, earlier snowmelt may increase facilitation. Some nurse plants are able to buffer microenvironmental changes in the long term and may ensure the persistence of other alpine plants through local migration events. For communities migrating to higher elevations, facilitation should play an important role in their reorganization because of the harsher environmental conditions. In particular, the absence of efficient nurse plants might slow down upward migration, possibly generating chains of extinction. Facilitation-climate change relationships are expected to shift along latitudinal gradients because (1) the magnitude of warming is predicted to vary along these gradients, and (2) alpine environments are significantly different at low vs. high latitudes. Data on these expected patterns are preliminary and thus need to be tested with further studies on facilitation among plants in alpine environments that have thus far not been considered. From a methodological standpoint, future studies will benefit from the spatial representation of the microclimatic environment of plants to predict their response to climate change. Moreover, the acquisition of long-term data on the dynamics of plant-plant interactions, either through permanent plots or chronosequences of glacial recession, may represent powerful approaches to clarify the relationship between plant interactions and climate change.


Posttransplantation lymphoproliferative disorder of the paranasal sinuses mimicking invasive fungal sinusitis: case report.
Posttransplantation lymphoproliferative disorder (PTLD) is a challenging complication associated with organ transplantation and is usually fatal if untreated. We describe the case of a transplant recipient who presented with rapidly progressive cranial nerve palsies due to PTLD that originated in the sphenoid sinus. In this case, the clinical and radiologic presentation of PTLD mimicked invasive fungal disease. Because the management of PTLD and the management of invasive fungal infection are vastly different, prompt pathologic diagnosis is required.


Gene Co-Expression Networks Offer New Perspectives on Sepsis Pathophysiology.
Sepsis is among the most common causes of death in intensive care units. Septic shock is a type of circulatory shock that shows signs and symptoms that are similar to non-septic shock. Despite the impact of shock on patients and the economic burden, knowledge of the pathophysiology of septic shock is scarce. In this context, weighted gene co-expression network analysis can help to elucidate the molecular mechanisms of this condition. The gene expression dataset used in this study was downloaded from the Gene Expression Omnibus, which contains 80 patients with septic shock, 33 patients with non-septic shock, and 15 healthy controls. Our novel analysis revealed five gene modules specific for patients with septic shock and three specific gene modules for patients with non-septic shock. Interestingly, genes related to septic shock were mainly involved in the immune system and endothelial cells, while genes related to non-septic shock were primarily associated with endothelial cells. Together, the results revealed the specificity of the genes related to the immune system in septic shock. The novel approach developed here showed its potential to identify critical pathways for the occurrence and progression of these conditions while offering new treatment strategies and effective therapies.


PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.
Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.


Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project.
A variety of diets have been studied for possible anti-aging effects. In particular, studies of intermittent fasting and time-restricted feeding in laboratory rodents have found evidence of beneficial health outcomes. Companion dogs represent a unique opportunity to study diet in a large mammal that shares human environments. The Dog Aging Project has been collecting data on thousands of companion dogs of all different ages, sizes, and breeds since 2019. We leveraged this diverse cross-sectional dataset to investigate associations between feeding frequency and cognitive function (n = 10,474) as well as nine broad categories of health conditions (n = 24,238). Controlling for sex, age, breed, and other potential confounders, we found that dogs fed once daily rather than more frequently had lower mean scores on a cognitive dysfunction scale, and lower odds of having gastrointestinal, dental, orthopedic, kidney/urinary, and liver/pancreas disorders. Therefore, we find that once-daily feeding is associated with better health in multiple domains. Future research with longitudinal data can provide stronger evidence for a possible causal effect of feeding frequency on health in companion dogs.


Extended Reality Technologies in Nutrition Education and Behavior: Comprehensive Scoping Review and Future Directions.
The use of Extended Reality (XR) (i.e. Virtual and Augmented Reality) for nutrition education and behavior change has not been comprehensively reviewed. This paper presents findings from a scoping review of current published research. Articles (n = 92) were extracted from PubMed and Scopus using a structured search strategy and selection approach. Pertinent study information was extracted using a standardized data collection form. Each article was independently reviewed and coded by two members of the research team, who then met to resolve any coding discrepancies. There is an increasing trend in publication in this area, mostly regarding Virtual Reality. Most studies used developmental testing in a lab setting, employed descriptive or observational methods, and focused on momentary behavior change like food selection rather than education. The growth and diversity of XR studies suggest the potential of this approach. There is a need and opportunity for more XR technology focused on children and other foundational theoretical determinants of behavior change to be addressed within nutrition education. Our findings suggest that XR technology is a burgeoning approach in the field of nutrition, but important gaps remain, including inadequate methodological rigor, community application, and assessment of the impact on dietary behaviors.


