Observations on the Life History and Geographic Range of the Giant Chemosymbiotic Shipworm Kuphus polythalamius (Bivalvia: Teredinidae).
Kuphus polythalamius (Teredinidae) is one of the world's largest, most rarely observed, and least understood bivalves. Kuphus polythalamius is also among the few shallow-water marine species and the only teredinid species determined to harbor sulfur-oxidizing chemoautotrophic (thioautotrophic) symbionts. Until the recent discovery of living specimens in the Philippines, this species was known only from calcareous hard parts, fossils, and the preserved soft tissues of a single large specimen. As a result, the anatomy, biology, life history, and geographic range of K. polythalamius remain obscure. Here we report the collection and description of the smallest living specimens of K. polythalamius yet discovered and confirm the species identity of these individuals by using sequences of three genetic markers. Unlike previously collected specimens, all of which have been reported to occur in marine sediments, these specimens were observed burrowing in wood, the same substrate utilized by all other members of the family. These observations suggest that K. polythalamius initially settles on wood and subsequently transitions into sediment, where this species may grow to enormous sizes. This discovery led us to search for and find previously unidentified and misidentified wood-boring specimens of this species within museum collections, and it allowed us to show that the recent geographic range (since 1933) of this species extends across a 3000-mile span from the Philippines to Papua New Guinea and the Solomon Islands.


Toll-like receptors: role of inflammation and commensal bacteria.
TLR ligands are present on both commensal and pathogenic microbes. Intestinal epithelial cells (IECs) have been observed to be largely unresponsive to TLR ligands. This observation has partly been explained by the fact that TLR expression on IECs is sparse. The discovery of the Toll-like receptors finally identified the innate immune receptors that were responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seem only to be involved in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms. One member of this group, interleukin-1β (IL-1β), together with tumour-necrosis factor (TNF), is defined as an alarm cytokine. It is secreted by macrophages and initiates inflammation on activation of TLRs.


Idiotype vaccination following ABMT can stimulate specific anti-idiotype immune responses in patients with B-cell lymphoma.
Vaccination with the idiotype (Id) protein derived from B-cell malignancies can produce Id-specific immune responses that correlate with improved remission duration and survival rates in patients with follicular non-Hodgkin's lymphoma (NHL). A state of minimal or no residual disease correlates strongly with the laboratory detection of a cellular or humoral immune response. High-dose cytotoxic therapy (HDCT) with autologous stem cell support (autologous bone marrow transplantation [ABMT]) can provide profound cytoreduction of B-cell NHL, but the potential immune suppression associated with myeloablative therapy may compromise a patient's ability to mount a specific immune response. To determine whether patients with NHL could mount detectable immuneresponses following ABMT, Id vaccines were administered at 2 to 12 months following myeloablative therapy to a series of patients with relapsed or resistant B-cell NHL. Two different vaccination strategies produced robust immune responses against KLH in all patients, supporting the capacity of the reconstituted immune system following HDCT to react against a strong antigen. Combining the results from both vaccination strategies, 10 of 12 patients mounted Id-specific humoral or cellular responses. Vaccinations were consistently well tolerated. Of the 12 patients, 7 have experienced prolonged remissions with a follow-up from HDCT ranging from 3 to more than 11 years. Our experience serves to document the ability of the recovering immune system to react against both self and xenotypic antigens and supports the feasibility and safety of antigen-specific vaccination following myeloablative therapy in patients with B-cell NHL.


Convergence among non-sister dendritic branches: an activity-controlled mean to strengthen network connectivity.
The manner by which axons distribute synaptic connections along dendrites remains a fundamental unresolved issue in neuronal development and physiology. We found in vitro and in vivo indications that dendrites determine the density, location and strength of their synaptic inputs by controlling the distance of their branches from those of their neighbors. Such control occurs through collective branch convergence, a behavior promoted by AMPA and NMDA glutamate receptor activity. At hubs of convergence sites, the incidence of axo-dendritic contacts as well as clustering levels, pre- and post-synaptic protein content and secretion capacity of synaptic connections are higher than found elsewhere. This coupling between synaptic distribution and the pattern of dendritic overlapping results in 'Economical Small World Network', a network configuration that enables single axons to innervate multiple and remote dendrites using short wiring lengths. Thus, activity-mediated regulation of the proximity among dendritic branches serves to pattern and strengthen neuronal connectivity.


Isotropic edge-enhancement by the Hilbert-transform in optical tomography of phase objects.
In optical tomography, isotropic edge-enhancement of phase-object slices under the refractionless limit approximation can be reconstructed using spatial filtering techniques. The optical Hilbert-transform of the transmittance function leaving the object at projection angles ϕ∈(0°,360°), is one of these techniques with some advantages. The corresponding irradiance of the so modified transmittance is considered as projection data, and is proved that they share two properties with the Radon transform: its symmetry property and its zeroth-moment conservation. Accordingly, a modified sinogram able to reconstruct edge-enhanced phase slices is obtained. In this paper, the theoretical model is amply discussed and illustrated both with numerical and experimental results.


Niacin-mediated Gene Expression and Role of NiaR as a Transcriptional Repressor of niaX, nadC, and pnuC in Streptococcus pneumoniae.
NAD (Nicotinamide Adenine Dinucleotide) biosynthesis is vital for bacterial physiology and plays an important role in cellular metabolism. A naturally occurring vitamin B complex, niacin (nicotinic acid), is a precursor of coenzymes NAD and NADP. Here, we study the impact of niacin on global gene expression of Streptococcus pneumoniae D39 and elucidate the role of NiaR as a transcriptional regulator of niaX, nadC, and pnuC. Transcriptome comparison of the D39 wild-type grown in chemically defined medium (CDM) with 0 to 10 mM niacin revealed elevated expression of various genes, including niaX, nadC, pnuC, fba, rex, gapN, pncB, gap, adhE, and adhB2 that are putatively involved in the transport and utilization of niacin. Niacin-dependent expression of these genes is confirmed by promoter lacZ-fusion studies. Moreover, the role of transcriptional regulator NiaR in the regulation of these genes is explored by DNA microarray analysis. Our transcriptomic comparison of D39 ΔniaR to D39 wild-type revealed that the transcriptional regulator NiaR acts as a transcriptional repressor of niaX, pnuC, and nadC. NiaR-dependent regulation of niaX, nadC, and pnuC is further confirmed by promoter lacZ-fusion studies. The putative operator site of NiaR (5'-TACWRGTGTMTWKACASYTRWAW-3') in the promoter regions of niaX, nadC, and pnuC is predicted and further confirmed by promoter mutational experiments.


The primary structure and heterogeneity of tau protein from mouse brain.
Tau protein is a family of microtubule binding proteins, heterogeneous in molecular weight, that are induced during neurite outgrowth and are found prominently in neurofibrillary tangles in Alzheimer's disease. The predicted amino acid sequences of two forms of tau protein from mouse brain were determined from complementary DNA clones. These forms are identical in their amino-terminal sequences but differ in their carboxyl-terminal domains. Both proteins contain repeated sequences that may be tubulin binding sites. The sequence suggests that tau is an elongated molecule with no extensive alpha-helical or beta-sheet domains. These complementary DNAs should enable the study of various functional domains of tau and the study of tau expression in normal and pathological states.


Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma.
Juvenile hemangiomas are the most common tumors of infancy, occurring in as many as 10% of all births. These benign vascular lesions enlarge rapidly during the first year of life by hyperplasia of endothelial cells and attendant pericytes and then spontaneously involute over a period of years, leaving loose fibrofatty tissue. Several hypotheses have been put forth concerning hemangiogenesis, including the possibility that the tumor is the result of somatic mutation in one or more components of critical vascular growth-regulatory pathways. To test this hypothesis, we obtained 15 proliferative-phase hemangiomas after surgical resection and dissected them to enrich for the lesional (endothelial and pericytic) components of each specimen. To determine whether hemangiomas represent a clonal expansion from a single progenitor cell, we assayed X-inactivation patterns for each lesion by using the polymorphic X-linked human androgen receptor gene. Twelve of 14 informative hemangiomas showed a significant degree of allelic loss after methylation-based and transcription-based polymerase chain reaction clonality assays, suggesting a nonrandom X-inactivation pattern and, thus, a monoclonal origin. We then sequenced genes encoding the receptors of the vascular endothelial growth factors (VEGFs) as candidates for potential somatic mutation. Mutations were found in two of the 15 hemangioma specimens: a missense mutation (P1147S) in the kinase domain of the VEGFR2 (FLK1/KDR) gene in one specimen and a missense mutation (P954S) in the kinase insert of the VEGFR3 (FLT4) gene in another specimen. In each case, the mutation was detected in tumor tissue but not in adjacent normal tissue. These results suggest that one potential mechanism involved in hemangioma formation is the alteration of the VEGF signaling pathway in endothelial and/or pericytic cells.


