Case management to improve adherence for HIV-infected patients receiving antiretroviral therapy in Ethiopia: a micro-costing study.
Adherence to antiretroviral medication regimens is essential to good clinical outcomes for HIV-infected patients. Little is known about the costs of case management (CM) designed to improve adherence for patients identified as being at risk for poor adherence in resource-constrained settings. This study analyzed the costs, outputs, unit costs and correlates of unit cost variation for CM services in 14 ART sites in Ethiopia from October 2008 through September 2009. This study applied standard micro-costing methods to identify the incremental costs of the CM program. We divided total CM-attributable costs by three output measures (patient-quarters of CM services delivered, number of patients served and successful patient exits) to derive three separate indices of unit costs. The relationships between unit costs and two operational factors (scale and service-volume to staff ratios) were quantified through bivariate analyses. The CM program delivered 4,598 patient-quarters of services, serving 5,056 patients and 1,995 successful exits at a cost of $167,457 over 12 months, or $36 per patient-quarter, $33 per patient served and $84 per successful exit from the CM program. Among the 14 sites, mean costs were $11,961 (sd, $3,965) for the 12-month study period, and $51 (sd, $36) per patient-quarter; $48 (sd, $32) per patient served; and $183 (sd, $157) per successful exit. Unit costs varied inversely with scale (r, -0.70 for cost per patient-quarter versus patient-quarters of service) and with the service-volume to staff ratio (r, -0.68 for cost per patient-quarter versus staff per patient-quarter). For those receiving CM, the program adds 0.52% to the lifetime cost of ART. These data reflect wide variation in unit costs among the study sites and suggest that high patient volume may be a major determinant of CM program efficiency. The observed variations in unit costs also indicate that there may be opportunities to identify staffing patterns that increase overall program efficiency.


Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors.
Exposure of aged mice to a young systemic milieu revealed remarkable rejuvenation effects on aged tissues, including skeletal muscle. Although some candidate factors have been identified, the exact identity and the underlying mechanisms of putative rejuvenating factors remain elusive, mainly due to the complexity of in vivo parabiosis. Here, we present an in vitro muscle parabiosis system that integrates young- and old-muscle stem cell vascular niche on a three-dimensional microfluidic platform designed to recapitulate key features of native muscle stem cell microenvironment. This innovative system enables mechanistic studies of cellular dynamics and molecular interactions within the muscle stem cell niche, especially in response to conditional extrinsic stimuli of local and systemic factors. We demonstrate that vascular endothelial growth factor (VEGF) signaling from endothelial cells and myotubes synergistically contribute to the rejuvenation of the aged muscle stem cell function. Moreover, with the adjustable on-chip system, we can mimic both blood transfusion and parabiosis and detect the time-varying effects of anti-geronic and pro-geronic factors in a single organ or multi-organ systems. Our unique approach presents a complementary in vitro model to supplement in vivo parabiosis for identifying potential anti-geronic factors responsible for revitalizing aging organs.


Azimuthal anisotropy and correlations at large transverse momenta in p + p and Au + Au collisions at square root sNN=200 GeV.
Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au + Au collisions at square root s(NN)=200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au + Au collisions to those in p + p at the same energy. The elliptic anisotropy v(2) is found to reach its maximum at p(t) approximately 3 GeV/c, then decrease slowly and remain significant up to p(t) approximately 7-10 GeV/c. Stronger suppression is found in the back-to-back high-p(t) particle correlations for particles emitted out of plane compared to those emitted in plane. The centrality dependence of v(2) at intermediate p(t) is compared to simple models based on jet quenching.


The use of ultrasound guidance for perioperative neuraxial and peripheral nerve blocks in children.
The use of ultrasound guidance for regional anaesthesia has become popular over the past two decades. However, it is not recognized by all experts as an essential tool. The cost of an ultrasound machine is substantially higher than the cost of other tools such as a nerve stimulator. To determine whether ultrasound guidance offers any clinical advantage when neuraxial and peripheral nerve blocks are performed in children in terms of increasing the success rate or decreasing the rate of complications. We searched the following databases to March 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), EMBASE (OvidSP) and Scopus (from inception to 27 January 2015). We included all parallel randomized controlled trials (RCTs) that evaluated the effects of ultrasound guidance used when a regional blockade technique was performed in children, and that included any of our selected outcomes. We assessed selected studies for risk of bias by using the assessment tool of The Cochrane Collaboration. Two review authors independently extracted data. We graded the level of evidence for each outcome according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Working Group scale. We included 20 studies (1241 participants) for which the source of funding was a government organization (two studies), a charitable organization (one study), an institutional department (four studies) or an unspecified source (11 studies); two studies declared that they received help from the industry (equipment loan). In 14 studies (939 participants), ultrasound guidance increased the success rate by decreasing the occurrence of a failed block: risk difference (RD) -0.11 (95% confidence interval (CI) -0.17 to -0.05); I(2) = 64%; number needed for additional beneficial outcome for a peripheral nerve block (NNTB) 6 (95% CI 5 to 8). Blocks were performed under general anaesthesia (usual clinical practice in this population); therefore, haemodynamic changes to the surgical stimulus (rather than classic sensory/motor blockade evaluation) were used to define success. For peripheral nerve blocks, the younger the child, the greater was the benefit. In eight studies (414 participants), pain scores at one hour in the post-anaesthesia care unit were reduced when ultrasound guidance was used; however, the clinical relevance of the difference was unclear (equivalent to -0.2 on a scale from 0 to 10). In eight studies (358 participants), block duration was longer when ultrasound guidance was used: standardized mean difference (SMD) 1.21 (95% CI 0.76 to 1.65; I(2) = 73%; equivalent to 62 minutes). Here again, younger children benefited most from ultrasound guidance. Time to perform the procedure was reduced when ultrasound guidance was used for pre-scanning before a neuraxial block (SMD -1.97, 95% CI -2.41 to -1.54; I(2) = 0%; equivalent to 2.4 minutes; two studies with 122 participants) or as an out-of-plane technique (SMD -0.68, 95% CI -0.96 to -0.40; I(2) = 0%; equivalent to 94 seconds; two studies with 204 participants). In two studies (122 participants), ultrasound guidance reduced the number of needle passes required to perform the block (SMD -0.90, 95% CI -1.27 to -0.52; I(2) = 0%; equivalent to 0.6 needle pass per participant). For two studies (204 participants), we could not demonstrate a difference in the incidence of bloody puncture when ultrasound guidance was used for neuraxial blockade, but we found that the number of participants was well below the optimal information size (RD -0.07, 95% CI -0.19 to 0.04). No major complications were reported for any of the 1241 participants. We rated the quality of evidence as high for success, pain scores at one hour, block duration, time to perform the block and number of needle passes. We rated the quality of evidence as low for bloody punctures. Ultrasound guidance seems advantageous, particularly in young children, for whom it improves the success rate and increases the block duration. Additional data are required before conclusions can be drawn on the effect of ultrasound guidance in reducing the rate of bloody puncture.