Trends in prevalence from 1990 to 2007 of patients hospitalized with heart failure in Sweden.
To investigate trends in absolute numbers and prevalence from 1990 to 2007 of patients hospitalized with heart failure (HF) in Sweden. National inpatient and cause-specific death registers were used to calculate age- and sex-specific trends in absolute numbers and prevalence from 1990 to 2007 of patients hospitalized with HF in Sweden. Absolute numbers increased from 105 449 in 1990 to 144 925 in 2007, with a 77% increase in patients aged 85-99 years. The overall age-adjusted prevalence in 1990 was 1.73%, and this increased with an estimated annual percentage change (EAPC) of 4.3% [95% confidence interval (CI) 3.6-4.9%] from 1990 to 1995, with no further significant change until 2002. The single year with the highest prevalence was 1998, when it peaked at 2.13%. The prevalence then declined slowly from 2002 (EAPC -1.1, 95% CI -1.5% to -0.6%) to 1.99% in 2007. The decrease in prevalence was not found in persons <65 years, where, instead, an increase was found throughout the period. Fears of an impending HF 'epidemic' could not be confirmed in this analysis of trends in prevalence for the period 1990-2007 of patients hospitalized with HF in Sweden. An overall slight decrease in age-adjusted prevalence was observed from 2002. The prevalence in patients <65 years increased markedly. In absolute numbers, there was a substantial increase among the very old, consistent with demographic changes.


[Effectiveness of antiinflammatory therapy in patients with interstitial lung diseases using re-assay of biomarker mucin 3EG5].
To investigate a potential of a new marker of activity of interstitial pulmonary diseases (IPD)--mucin 3EG5--in monitoring of effectiveness of the antiinflammatory therapy. Serum mucin antigen 3EG5 (glycolyl-sialylated glycoprotein) was assessed with sandwich immunoassay constructed using a monoclonal antibody 3E1.2 (Medical Innovations, Australia) and affinity-purified polyclonal antibody G5 (Xema, Russia) against total mucin antigen family. The level of serum 3EG5 was studied in 16 IPD patients (9 had idiopathic pulmonary fibrosis and 7--chronic hypersensitivity pneumonitis) before and after 6 months of immunosuppressive therapy. By changes in pulmonary function tests during 6 months of steroid treatment all the patients were divided into two groups: responders (a 15% increase in FVC, 20% increase in DLCO and reduction in the PA-aO2 of 5 mm Hg) and nonresponders (worsening or insignificant changes in these indices). In responders (n = 7) after treatment serum levels of 3EG5 fell from 230 +/- 97 to 88 +/- 40 units/ml (p < 0.01). In nonresponders serum 3EG5 was not different before and after therapy: 249 +/- 153 and 247 +/- 170 units/m, although in this group two patients with unchanged lung function showed a significant decrease in 3EG5, so the accuracy of changes in serum 3EG5 to reflect response to therapy was 88%. There was a significant difference between the posttreatment levels of 3EG5 of the two groups of patients (p = 0.03). Successive measurements of serum mucin 3EG5 may be used for monitoring of the response to immunosuppressive therapy in IPD patients.