Multipole moments for embedding potentials: Exploring different atomic allocation algorithms.
Polarizable quantum mechanical (QM)/molecular mechanics (MM)-embedding methods are currently among the most promising methods for computationally feasible, yet reliable, production calculations of localized excitations and molecular response properties of large molecular complexes, such as proteins and RNA/DNA, and of molecules in solution. Our aim is to develop a computational methodology for distributed multipole moments and their associated multipole polarizabilities which is accurate, computationally efficient, and with smooth convergence with respect to multipole order. As the first step toward this goal, we herein investigate different ways of obtaining distributed atom-centered multipole moments that are used in the construction of the electrostatic part of the embedding potential. Our objective is methods that not only are accurate and computationally efficient, but which can be consistently extended with site polarizabilities including internal charge transfer terms. We present a new way of dealing with well-known problems in relation to the use of basis sets with diffuse functions in conventional atomic allocation algorithms, avoiding numerical integration schemes. Using this approach, we show that the classical embedding potential can be systematically improved, also when using basis sets with diffuse functions, and that very accurate embedding potentials suitable for QM/MM embedding calculations can be acquired. © 2016 Wiley Periodicals, Inc.


Neural mechanisms underlying the induction and relief of perceptual curiosity.
Curiosity is one of the most basic biological drives in both animals and humans, and has been identified as a key motive for learning and discovery. Despite the importance of curiosity and related behaviors, the topic has been largely neglected in human neuroscience; hence little is known about the neurobiological mechanisms underlying curiosity. We used functional magnetic resonance imaging (fMRI) to investigate what happens in our brain during the induction and subsequent relief of perceptual curiosity. Our core findings were that (1) the induction of perceptual curiosity, through the presentation of ambiguous visual input, activated the anterior insula and anterior cingulate cortex (ACC), brain regions sensitive to conflict and arousal; (2) the relief of perceptual curiosity, through visual disambiguation, activated regions of the striatum that have been related to reward processing; and (3) the relief of perceptual curiosity was associated with hippocampal activation and enhanced incidental memory. These findings provide the first demonstration of the neural basis of human perceptual curiosity. Our results provide neurobiological support for a classic psychological theory of curiosity, which holds that curiosity is an aversive condition of increased arousal whose termination is rewarding and facilitates memory.


Influence of Oxygen Partial Pressure during Processing on the Thermoelectric Properties of Aerosol-Deposited CuFeO₂.
In the field of thermoelectric energy conversion, oxide materials show promising potential due to their good stability in oxidizing environments. Hence, the influence of oxygen partial pressure during synthesis on the thermoelectric properties of Cu-Delafossites at high temperatures was investigated in this study. For these purposes, CuFeO₂ powders were synthetized using a conventional mixed-oxide technique. X-ray diffraction (XRD) studies were conducted to determine the crystal structures of the delafossites associated with the oxygen content during the synthesis. Out of these powders, films with a thickness of about 25 µm were prepared by the relatively new aerosol-deposition (AD) coating technique. It is based on a room temperature impact consolidation process (RTIC) to deposit dense solid films of ceramic materials on various substrates without using a high-temperature step during the coating process. On these dense CuFeO₂ films deposited on alumina substrates with electrode structures, the Seebeck coefficient and the electrical conductivity were measured as a function of temperature and oxygen partial pressure. We compared the thermoelectric properties of both standard processed and aerosol deposited CuFeO₂ up to 900 °C and investigated the influence of oxygen partial pressure on the electrical conductivity, on the Seebeck coefficient and on the high temperature stability of CuFeO₂. These studies may not only help to improve the thermoelectric material in the high-temperature case, but may also serve as an initial basis to establish a defect chemical model.


Stereoscopic and contrast-defined motion in human vision.
There is considerable evidence for the existence of a specialized mechanism in human vision for detecting moving contrast modulations and some evidence for a mechanism for detecting moving stereoscopic depth modulations. It is unclear whether a single second-order motion mechanism detects both types of stimulus or whether they are detected separately. We show that sensitivity to stereo-defined motion resembles that to contrast-defined motion in two important ways. First, when a missing-fundamental disparity waveform is moved in steps of 0.25 cycles, its perceived direction tends to reverse. This is a property of both luminance-defined and contrast-defined motion and is consistent with independent detection of motion at different spatial scales. Second, thresholds for detecting the direction of a smoothly drifting sinusoidal disparity modulation are much higher than those for detecting its orientation. This is a property of contrast-modulated gratings but not luminance-modulated gratings, for which the two thresholds are normally identical. The results suggest that stereo-defined and contrast-defined motion stimuli are detected either by a common mechanism or by separate mechanisms sharing a common principle of operation.


Negotiating Verification: International Diplomacy and the Evolution of Nuclear Safeguards, 1945-1972.
Nuclear safeguards have been an essential part of the global order since the beginnings of the nuclear age. The International Atomic Energy Agency [IAEA], an international bureaucracy that is supposed to be a non-political, technical institution administers this global nuclear safeguards regime. Even though safeguards have always been controversial, they have turned out to be the most enduring item in the international community's toolbox to prevent or slow down the spread of nuclear weapons to non-nuclear states. This analysis shows that nuclear safeguards, whilst they survived the fall of the Iron Curtain, were a genuine invention of the Cold War. At the beginning of the nuclear age, there was an overall understanding that safeguards were not strong enough to prevent the global spread of nuclear weapons. It was only over the course of the late 1950s and 1960s that safeguards moved from the margins to the centre of diplomatic negotiations about global nuclear order. Newly declassified records from the IAEA Archives in Vienna offer insights into the evolution of early nuclear safeguards and suggest that negotiation patterns, proceedings, and settings affected the outcome of this nuclear diplomacy.


Limited resection for the treatment of patients with stage IA lung cancer.
Lobectomy is the standard of care for stage IA lung cancer. Some small retrospective studies have suggested similar results after limited resection for tumors < or =2 cm in size. The objective of the study was to compare survival after lobectomy and limited resection among Medicare patients with lung cancer. Using the Surveillance, Epidemiology, and End Results registry, linked to Medicare records, we identified 1165 cases of stage I lung cancer < or =2 cm in size that underwent lobectomy or limited resection (segmentectomy or wedge resection). We used logistic regression to determine propensity scores for undergoing limited resection based on the patients' preoperative characteristics. Overall and lung cancer-specific survival of patients treated with lobectomy or limited resection was compared after adjusting for their propensity score. Overall, 196 (17%) patients underwent limited resection. For the entire sample, the adjusted hazard ratio for all cause mortality (1.09; 95% confidence interval: 0.85-1.40) or lung cancer-specific death (hazard ratio: 1.39; 95% confidence interval: 0.97-2.01) for patients undergoing limited resection were not significantly different from those having lobectomy. Similarly, we found no significant differences in overall or lung cancer-specific survival for patients treated with limited resection compared with lobectomy when data was analyzed stratifying and matching patients by their propensity scores. These results suggest that survival of patients >65 years of age undergoing limited resection or lobectomy for stage IA tumors < or =2 cm appears to be similar. Although these findings should be confirmed in prospective trials, our results suggest that limited resection may be an effective therapeutic alternative for these patients.


What is the Difference in Morphologic Features of the Thoracic Pedicle Between Patients With Adolescent Idiopathic Scoliosis and Healthy Subjects? A CT-based Case-control Study.
Describing the morphologic features of the thoracic pedicle in patients with adolescent idiopathic scoliosis is necessary for placement of pedicle screws. Previous studies showed inadequate reliability owing to small sample size and heterogeneity of the patients surveyed. To use CT scans (1) to describe the morphologic features of 2718 thoracic pedicles from 60 female patients with Lenke Type 1 adolescent idiopathic scoliosis and 60 age-, sex-, and height-matched controls; and (2) to classify the pedicles in three types based on pedicle width and analyze the distribution of each type. A total of 2718 pedicles from 60 female patients with Lenke Type 1 adolescent idiopathic scoliosis and 60 matched female controls were analyzed via CT. All patients surveyed were diagnosed with adolescent idiopathic scoliosis, Lenke Type 1, at the First Affiliated Hospital of Sun Yat-sen University, and all underwent pedicle screw fixation between January 2008 and December 2013 with preoperative radiographs and CT images on file. We routinely obtained CT scans before these procedures; all patients who underwent surgery during that period had CT scans, and all were available for analysis here. Control subjects had CT scans for other clinical indications and had no abnormal findings of the spine. The control subjects were chosen to match patients in terms of age (15 ± 2.6 years versus 15 ± 2.6 years) and sex. Height of the two groups also was matched (154 ± 9 cm versus 155 ± 10 cm; mean difference, -1.06 cm; 95% CI, -1.24 to -0.81 cm; p < 0.001). Pedicle width and length were measured from T1 to T12. The thoracic spine was classified in four regions: apical vertebra in the structural curve (AV-SC), nonapical vertebra in the structural curve (NAV-SC), apical vertebra in the nonstructural curve (AV-NSC), and nonapical vertebra in the nonstructural curve (NAV-NSC). Pedicles were classified in three types: pedicle width less than 2 mm as Type I, 2 mm to 4 mm as Type II, and greater than 4 mm as Type III. Types I and II were defined as dysplastic pedicles. Paired t test, independent samples t test, one-way ANOVA, followed by Bonferroni's post hoc test and chi-square or Fisher's exact tests were used for statistical comparisons between patients and controls, as appropriate. No difference was found between pedicle width on the convex side (PWv) and in controls (PWn), but pedicle width on the concave side (PWc) (4.99 ± 1.87 mm) was found to be narrower than PWv (6 ± 1.66 mm) and PWn (6 ± 1.45 mm). The variation degree of pedicle width (VDPW) was greatest in the AV-SC region (34% ± 37%), in comparison to AV-NSC (20% ± 25%) (mean difference, 14%; 95% CI, 1.15%-27%; p = 0.025), NAV-SC (17% ± 30%) (mean difference, 17%; 95% CI, 7%-27%; p < 0.001), and NAV-NSC (11% ± 24%) (mean difference, 24%; 95% CI, 13%-34%; p < 0.001). Dysplastic pedicles appeared more in patients with adolescent idiopathic scoliosis (22%; 293 of 1322) compared with controls (13%; 178 of 1396) (odds ratio [OR] = 0.51; 95% CI, 0.42-0.63; p < 0.001). In patients with adolescent idiopathic scoliosis, they commonly occurred on the concave side 34% (228 of 661) and on the AV-SC region (32%; 43 of 136). Pedicle width on the concave side was narrower than pedicle width on the convex side and pedicle width in healthy control subjects. The apical vertebra in the structural curve was the most variegated region of the curve with the highest prevalence of dysplastic pedicles. Our study can help surgeons perform preoperative assessments in females with adolescent idiopathic scoliosis, and with preoperative and intraoperative management for difficult pedicle screw placement. In particular, our results suggest that surgeons should exercise increased vigilance when selecting pedicle screw dimensions, especially in the concave aspect of the mid-thoracic curve, to avoid cortical breeches. Future studies should evaluate other Lenke types of adolescent idiopathic scoliosis, and males with adolescent idiopathic scoliosis.


Dissociated neural processing for decisions in managers and non-managers.
Functional neuroimaging studies of decision-making so far mainly focused on decisions under uncertainty or negotiation with other persons. Dual process theory assumes that, in such situations, decision making relies on either a rapid intuitive, automated or a slower rational processing system. However, it still remains elusive how personality factors or professional requirements might modulate the decision process and the underlying neural mechanisms. Since decision making is a key task of managers, we hypothesized that managers, facing higher pressure for frequent and rapid decisions than non-managers, prefer the heuristic, automated decision strategy in contrast to non-managers. Such different strategies may, in turn, rely on different neural systems. We tested managers and non-managers in a functional magnetic resonance imaging study using a forced-choice paradigm on word-pairs. Managers showed subcortical activation in the head of the caudate nucleus, and reduced hemodynamic response within the cortex. In contrast, non-managers revealed the opposite pattern. With the head of the caudate nucleus being an initiating component for process automation, these results supported the initial hypothesis, hinting at automation during decisions in managers. More generally, the findings reveal how different professional requirements might modulate cognitive decision processing.


Comparison among bone marrow mesenchymal stem and mononuclear cells to promote functional recovery after spinal cord injury in rabbits.
To investigate the efficacy of allogeneic mesenchymal stem-cells and autologous mononuclear cells to promote sensorimotor recovery and tissue rescue. Female rabbits were submitted to the epidural balloon inflation method and the intravenous cells administrations were made after 8 hours or seven days after injury induction. Sensorimotor evaluation of the hindlimbs was performed, and the euthanasia was made thirty days after the treatment. Spinal cords were stained with hematoxylin and eosin. Both therapies given 8 hours after the injury promoted the sensorimotor recovery after a week. Only the group treated after a week with mononuclear cells showed no significant recovery at post-injury day 14. In the days 21 and 28, all treatments promoted significant recovery. Histopathological analysis showed no difference among the experimental groups. Our results showed that both bone marrow-derived cell types promoted significant sensorimotor recovery after injury, and the treatment made at least a week after injury is efficient. The possibilities of therapy with bone marrow-derived cells are large, increasing the therapeutic arsenal for the treatment of spinal cord injury.


Formidability and the logic of human anger.
Eleven predictions derived from the recalibrational theory of anger were tested. This theory proposes that anger is produced by a neurocognitive program engineered by natural selection to use bargaining tactics to resolve conflicts of interest in favor of the angry individual. The program is designed to orchestrate two interpersonal negotiating tactics (conditionally inflicting costs or conditionally withholding benefits) to incentivize the target of the anger to place greater weight on the welfare of the angry individual. Individuals with enhanced abilities to inflict costs (e.g., stronger individuals) or to confer benefits (e.g., attractive individuals) have a better bargaining position in conflicts; hence, it was predicted that such individuals will be more prone to anger, prevail more in conflicts of interest, and consider themselves entitled to better treatment. These predictions were confirmed. Consistent with an evolutionary analysis, the effect of strength on anger was greater for men and the effect of attractiveness on anger was greater for women. Also as predicted, stronger men had a greater history of fighting than weaker men, and more strongly endorsed the efficacy of force to resolve conflicts--both in interpersonal and international conflicts. The fact that stronger men favored greater use of military force in international conflicts provides evidence that the internal logic of the anger program reflects the ancestral payoffs characteristic of a small-scale social world rather than rational assessments of modern payoffs in large populations.


Sauna bathing is associated with reduced cardiovascular mortality and improves risk prediction in men and women: a prospective cohort study.
Previous evidence indicates that sauna bathing is related to a reduced risk of fatal cardiovascular disease (CVD) events in men. The aim of this study was to investigate the relationship between sauna habits and CVD mortality in men and women, and whether adding information on sauna habits to conventional cardiovascular risk factors is associated with improvement in prediction of CVD mortality risk. Sauna bathing habits were assessed at baseline in a sample of 1688 participants (mean age 63; range 53-74 years), of whom 51.4% were women. Multivariable-adjusted hazard ratios (HRs) were calculated to investigate the relationships of frequency and duration of sauna use with CVD mortality. A total of 181 fatal CVD events occurred during a median follow-up of 15.0 years (interquartile range, 14.1-15.9). The risk of CVD mortality decreased linearly with increasing sauna sessions per week with no threshold effect. In age- and sex-adjusted analysis, compared with participants who had one sauna bathing session per week, HRs (95% CIs) for CVD mortality were 0.71 (0.52 to 0.98) and 0.30 (0.14 to 0.64) for participants with two to three and four to seven sauna sessions per week, respectively. After adjustment for established CVD risk factors, potential confounders including physical activity, socioeconomic status, and incident coronary heart disease, the corresponding HRs (95% CIs) were 0.75 (0.52 to 1.08) and 0.23 (0.08 to 0.65), respectively. The duration of sauna use (minutes per week) was inversely associated with CVD mortality in a continuous manner. Addition of information on sauna bathing frequency to a CVD mortality risk prediction model containing established risk factors was associated with a C-index change (0.0091; P = 0.010), difference in - 2 log likelihood (P = 0.019), and categorical net reclassification improvement (4.14%; P = 0.004). Higher frequency and duration of sauna bathing are each strongly, inversely, and independently associated with fatal CVD events in middle-aged to elderly males and females. The frequency of sauna bathing improves the prediction of the long-term risk for CVD mortality.


Bacterial Contamination of Multi-dose Eye Drops at Ophthalmology Department, University of Gondar, Northwest Ethiopia.
Ophthalmic solutions used for both diagnostic and therapeutic purposes were found to be contaminated with bacteria pathogens and caused serious ocular infections such as keratitis and endophthalmitis. The objective was to assess the magnitude and pattern of bacterial contamination of multi-dose ophthalmic medications and investigate the drug susceptibility pattern of the isolates in the Department of Ophthalmology at Gondar University Teaching Hospital. A total of 100 ophthalmic medications in-use by patients and eye-care workers have been taken and cultured for potential bacterial contamination in the Microbiology Department after 1 week and >1 week of use. The dropper tip and the residual eye medications were examined for contamination. The contaminating bacteria were identified using a standard procedure and drug susceptibility testing to selected antimicrobial agents was done. Eleven ophthalmic medications were contaminated by different bacterial species with a prevalence of 11%. Multi-use and longer duration of use of eye medications were associated with higher rate of contamination. The contamination level ranges from 0% for antibiotics, 20% for local anesthetics, and 40% for povidone iodine. Among bacteria identified, Staphylococcus aureus and coagulase-negative Staphylococcus species were resistant to methicillin while others were sensitive to the antibiotics tested. The prevalence of contamination was low, but methicillin-resistant Staphylococcus was a potential risk. It is recommended that the Department of Ophthalmology should design set of rules about duration of use and safe handling of ophthalmic medications by the staff and patients.


[Mitochondrial diseases; thinking beyond organ specialism necessary].
Mitochondrial disorders are caused by a defect in intracellular energy production. In general, these are multi-system disorders, predominantly affecting organs with high energy requirements. Due to the fact that mitochondrial disorders are not as rare as is generally assumed, and due to the diversity of symptoms, many different medical specialists will at some time be confronted with these patients. Early recognition ofa mitochondrial disorder reduces patient anxiety and avoids unnecessary ancillary investigations and potentially hazardous treatments. A mitochondrial disease should be considered in the event of dysfunction of more than 2 organ systems or processes with high energy requirements, certainly if there is a positive maternal family history. If fatigue includes exercise-induced muscle pain or muscle weakness, and if muscle pain predominantly occurs during exertion, a mitochondrial disease should be considered. The combination ofdiabetes mellitus and deafness is also a strong indicator of mitochondrial disease. An extensive family history should always be taken. In adults, the most frequently occurring mitochondrial syndromes are chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness syndrome (MIDDS) and Leber's hereditary optic neuropathy. Since much research effort is currently being invested in the development of causal medical treatments, the importance of an early diagnosis is likely to become of increasing importance in the future.