AIDS and declining support for dependent elderly people in Africa: retrospective analysis using demographic and health surveys.
To determine the relation between the HIV/AIDS epidemic and support for dependent elderly people in Africa. Retrospective analysis using data from Demographic and Health Surveys. 22 African countries between 1991 and 2006. 123,176 individuals over the age of 60. We investigated how three measures of the living arrangements of older people have been affected by the HIV/AIDS epidemic: the number of older individuals living alone (that is, the number of unattended elderly people); the number of older individuals living with only dependent children under the age of 10 (that is, in missing generation households); and the number of adults age 18-59 (that is, prime age adults) per household where an older person lives. An increase in annual AIDS mortality of one death per 1000 people was associated with a 1.5% increase in the proportion of older individuals living alone (95% CI 1.2% to 1.9%) and a 0.4% increase in the number of older individuals living in missing generation households (95% CI 0.3% to 0.6%). Increases in AIDS mortality were also associated with fewer prime age adults in households with at least one older person and at least one prime age adult (P<0.001). These findings suggest that in our study countries, which encompass 70% of the sub-Saharan population, the HIV/AIDS epidemic could be responsible for 582,200-917,000 older individuals living alone without prime age adults and 141,000-323,100 older individuals being the sole caregivers for young children. Africa's HIV/AIDS epidemic might be responsible for a large number of older people losing their support and having to care for young children. This population has previously been under-recognised. Efforts to reduce HIV/AIDS deaths could have large "spillover" benefits for elderly people in Africa.


Physicians' experiences, attitudes and challenges in a Pediatric Telemedicine Service.
Telemedicine in general, and telephone triage, in particular, is considered a high-stress clinical activity and involves decision making under conditions of uncertainty and urgency. We wanted to explore the experiences, attitudes, and challenges of the physicians in a Pediatric Telemedicine Service operated in Israel, and to explore whether the doctors are using non-medical factors (not related to the medical problem), when making the clinical decisions in this setting. We used a qualitative methodology in order to obtain rich data that would reflect the participants' subjective experiences. Fifteen physicians who worked during the last 5 years in the "Pediatrician Online of Clalit" service were interviewed. Data were analyzed thematically. Seven main themes concerning the physicians' challenges during their work at this service were revealed, including difficulties diagnosing from a distance, treating unfamiliar patients, working alone, urgency and load of calls, technological obstacles, and a "moral conflict" between the desire to meet parents' expectations and maintain standards of care. The physicians stated that non-medical factors also affect their decisions. In telemedicine setting, physicians face various difficulties and challenges, requiring special expertise, qualities and skills. Special measures are needed to obtain proper diagnosis and decisions.


The G199X and V157fs mutations in the TP53 gene promote malignancy in serous ovarian cancer: an analysis using whole-exome sequencing.
The carcinogenic mechanisms underlying serous ovarian cancer are not fully understood. Whole-exome sequencing and targeted sequencing were performed in ovarian cancer samples to identify novel molecular markers involved in the process of cell malignancy in ovarian cancer. In vitro experiments, the oncogenic roles such as cell proliferation, migration and invasion of TP53 G199X and V157fs mutations were investigated deeply. The present study identified the G199X and V157fs point mutations in the tumor protein P53 gene (TP53). The rate of TP53 mutation was 59.2% in a cohort of 76 ovarian cancer patients, compared with 9.0% in a cohort of 156 healthy women. Kaplan-Meier analysis showed that patients with a TP53 mutation had a lower 5-year overall survival (OS) rate compared with patients harboring wild type TP53. In vitro experiments in an ovarian cancer cell line demonstrated that the G199X and V157fs mutants inhibited P53 protein expression, enhanced proliferation, promoted migration and increased invasion. This study identified two novel markers, TP53 G199X and V157fs mutations in TP53. Functional assays indicated that these mutations enhanced the malignant phenotype in ovarian cancer cells. These novel markers will assist in the diagnosis of ovarian tumors and represent potential targets for the treatment of TP53 mutant ovarian cancers.


Modern management of haemophilic arthropathy.
Currently available factor concentrates for treatment of patients with haemophilia are virally inactivated or are made by recombinant technology and their broad use in developed nations has resulted in the dramatic elimination of the treatment-related viral illnesses that decimated the haemophilia community in the late 20th century. The major morbidity experienced by patients with haemophilia today is joint disease, a result of repeated bleeding episodes into joint spaces. Although administration of factor concentrates to prevent bleeding has been demonstrated to prevent haemophilic joint disease when applied assiduously, repeated bleeding episodes induce synovitis that is irreversible and may progress despite subsequent prophylaxis. Surgical and nuclear medicine interventions are available to reduce the pain of haemophilic arthropathy and to reduce further bleeding episodes. Patients with high titre inhibitors are at great risk for the development of joint disease and present the greatest therapeutic challenges when joint surgery is needed.