An examination of healthcare-associated infections in elderly patients
Background/aim: Healthcare-associated infections (HCAIs) are increasing due to the growing numbers of elderly people requiring long-term care and immunosuppressive therapies. The purpose of this study was to examine HCAIs occurring in elderly inpatients in our hospital.Materials and methods: This study prospectively investigated HCAIs developing in all patients hospitalized over a 1-year period. Diagnosis was based on Centers for Disease Control criteria. The results were subjected to statistical analysis between patients aged over and under 65.Results: A total of 24,692 patients were evaluated and 894 HCAIs were identified. Of these infections, 214 were seen in patients aged 65 or over. The rate of HCAIs in elderly patients was 15.1, compared to 2.9 in the under-65 patient group (P < 0.001). Seventy-nine (36.9%) infections in elderly patients were urinary system infections, 60 (28.0%) were bacteremia, 43 (20.1%) were pneumonia, 29 (13.6%) were surgical site infections, and 3 (1.4%) were other infections. Forty-three of the 187 elderly patients followed with a diagnosis of HCAI died. Seventeen patients had mortality attributable to HCAI. Conclusion: Awareness that HCAIs seen in the elderly have different clinical and microbiological characteristics than those of other patients, and the appropriate precautions being taken, will reduce the problems that may result from these diseases with high mortality and morbidity.


Willingness to pay for dentin regeneration in a sample of dentate adults.
Measurement of individuals' valuation of dental treatments is important in the evaluation of new technologies. In this paper the value of dentin regeneration, a new treatment for teeth with reversible pulpitis, is measured based on what individuals say they would be willing to pay to receive the treatment. A total of 611 randomly selected dentate adults answered willingness to pay (WTP) and dental insurance questions. Detailed descriptions of the process and expected outcomes for dentin regeneration were presented to subjects as part of a larger study measuring preferences for different treatments. WTP was determined for two different levels of success for dentin regeneration. At a success rate of 95%, the mean WTP for dentin regeneration was $262.70 (noninsured) and $11.00 per month (insured subjects). For success rate of 75%, the corresponding values were $210.90 and $9.20 per month. Multivariate analyses were used to identify any significant relationships between WTP and a range of variables covering socio-demographic, socio-economic, dental experience and oral health status variables. The findings indicate that individuals' valuations of treatments involve substantial unexplained variation. About half of the noninsured subjects would pay for dentin regeneration if it cost $200 per tooth. The data on the WTP for dentin regeneration indicate that a substantial percentage of adults will pay for this new technology. This study provides for the first time an estimate of WTP for dentin regeneration among the population.


Spatiotemporal evolution of the chlorophyll a trend in the North Atlantic Ocean.
Analyses of the chlorophyll a concentration (chla) from satellite ocean color products have suggested the decadal-scale variability of chla linked to the climate change. The decadal-scale variability in chla is both spatially and temporally non-uniform. We need to understand the spatiotemporal evolution of chla in decadal or multi-decadal timescales to better evaluate its linkage to climate variability. Here, the spatiotemporal evolution of the chla trend in the North Atlantic Ocean for the period 1997-2016 is analyzed using the multidimensional ensemble empirical mode decomposition method. We find that this variable trend signal of chla shows a dipole pattern between the subpolar gyre and along the Gulf Stream path, and propagation along the opposite direction of the North Atlantic Current. This propagation signal has an overlapping variability of approximately twenty years. Our findings suggest that the spatiotemporal evolution of chla during the two most recent decades is part of the multidecadal variations and possibly regulated by the changes of Atlantic Meridional Overturning Circulation, whereas the mechanisms of such evolution patterns still need to be explored.


Wetting at nonplanar substrates: unbending and unbinding.
We consider fluid wetting on a corrugated substrate using effective interfacial Hamiltonian theory and show that breaking the translational invariance along the wall can induce an unbending phase transition in addition to unbinding. Both first-order and second-order unbending transitions can occur at and out of coexistence. Results for systems with short-ranged and long-ranged forces establish that the unbending critical point is characterized by hyperuniversal scaling behavior. We show that, at bulk coexistence, the adsorption at the unbending critical point is a universal multiple of the adsorption for the correspondent planar system.


Preventing the Next Pandemic: The Case for Investing in Circulatory Health - A Global Coalition for Circulatory Health Position Paper.
The Coronavirus Disease 2019 (COVID-19) has had a continuous and robust impact on world health. The resulting COVID-19 pandemic has had a devastating physical, mental and fiscal impact on the millions of people living with noncommunicable diseases (NCDs). In addition to older age, people living with CVD, stroke, obesity, diabetes, kidney disease, and hypertension are at a particularly greater risk for severe forms of COVID-19 and its consequences. Meta-analysis indicates that hypertension, diabetes, chronic kidney disease, and thrombotic complications have been observed as both the most prevalent and most dangerous co-morbidities in COVID-19 patients. And despite the nearly incalculable physical, mental, emotional, and economic toll of this pandemic, forthcoming public health figures continue to place cardiovascular disease as the number one cause of death across the globe in the year 2020. The world simply cannot wait for the next pandemic to invest in NCDs. Social determinants of health cannot be addressed only through the healthcare system, but a more holistic multisectoral approach with at its basis the Sustainable Development Goals (SDGs) is needed to truly address social and economic inequalities and build more resilient systems. Yet there is reason for hope: the 2019 UN Political Declaration on UHC provides a strong framework for building more resilient health systems, with explicit calls for investment in NCDs and references to fiscal policies that put such investment firmly within reach. By further cementing the importance of addressing circulatory health in a future Framework Convention on Emergency Preparedness, WHO Member States can take concrete steps towards a pandemic-free future. As the chief representatives of the global circulatory health community and patients, the Global Coalition for Circulatory Health calls for increased support for the healthcare workforce, global vaccine equity, embracing new models of care and digital health solutions, as well as fiscal policies on unhealthy commodities to support these investments.


Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.
The purpose of the workshop was to identify still obscure or novel cellular components of the lung, to determine cell function in lung development and in health that impacts on disease, and to decide promising avenues for future research to extract and phenotype these cells. Since robust technologies are now available to identify, sort, purify, culture, and phenotype cells, progress is now within sight to unravel the origins and functional capabilities of lung cells in developmental stages and in disease. The Workshop's agenda was to first discuss the lung's embryologic development, including progenitor and stem cells, and then assess the functional and structural cells in three main compartments of the lung: (1) airway cells in bronchial and bronchiolar epithelium and bronchial glands (basal, secretory, ciliated, Clara, and neuroendocrine cells); (2) alveolar unit cells (Type 1 cells, Type 2 cells, and fibroblasts in the interstitium); and (3) pulmonary vascular cells (endothelial cells from different vascular structures, smooth muscle cells, and adventitial fibroblasts). The main recommendations were to: (1) characterize with better cell markers, both surface and nonsurface, the various cells within the lung, including progenitor cells and stem cells; (2) obtain more knowledge about gene expression in specific cell types in health and disease, which will provide insights into biological and pathologic processes; (3) develop more methodologies for cell culture, isolation, sorting, co-culture, and immortalization; and (4) promote tissue banks to facilitate the procurement of tissue from normal and from diseased lung for analysis at all levels.


A single subunit directs the assembly of the Escherichia coli DNA sliding clamp loader.
Multi-protein clamp loader complexes are required to load sliding clamps onto DNA. In Escherichia coli the clamp loader contains three DnaX (tau/gamma) proteins, delta, and delta', which together form an asymmetric pentameric ring that also interacts with psichi. Here we used mass spectrometry to examine the assembly and dynamics of the clamp loader complex. We find that gamma exists exclusively as a stable homotetramer, while tau is in a monomer-dimer-trimer-tetramer equilibrium. delta' plays a direct role in the assembly as a tau/gamma oligomer breaker, thereby facilitating incorporation of lower oligomers. With delta', both delta and psichi stabilize the trimeric form of DnaX, thus completing the assembly. When tau and gamma are present simultaneously, mimicking the situation in vivo, subunit exchange between tau and gamma tetramers occurs rapidly to form heterocomplexes but is retarded when deltadelta' is present. The implications for intracellular assembly of the DNA polymerase III holoenzyme are discussed.


Network analysis reveals common host protein/s modulating pathogenesis of neurotropic viruses.
Network analysis through graph theory provides a quantitative approach to characterize specific proteins and their constituent assemblies that underlie host-pathogen interactions. In the present study, graph theory was used to analyze the interactome designed out of 50 differentially expressing proteins from proteomic analysis of Chandipura Virus (CHPV, Family: Rhabdoviridae) infected mouse brain tissue to identify the primary candidates for intervention. Using the measure of degree centrality, that quantifies the connectedness of a single protein within a milieu of several other interacting proteins, DJ-1 was selected for further molecular validation. To elucidate the generality of DJ-1's role in propagating infection its role was also monitored in another RNA virus, Japanese Encephalitis Virus (JEV, Family: Flaviviridae) infection. Concurrently, DJ-1 got over-expressed in response to reactive oxygen species (ROS) generation following viral infection which in the early phase of infection migrated to mitochondria to remove dysfunctional mitochondria through the process of mitophagy. DJ-1 was also observed to modulate the viral replication and interferon responses along with low-density lipoprotein (LDL) receptor expression in neurons. Collectively these evidences reveal a comprehensive role for DJ-1 in neurotropic virus infection in the brain.


Patient perspectives on loss of local obstetrical services in rural northern Minnesota.
Obstetrical care has been declining in rural communities. We examined patient choices and perspectives from two rural northern Minnesota communities who lost their local obstetrical services in July 2015. Our purpose was to characterize obstetrical use patterns through the years leading to and following the closure and to explore the effects of the closure on these communities. Information introducing the project and providing access to the survey was mailed to women who received prenatal care in the communities of interest. Responses were analyzed quantitatively and qualitatively. Two hundred and one participants completed the survey with 356 deliveries reported from 1990 to 2016. Before the closure, there was a trend toward an increasing percentage of women electing regional delivery (P < .001); however, women were still 1.6 times more likely to choose local (62%) than regional (38%) delivery. Reasons for choosing delivery location changed over the decades. While birth experiences remained positive or extremely positive, anxiety about getting to the hospital rose 10-fold from 1990 to 2016 (5%-51%, P < .001). Women voiced substantial concern about the lack of local obstetrical services. Qualitative analysis revealed significant negative emotional reactions and concerns for the consequences of this loss for the viability of their rural communities. Choices and opinions about obstetric care have significantly changed from 1990 to 2016 in rural Minnesota. Understanding these changes can help address shifting risks and costs to rural communities here and elsewhere in an effort to support and sustain healthy, viable rural communities.


Three-dimensional virtual reality surgical planning and simulation workbench for orthognathic surgery.
A new integrated computer system, the 3-dimensional (3D) virtual reality surgical planning and simulation workbench for orthognathic surgery (VRSP), is presented. Five major functions are implemented in this system: post-processing and reconstruction of computed tomographic (CT) data, transformation of 3D unique coordinate system geometry, generation of 3D color facial soft tissue models, virtual surgical planning and simulation, and presurgical prediction of soft tissue changes. The basic mensuration functions, such as linear and spatial measurements, are also included. The surgical planning and simulation are based on 3D CT reconstructions, whereas soft tissue prediction is based on an individualized, texture-mapped, color facial soft tissue model. The surgeon "enters" the virtual operatory with virtual reality equipment, "holds" a virtual scalpel, and "operates" on a virtual patient to accomplish actual surgical planning, simulation of the surgical procedure, and prediction of soft tissue changes before surgery. As a final result, a quantitative osteotomy-simulated bone model and predicted color facial model with photorealistic quality can be visualized from any arbitrary viewing point in a personal computer system. This system can be installed in any hospital for daily use.


Sustainability and Long Term-Tenure: Lion Trophy Hunting in Tanzania.
It is argued that trophy hunting of large, charismatic mammal species can have considerable conservation benefits but only if undertaken sustainably. Social-ecological theory suggests such sustainability only results from developing governance systems that balance financial and biological requirements. Here we use lion (Panthera leo) trophy hunting data from Tanzania to investigate how resource ownership patterns influence hunting revenue and offtake levels. Tanzania contains up to half of the global population of free-ranging lions and is also the main location for lion trophy hunting in Africa. However, there are concerns that current hunting levels are unsustainable. The lion hunting industry in Tanzania is run by the private sector, although the government leases each hunting block to companies, enforces hunting regulation, and allocates them a species-specific annual quota per block. The length of these leases varies and theories surrounding property rights and tenure suggest hunting levels would be less sustainable in blocks experiencing a high turnover of short-term leases. We explored this issue using lion data collected from 1996 to 2008 in the Selous Game Reserve (SGR), the most important trophy hunting destination in Tanzania. We found that blocks in SGR with the highest lion hunting offtake were also those that experienced the steepest declines in trophy offtake. In addition, we found this high hunting offtake and the resultant offtake decline tended to be in blocks under short-term tenure. In contrast, lion hunting levels in blocks under long-term tenure matched more closely the recommended sustainable offtake of 0.92 lions per 1000 km2. However, annual financial returns were higher from blocks under short-term tenure, providing $133 per km2 of government revenue as compared to $62 per km2 from long-term tenure blocks. Our results provide evidence for the importance of property rights in conservation, and support calls for an overhaul of the system in Tanzania by developing competitive market-based approaches for block allocation based on long-term tenure of ten years.


Adiaspiromycosis mimicking widespread malignancy in a patient with pulmonary adenocarcinoma.
Adiaspiromycosis, a mycotic disease of small animals, has rarely been reported in humans. The principle causative organism in Europe is Emmonsia crescens. Inhaled, dust-borne spores of E crescens fail to germinate in host tissue, instead increasing in size dramatically to become thick-walled, round adiapsores, which induce a granulomatous response. The pathological effects depend on the spore burden and host immunocompetence, and range from asymptomatic infection through to necrogranulomatous pneumonia, respiratory failure and, rarely, death. Diagnosis is principally made through histological examination. This report describes a case of a patient with low-grade, localised pulmonary adenocarcinoma with occult adiaspiromycosis that radiologically mimicked widespread malignancy. It is believed to be the first reported human case of adiaspiromycosis in the UK.


Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project.
The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine.


Predicting Mab product yields from cultivation media components, using near-infrared and 2D-fluorescence spectroscopies.
The yield of monoclonal antibody (Mab) production processes depends on media formulation, inocula quality, and process conditions. As in industrial processes tight cultivation conditions are used, and inocula quality and viable cell densities are controlled to reasonable levels, media formulation and raw materials lot-to-lot variability in quality will have, in those circumstances, the highest impact on process performance. In the particular Mab process studied, two different raw materials were used: a complex carbon and nitrogen source made of specific peptones and defined chemical media containing multiple components. Using different spectroscopy techniques for each of the raw material types, it was concluded that for the complex peptone-based ingredient, near-infrared (NIR) spectroscopy was more capable of capturing lot-to-lot variability. For the chemically defined media containing fluorophores, two-dimensional (2D)-fluorescence spectroscopy was more capable of capturing lot-to-lot variability. Because in Mab cultivation processes both types of raw materials are used, combining the NIR and 2D-fluorescence spectra for each of the media components enabled predictive models for yield to be developed that out-performed any other model involving either one raw material alone, or only one type of spectroscopic tool for both raw materials. For each particular raw material, the capability of each spectroscopy to detect lot-to-lot differences was demonstrated after spectra preprocessing and specific wavelength regions selection. The work described and the findings reported here open up several possibilities that could be used to feed-forward control the process. These include, for example, enabling specific actions to be taken regarding media formulation with particular lots, and all types of predictive control actions aimed at increasing batch-to-batch yield and product quality consistency at harvest.


Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation.
Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.


Disruption of mouse cytochrome p450 4f14 (Cyp4f14 gene) causes severe perturbations in vitamin E metabolism.
Vitamin E is a family of naturally occurring and structurally related lipophilic antioxidants, one of which, α-tocopherol (α-TOH), selectively accumulates in vertebrate tissues. The ω-hydroxylase cytochrome P450-4F2 (CYP4F2) is the only human enzyme shown to metabolize vitamin E. Using cDNA cloning, cell culture expression, and activity assays, we identified Cyp4f14 as a functional murine ortholog of CYP4F2. We then investigated the effect of Cyp4f14 deletion on vitamin E metabolism and status in vivo. Cyp4f14-null mice exhibited substrate-specific reductions in liver microsomal vitamin E-ω-hydroxylase activity ranging from 93% (γ-TOH) to 48% (γ-tocotrienol). In vivo data obtained from metabolic cage studies showed whole-body reductions in metabolism of γ-TOH of 90% and of 68% for δ- and α-TOH. This metabolic deficit in Cyp4f14(-/-) mice was partially offset by increased fecal excretion of nonmetabolized tocopherols and of novel ω-1- and ω-2-hydroxytocopherols. 12'-OH-γ-TOH represented 41% of whole-body production of γ-TOH metabolites in Cyp4f14(-/-) mice fed a soybean oil diet. Despite these counterbalancing mechanisms, Cyp4f14-null mice fed this diet for 6 weeks hyper-accumulated γ-TOH (2-fold increase over wild-type littermates) in all tissues and appeared normal. We conclude that CYP4F14 is the major but not the only vitamin E-ω-hydroxylase in mice. Its disruption significantly impairs whole-body vitamin E metabolism and alters the widely conserved phenotype of preferential tissue deposition of α-TOH. This model animal and its derivatives will be valuable in determining the biological actions of specific tocopherols and tocotrienols in vivo.


Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells.
The normal cell cycle is regulated by several molecules, such as the tumor-suppressor protein pRb, the G1 cyclins, the cyclin-dependent kinases, and their inhibitors. These regulators are targeted by negative growth regulatory signals, such as that provided by TGF-beta. Here, we show that the presence of either wild-type EBV or its transforming latent membrane protein-1 (LMP-1) results in the loss of TGF-beta 1-mediated growth inhibition in human B cells. Chemical cross-linking with 125I-labeled TGF-beta 1 showed an essentially normal TGF-beta receptor profile in EBV-positive and EBV-negative Burkitt's lymphoma cell lines, and these receptors were shown to be functional in transducing signals, as evidenced by the TGF-beta 1-mediated modulation of junB gene expression. However, TGF-beta 1 did not induce dephosphorylation of pRb in EBV (or LMP-1)-positive cells as opposed to EBV-negative cells, suggesting a dichotomy in the TGF-beta 1 signaling pathway leading to separable gene regulatory and growth inhibitory responses. Furthermore, LMP-1 was found to induce the expression of cyclin D2; normal B cells or EBV-negative Burkitt's lymphoma cells do not express D-type cyclins. Taken together, these data point to a potential mechanism underlying EBV-mediated B cell transformation whereby constitutive induction of key cell cycle regulators by LMP-1 can lead to pRb hyperphosphorylation and uncontrolled cell proliferation.


Real-time visual feedback of COM and COP motion properties differentially modifies postural control structures.
The experiment was setup to investigate the control of human quiet standing through the manipulation of augmented visual information feedback of selective properties of the motion of two primary variables in postural control: center of pressure (COP) and center of mass (COM). Five properties of feedback information were contrasted to a no feedback dual-task (watching a movie) control condition to determine the impact of visual real-time feedback on the coordination of the joint motions in postural control in both static and dynamic one-leg standing postures. The feedback information included 2D COP or COM position and macro variables derived from the COP and COM motions, namely virtual time-to-contact (VTC) and the COP-COM coupling. The findings in the static condition showed that the VTC and COP-COM coupling feedback conditions decreased postural motion more than the 2D COP or COM positional information. These variables also induced larger sway amplitudes in the dynamic condition showing a more progressive search strategy in exploring the stability limits. Canonical correlation analysis (CCA) found that COP-COM coupling contributed less than the other feedback variables to the redundancy of the system reflected in the common variance between joint motions and properties of sway motion. The COP-COM coupling had the lowest weighting of the motion properties to redundancy under the feedback conditions but overall the qualitative pattern of the joint motion structures was preserved within the respective static and dynamic balance conditions.


40 GHz pulse source based on cross-phase modulation-induced focusing in normally dispersive optical fibers.
We theoretically and experimentally investigate the design of a high-repetition rate source delivering well-separated optical pulses due to the nonlinear compression of a dual-frequency beat signal within a cavity-less normally dispersive fiber-based setup. This system is well described by a set of two coupled nonlinear Schrödinger equations for which the traditional normally dispersive defocusing regime is turned in a focusing temporal lens through a degenerated cross-phase modulation process (XPM). More precisely, the temporal compression of the initial beating is performed by the combined effects of normal dispersion and XPM-induced nonlinear phase shift provided by an intense beat signal on its weak out-of-phase replica co-propagating with orthogonal polarizations. This adiabatic reshaping process allows us to experimentally demonstrate the generation of a 40 GHz well-separated 3.3 ps pulse train at 1550 nm in a 5 km long normally dispersive fiber.


Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action.
Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development. UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle. Magnolol pretreated groups (30, 60 μ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice.Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells. Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.


E2F1 promotes hepatic gluconeogenesis and contributes to hyperglycemia during diabetes.
Aberrant hepatic glucose production contributes to the development of hyperglycemia and is a hallmark of type 2 diabetes. In a recent study, we showed that the transcription factor E2F1, a component of the cell cycle machinery, contributes to hepatic steatosis through the transcriptional regulation of key lipogenic enzymes. Here, we investigate if E2F1 contributes to hyperglycemia by regulating hepatic gluconeogenesis. We use different genetic models to investigate if E2F1 regulates gluconeogenesis in primary hepatocytes and in vivo. We study the impact of depleting E2F1 or inhibiting E2F1 activity in diabetic mouse models to evaluate if this transcription factor contributes to hyperglycemia during insulin resistance. We analyze E2F1 mRNA levels in the livers of human diabetic patients to assess the relevance of E2F1 in human pathophysiology. Lack of E2F1 impaired gluconeogenesis in primary hepatocytes. Conversely, E2F1 overexpression increased glucose production in hepatocytes and in mice. Several genetic models showed that the canonical CDK4-RB1-E2F1 pathway is directly involved in this regulation. E2F1 mRNA levels were increased in the livers from human diabetic patients and correlated with the expression of the gluconeogenic enzyme Pck1. Genetic invalidation or pharmacological inhibition of E2F1 improved glucose homeostasis in diabetic mouse models. Our study unveils that the transcription factor E2F1 contributes to mammalian glucose homeostasis by directly controlling hepatic gluconeogenesis. Together with our previous finding that E2F1 promotes hepatic steatosis, the data presented here show that E2F1 contributes to both hyperlipidemia and hyperglycemia in diabetes, suggesting that specifically targeting E2F1 in the liver could be an interesting strategy for therapies against type 2 diabetes.


Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: The TIMI III registry.
To investigate the natural history and response to treatment of patients with unstable angina or non-Q-wave myocardial infarction (MI). Inception cohort. Patients in general community, primary care, or referral hospitals. All patients with an episode of unstable exertional chest pain or chest pain at rest presumed to be ischemic in origin lasting 5 minutes or more but without persisting ST-segment elevation greater than 30 minutes or the development of Q-waves were identified and enumerated in 18 participating hospitals. A subset of enumerated patients was selected to be followed prospectively using specific sampling strategies that would provide adequate numbers of black, women, and elderly (aged > or = 75 years) patients for comparison with their respective counterparts. The primary analysis compared the incidence of death or MI at 42 days after entry into the prospective study according to race, sex, and age. Other outcomes considered were recurrent ischemia and the combined outcomes of death, MI, or recurrent ischemia by 42 days after entry. A total of 8676 admissions with unstable angina or non-Q-wave MI were enumerated and, of these, 3318 patients were selected for the prospective study. The direct adjusted mean age of 3318 patients was 63.8 years. There were 943 blacks and 2375 nonblacks. Compared with nonblacks, blacks were less likely to be treated with intensive anti-ischemic therapy for their qualifying anginal episode and less likely to undergo invasive procedures (risk ratio [RR], 0.65%; 95% confidence interval [CI], 0.58 to 0.72; P<.001). However, of those who underwent angiography (45% of blacks and 61% of nonblacks), blacks had less extensive and severe coronary stenoses than nonblacks. The incidence of death and MI was similar for blacks and nonblacks, but blacks had a lower incidence of recurrent ischemia. There were 1678 men and 1640 women. Women were less likely than men to receive intensive anti-ischemic therapy and less likely to undergo coronary angiography (RR, 0.71; 95% CI, 0.65 to 0.78; P<.001). Women had less severe and extensive coronary disease and were less likely to undergo revascularization, yet had a similar risk of experiencing an adverse cardiac event by 6 weeks. There were 2490 patients aged 75 years or less and 828 patients aged more than 75 years. Elderly patients received less aggressive anti-ischemic therapy and were less likely to undergo coronary angiography than their younger counterparts. Elderly patients had more severe and extensive coronary disease but fewer revascularization procedures than younger patients and experienced a much higher incidence of adverse cardiac events both in hospital and by 6 weeks. Among patients presenting with acute ischemic chest pain without persistent ST-segment elevation, blacks appeared to have less severe coronary disease, received revascularization less frequently, and had less recurrent ischemia compared with nonblacks. Women were also found to have less severe coronary disease and were treated less intensely than men, but experienced similar outcomes. Elderly patients had more severe coronary disease than younger patients on coronary angiography, but were more likely to be treated medically, and they experienced far more adverse outcomes. These data suggest that more aggressive strategies should be directed to those patients with the greatest likelihood of adverse outcomes.


Ten-year persistence and evolution of Plasmodium falciparum antifolate and anti-sulfonamide resistance markers pfdhfr and pfdhps in three Asian countries.
The amplification of GTP cyclohydrolase 1 (pfgch1) in Plasmodium falciparum has been linked to the upregulation of the pfdhfr and pfdhps genes associated with resistance to the antimalarial drug sulfadoxine-pyrimethamine. During the 1990s and 2000s, sulfadoxine-pyrimethamine was withdrawn from use as first-line treatment in southeast Asia due to clinical drug resistance. This study assessed the temporal and geographic changes in the prevalence of pfdhfr and pfdhps gene mutations and pfgch1 amplification a decade after sulfadoxine-pyrimethamine had no longer been widely used. A total of 536 P. falciparum isolates collected from clinical trials in Thailand, Cambodia, and Lao PDR between 2008 and 2018 were assayed. Single nucleotide polymorphisms of the pfdhfr and pfdhps genes were analyzed using nested PCR and Sanger sequencing. Gene copy number variations of pfgch1 were investigated using real-time polymerase chain reaction assay. Sequences of the pfdhfr and pfdhps genes were obtained from 96% (517/536) and 91% (486/536) of the samples, respectively. There were 59 distinct haplotypes, including single to octuple mutations. The two major haplotypes observed included IRNI-AGEAA (25%) and IRNL-SGKGA (19%). The sextuple mutation IRNL-SGKGA increased markedly over time in several study sites, including Pailin, Preah Vihear, Ratanakiri, and Ubon Ratchathani, whereas IRNI-AGEAA decreased over time in Preah Vihear, Champasak, and Ubon Ratchathani. Octuple mutations were first observed in west Cambodia in 2011 and subsequently in northeast Cambodia, as well as in southern Laos by 2018. Amplification of the pfgch1 gene increased over time across the region, particularly in northeast Thailand close to the border with Laos and Cambodia. Despite the fact that SP therapy was discontinued in Thailand, Cambodia, and Laos decades ago, parasites retained the pfdhfr and pfdhps mutations. Numerous haplotypes were found to be prevalent among the parasites. Frequent monitoring of pfdhfr and pfdhps in these areas is required due to the relatively rapid evolution of mutation patterns.


Seen gaze-direction modulates fusiform activity and its coupling with other brain areas during face processing.
Gaze-contact is often a preliminary to social interaction and so constitutes a signal for the allocation of processing resources to the gazing face. We investigated how gaze direction influences face processing in an fMRI study, where seen gaze and head direction could independently be direct or deviated. Direct relative to averted gaze elicited stronger activation for faces in ventral occipitotemporal cortices around the fusiform gyrus, regardless of head orientation. Moreover, direct gaze led to greater correlation between activity in the fusiform and the amygdala, a region associated with emotional responses and stimulus saliency. By contrast, faces with averted gaze (again, regardless of head orientation) yielded increased correlation between activity in the fusiform and the intraparietal sulcus, a region associated with shifting attention to the periphery.


Comparison of three algorithms of non-invasive markers of fibrosis in chronic hepatitis C.
Preliminary data suggest that performance of non-invasive markers for liver fibrosis in hepatitis C may improve when combined. Three algorithms based on the combination of Fibrotest, Forns' index and AST-to-platelet ratio (APRI) have been proposed: Sequential Algorithm for Fibrosis Evaluation (SAFE biopsy); Fibropaca algorithm; Leroy algorithm. To compare three algorithms to diagnose significant fibrosis (≥ F2 by METAVIR) and cirrhosis (F4). A total of 1013 HCV monoinfected cases undergoing liver biopsy were consecutively enrolled in seven centres. Fibrotest, APRI and Forns' index were measured at the time of liver biopsy, considered the reference standard. Overall, performance of combination algorithms was significantly higher than the single non-invasive methods (P < 0.0001). SAFE biopsy and Fibropaca algorithm saved a significantly higher number of liver biopsies than the single methods (P < 0.0001). For ≥ F2, Fibropaca algorithm saved more biopsies than SAFE biopsy (51.7% vs. 43.8%, P = 0.0003), but with lower accuracy (87.6% vs. 90.3%, P = 0.05). Regarding F4, the number of saved liver biopsies did not differ between SAFE biopsy and Fibropaca algorithm (79.1% vs. 76.2%, P = 0.12). However, SAFE biopsy showed a lower accuracy when compared with Fibropaca algorithm (91.2% vs. 94%, P = 0.02). As to Leroy algorithm, although it showed a good performance for ≥ F2 (93.5% accuracy), it saved less liver biopsies than SAFE biopsy and Fibropaca algorithm (29.2% vs. 43.8% and 51.7% respectively, P < 0.0001). SAFE biopsy and the Fibropaca algorithm have excellent performance for liver fibrosis in hepatitis C, allowing a significant reduction in the need for liver biopsies. They can be useful in clinical practice and for large-scale screening.


Sensitivity and specificity of body mass index as a definition of the obesity component of metabolic syndrome.
Metabolic syndrome (MS) is a combination of risk factors that are associated with several chronic diseases. Its components (obesity, dyslipidemia, carbohydrate intolerance, hypertension, microalbumineria) are diverse, whose thresholds vary in different definitions of MS. For example, a World Health Organization (WHO) panel defined the obesity component of MS based on waist-hip ratio, or body mass index (BMI), while the National Cholesterol Education Program (NCEP) defined the obesity component of MS by waist circumference. Since BMI is the common measure of obesity in most epidemiological studies, this research addressed how accurately the obesity component of MS is captured by BMI alone. Data presented showed that in a population with high prevalence of obesity, the specificity of detecting the obesity component of MS by BMI alone is almost 100%, but the sensitivity is low (e.g., < 50%). Individuals with high BMI generally have large waist-hip ratio and wide waist circumference, but the converse is not necessarily true. Consequently, centralized obesity (a risk factor for several chronic diseases) is not always captured by a high BMI alone.


Brain Changes Associated With Long-Term Ketamine Abuse, A Systematic Review.
Recently, the abuse of ketamine has soared. Therefore, it is of great importance to study its potential risks. The effects of prolonged ketamine on the brain can be observationally studied in chronic recreational users. We performed a systematic review of studies reporting functional and structural brain changes after repeated ketamine abuse. We searched the following electronic databases: Medline, Embase and PsycINFO We screened 11,438 records and 16 met inclusion criteria, totaling 440 chronic recreational ketamine users (2-9.7 years; mean use 2.4 g/day), 259 drug-free controls and 44 poly-drug controls. Long-term recreational ketamine use was associated with lower gray matter volume and less white matter integrity, lower functional thalamocortical and corticocortical connectivity. The observed differences in both structural and functional neuroanatomy between ketamine users and controls may explain some of its long-term cognitive and psychiatric side effects, such as memory impairment and executive functioning. Given the effect that long-term ketamine exposure may yield, an effort should be made to curb its abuse.


Projection neuron circuits resolved using correlative array tomography.
Assessment of three-dimensional morphological structure and synaptic connectivity is essential for a comprehensive understanding of neural processes controlling behavior. Different microscopy approaches have been proposed based on light microcopy (LM), electron microscopy (EM), or a combination of both. Correlative array tomography (CAT) is a technique in which arrays of ultrathin serial sections are repeatedly stained with fluorescent antibodies against synaptic molecules and neurotransmitters and imaged with LM and EM (Micheva and Smith, 2007). The utility of this correlative approach is limited by the ability to preserve fluorescence and antigenicity on the one hand, and EM tissue ultrastructure on the other. We demonstrate tissue staining and fixation protocols and a workflow that yield an excellent compromise between these multimodal imaging constraints. We adapt CAT for the study of projection neurons between different vocal brain regions in the songbird. We inject fluorescent tracers of different colors into afferent and efferent areas of HVC in zebra finches. Fluorescence of some tracers is lost during tissue preparation but recovered using anti-dye antibodies. Synapses are identified in EM imagery based on their morphology and ultrastructure and classified into projection neuron type based on fluorescence signal. Our adaptation of array tomography, involving the use of fluorescent tracers and heavy-metal rich staining and embedding protocols for high membrane contrast in EM will be useful for research aimed at statistically describing connectivity between different projection neuron types and for elucidating how sensory signals are routed in the brain and transformed into a meaningful motor output.


Comparison of the Technique of the Football Quarterback Pass Between High School and University Athletes.
Toffan, A, Alexander, MJL, and Peeler, J. Comparison of the technique of the football quarterback pass between high school and university athletes. J Strength Cond Res 32(9): 2474-2497, 2018-The purpose of the study was to compare the most effective joint movements, segment velocities, and body positions to perform the fastest and most accurate pass of high school and university football quarterbacks. Secondary purposes were to develop a quarterback throwing test to assess skill level, to determine which kinematic variables were different between high school and university athletes, and to determine which variables were significant predictors of quarterback throwing test performance. Ten high school and 10 university athletes were filmed for the study, performing 9 passes at a target and 2 passes for maximum distance. Thirty variables were measured using Dartfish Team Pro 4.5.2 video analysis system, and Microsoft Excel was used for statistical analyses. University athletes scored slightly higher than the high school athletes on the throwing test; however, this result was not statistically significant. Correlation analysis and forward stepwise multiple regression analysis were performed on both the high school players and the university players to determine which variables were significant predictors of throwing test score. Ball velocity was determined to have the strongest predictive effect on throwing test score (r = 0.900) for the high school athletes; however, position of the back foot at release was also determined to be important (r = 0.661) for the university group. Several significant differences in throwing technique between groups were noted during the pass; however, body position at release showed the greatest differences between the 2 groups. High school players could benefit from more complete weight transfer and decreased throw time to increase throwing test score. University athletes could benefit from increased throw time and greater range of motion in external shoulder rotation and trunk rotation to increase their throwing test score. Coaches and practitioners will be able to use the findings of this research to help improve these and related throwing variables in their high school and university quarterbacks.


Effectiveness of beclomethasone dipropionate aerosolized through different nebulizers to asthmatic patients.
The aim of our study was to verify if the type of nebulizer used could influence the results of aerosol therapy with beclomethasone dipropionate (BDP) in mild allergic asthma. We assigned 27 asthmatics allergic to grasses to 3 groups and treated them from May to July 1998 with aerosol therapy with BDP (800 microg) b. i. d. via nebulizer + pMDI salbutamol (200 microg) if necessary. Each group used a different type of nebulizer: jet nebulizer with glass ampoule (group JG); jet nebulizer with polycarbonate ampoule (group JP); ultrasonic nebulizer (group US). During the study patients underwent periodic lung function tests and methacholine bronchial challenges, recorded twice a day self-monitoring PEF and filled out a daily diary for the presence and intensity of asthmatic symptoms. At the end of the study the provocative dose of methacholine causing a 20% fall in FEV1 (PD20), the self-monitoring PEF and the clinical scores were all greatly improved, but without any statistically significant difference among the three groups. On the contrary, the variations during the study of basal spirometric parameters (specifically FEV1, PEF, FEF25) were significantly better in jet nebulizer groups than in group US. The results coming from the aerosol characterization that we carried out for each of the three nebulizers confirmed the clinical findings, since jet nebulizers showed greatly lower MMAD than the ultrasonic nebulizer (2.9 and 3.7 vs 5.8). Our data suggest that jet nebulizers are more appropriate than ultrasonic nebulizers for delivering BDP in aerosol therapy.


Crystal structure of human aurora B in complex with INCENP and VX-680.
We present the structure of the human Aurora B kinase domain in complex with the C-terminal Aurora-binding region of human INCENP and the Aurora kinase inhibitor VX-680. The structure unexpectedly reveals a dimeric arrangement of the Aurora B:INCENP complex, which was confirmed to exist in solution by analytical ultracentrifugation. The dimerization involves a domain swap of the activation loop, resulting in a different conformation of the DFG motif as compared to that seen in other kinase complexes with VX-680. The binding of INCENP differs significantly from that seen in the Xenopus laevis Aurora B:INCENP complex currently used as a model for structure-based design for this important oncology target.


Iatrogenesis in neonatal intensive care units: observational and interventional, prospective, multicenter study.
The goals were to determine the incidence of iatrogenic events in NICUs and to determine whether awareness of iatrogenic events could influence their occurrence. We performed a prospective, observational, interventional, multicenter study including all consecutive infants hospitalized in 4 NICUs. In the first 3 months (observation period), the medical teams were unaware of the study; in the next 3 months (intervention period), they were made aware of daily ongoing monitoring of iatrogenic events by a designated "Iatrogenesis Advocate." The numbers of infants admitted to the NICUs were comparable during the observation and intervention periods (328 and 369 infants, respectively). There was no difference between the 2 periods with respect to the number of infants of <1500 g, hospitalization days, or mean daily occupancy of the NICUs. Although the prevalence rates of iatrogenic events were comparable in the observation and intervention periods (18.0 and 18.2 infants with iatrogenic events per 100 hospitalized infants, respectively), the incidence rate decreased significantly during the intervention period (3.2 and 2.4 iatrogenic events per 100 hospitalization days of new admissions, respectively). Of all iatrogenic events, 7.9% were classified as life-threatening and 45.1% as harmful. There was no death related to an iatrogenic event. Eighty-three percent of iatrogenic events were considered preventable, of which 26.9% resulted from medical errors in ordering or delivery of medical care. Only 1.6% of all iatrogenic events were intercepted before reaching the infants, and only 47.0% of iatrogenic events were corrected. For younger and smaller infants, the rate of iatrogenic events was higher (57% at gestational ages of 24 to 27 weeks, compared with 3% at term) and the iatrogenic events were more severe and harmful. Increased length of stay was associated independently with more iatrogenic events. Neonatal medical teams and parents should be aware of the burden of iatrogenesis, which occurs at a significant rate.


Monoclonal antibodies in immune and inflammatory diseases.
The era of monoclonal antibody-based therapeutics has arrived. Monoclonal antibodies of high quality targeting almost any antigen can now be engineered and manufactured in large quantities. In the clinic, monoclonal antibodies are proving to be safe and effective for the treatment of a wide range of diseases including rheumatoid arthritis, Crohn's disease, spondyloarthropathies, psoriasis and allograft rejection.


Informal care, older people, and COVID-19: Evidence from the UK.
The negative health effects and mortality caused by the COVID-19 pandemic disproportionately fell upon older and disabled people. Protecting these vulnerable groups has been a key policy priority throughout the pandemic and related vaccination campaigns. Using data from the latest survey of the UK Household Longitudinal Study on COVID-19 we found that people who receive informal care have higher probability of being infected when compared to those not receiving informal care. Further, we found that care recipients who are in the lowest income groups have a higher probability of catching the virus when compared to those in the highest income groups. We also estimated the likelihood of being infected for informal carers versus those who did not provide any care during the pandemic and found no significant differences between these two groups. Our empirical findings suggest that the standard measures introduced with the aim of protecting vulnerable groups, such as closing care homes or prioritising the vaccination of their staff, were not sufficient to avoid the spread of the virus amongst disabled and older people. Informal carers play an important role in the social care sector. As such, protecting vulnerable people by investing in the informal care sector should be a priority for future health policy.


The BEG (PP2A-B55/ENSA/Greatwall) pathway ensures cytokinesis follows chromosome separation.
Cytokinesis follows separase activation and chromosome segregation. This order is ensured in budding yeast by the mitotic exit network (MEN), where Cdc14p dephosphorylates key conserved Cdk1-substrates exemplified by the anaphase spindle-elongation protein Ase1p. However, in metazoans, MEN and Cdc14 function is not conserved. Instead, the PP2A-B55α/ENSA/Greatwall (BEG) pathway controls the human Ase1p ortholog PRC1. In this pathway, PP2A-B55 inhibition is coupled to Cdk1-cyclin B activity, whereas separase inhibition is maintained by cyclin B concentration. This creates two cyclin B thresholds during mitotic exit. Simulation and experiments using PRC1 as a model substrate show that the first threshold permits separase activation and chromosome segregation, and the second permits PP2A-B55 activation and initiation of cytokinesis. Removal of the ENSA/Greatwall (EG) timer module eliminates this second threshold, as well as associated delay in PRC1 dephosphorylation and initiation of cytokinesis, by uncoupling PP2A-B55 from Cdk1-cyclin B activity. Therefore, temporal order during mitotic exit is promoted by the metazoan BEG pathway.


Role of assessment for retreatment with Transarterial chemoembolization score in decision of Retreatment with trans-arterial chemo-embolization Sessions in patients with hepatocellular carcinoma.
The objective behind this study was to determine that Assessment for Retreatment with Transarterial chemoembolization (ART) score is really applicable in patients with hepatocellular carcinoma. A cross sectional observational study was conducted on all patients with hepatocellular carcinoma of intermediate stage and undergone ≥2 Transarterial chemoembolization. ART score was assessed before and after each session of Transarterial chemoembolization. Multi-logistic regression analysis was performed to compare the final outcome of patients with ART score of ≥2.5 into groups with two and more than two Trans-arterial chemo-embolization sessions. A total of 100 HCC patients were recruited for final analysis. Our study participants consisted of total 100 HCC patients. Mean Child Pugh score was 6.1±0.95. In our study, most of the study participants (n=63) had ART score of less than 1.5 as compared to ART score >2.5 (n=37). A significant proportion of patients with ART score of <1.5 prior to second Trans-arterial chemo-embolization had better median survival as compared to patients with ART score of >2.5, p-value<0.001. Patients with ART score of more than 2.5 did not show any survival benefit after having 3rd or 4th Trans-arterial chemo-embolization session, p=0.47. Our study findings suggest that those HCC patients who receive multiple sessions of TACE with a low ART score have more favourable outcomes with increased survival rate.


Classification and treatment of shoulder dysfunction in the overhead athlete.
There are two distinct pathological categories of shoulder injury. In the older population, shoulder injury is generally a result of the degenerative aging process. In the younger population, it is commonly a result of the repetitiousness of an overhead sport. In the latter group, instability is typically the core problem, leading to the continuum of subluxation, impingement, and rotator cuff tear. A classification scheme, proposing four definitive types of shoulder injury, assists in directing an effective management program. Once diagnosed (the first step of treatment) a conservative rehabilitation program that emphasizes strengthening of the glenohumeral protectors, scapulohumeral pivotors, humeral positioners, and power drivers is advised. The surgery of choice, for the small minority who fail to respond to the rehabilitation program, is the anterior capsulolabral reconstruction. A sports medicine team working together with the athlete is instrumental in his/her return to sport.


Investigation of Snoring and Obstructive Sleep Apnea Using Portable Polysomnography in Patients with Temporomandibular Disorder.
To investigate snoring and obstructive sleep apnea (OSA) in patients with temporomandibular disorder (TMD) using portable polysomnography and identify sex-based differences in clinical features and sleep-related results. Seventy consecutive patients (44 female; mean age, 46.6918.18 years) with myofascial pain-associated TMD, diagnosed based on the criteria for TMD Axis I, were enrolled. Sleep quality and quantity were measured using portable polysomnography. Clinical characteristics were investigated using well-structured standardized reports on clinical signs and symptoms, questionnaires, and clinical examination by TMD specialists. Among 70 TMD patients, 50.0% had OSA and 15.7% had snoring, with no sex-based differences. The mean Mallampati scores for OSA prediction (2.69±1.12 vs. 1.70±0.82, p<0.001), mean body mass index (BMI) (24.94±1.78 vs. 22.02±2.24, p<0.001), and ratio of overweight patients (57.7 vs. 11.4%) with BMI ≥25 were significantly higher in males than in females (all p<0.001). Conversely, the mixed sleep apnea index was significantly higher in females than in males (0.81±0.80 vs. 0.44±0.54, p=0.022). Female sex was associated with the absence of snoring (OR=0.146, p=0.022). Based on the area under curve (AUC) value for snoring prediction, Mallampati score was the strongest predictor (AUC>0.932, p<0.001), followed by BMI, overweight, and obstructive sleep apnea index (AUC>0.8, all p<0.001). Our results support the necessity of investigating sex-based differences when examining sleep problems, including snoring and OSA, in TMD patients. Mallampati scoring could be a useful tool for physical examination prior to polysomnography. Sleep and biopsychosocial factors are important for the diagnosis and treatment of TMD.