Prevalence of systemic immunoreactivity to Aggregatibacter actinomycetemcomitans leukotoxin in relation to the incidence of myocardial infarction.
Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular disease (CVD). The proinflammatory cytokine, interleukin (IL)-1β, is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Aggregatibacter actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1β from macrophages. The aim of the present study was to compare the prevalence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin in myocardial infarction (MI) cases (n = 532) and matched controls (n = 1,000) in a population-based case and referents study in northern Sweden. Capacity to neutralize A. actinomycetemcomitans leukotoxin was analyzed in a bioassay with leukocytes, purified leukotoxin, and plasma. Plasma samples that inhibited lactate-dehydrogenase release from leukotoxin-lysed cells by ≥ 50% were classified as positive. Neutralizing capacity against A. actinomycetemcomitans leukotoxin was detected in 53.3% of the plasma samples. The ability to neutralize leukotoxin was correlated to increasing age in men (n = 1,082) but not in women (n = 450). There was no correlation between presence of systemic leukotoxin-neutralization capacity and the incidence of MI, except for women (n = 146). Women with a low neutralizing capacity had a significantly higher incidence of MI than those who had a high neutralizing capacity. Systemic immunoreactivity against A. actinomycetemcomitans leukotoxin was found at a high prevalence in the analyzed population of adults from northern Sweden. The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI.


Characterization of global transcription profile of normal and HPV-immortalized keratinocytes and their response to TNF treatment.
Persistent infection by high risk HPV types (e.g. HPV-16, -18, -31, and -45) is the main risk factor for development of cervical intraepithelial neoplasia and cervical cancer. Tumor necrosis factor (TNF) is a key mediator of epithelial cell inflammatory response and exerts a potent cytostatic effect on normal or HPV16, but not on HPV18 immortalized keratinocytes. Moreover, several cervical carcinoma-derived cell lines are resistant to TNF anti-proliferative effect suggesting that the acquisition of TNF-resistance may constitute an important step in HPV-mediated carcinogenesis. In the present study, we compared the gene expression profiles of normal and HPV16 or 18 immortalized human keratinocytes before and after treatment with TNF for 3 or 60 hours. In this study, we determined the transcriptional changes 3 and 60 hours after TNF treatment of normal, HPV16 and HPV18 immortalized keratinocytes by microarray analysis. The expression pattern of two genes observed by microarray was confirmed by Northern Blot. NF-kappaB activation was also determined by electrophoretic mobility shift assay (EMSA) using specific oligonucleotides and nuclear protein extracts. We observed the differential expression of a common set of genes in two TNF-sensitive cell lines that differs from those modulated in TNF-resistant ones. This information was used to define genes whose differential expression could be associated with the differential response to TNF, such as: KLK7 (kallikrein 7), SOD2 (superoxide dismutase 2), 100P (S100 calcium binding protein P), PI3 (protease inhibitor 3, skin-derived), CSTA (cystatin A), RARRES1 (retinoic acid receptor responder 1), and LXN (latexin). The differential expression of the KLK7 and SOD2 transcripts was confirmed by Northern blot. Moreover, we observed that SOD2 expression correlates with the differential NF-kappaB activation exhibited by TNF-sensitive and TNF-resistant cells. This is the first in depth analysis of the differential effect of TNF on normal and HPV16 or HPV18 immortalized keratinocytes. Our findings may be useful for the identification of genes involved in TNF resistance acquisition and candidate genes which deregulated expression may be associated with cervical disease establishment and/or progression.


Chest reconstruction: II. Regional reconstruction of chest wall wounds that do not affect respiratory function (axilla, posterolateral chest, and posterior trunk).
The reader of this review will develop knowledge and understanding of the following: 1. Indications for posterior trunk and axillary reconstruction. 2. The reconstructive requirements of posterior chest wall and axillary wounds. 3. Flaps for regional reconstruction of the torso and axilla. 4. Congenital posterior trunk deformities and their management. 5. The role of microvascular surgery in chest wall reconstruction. 6. The recent emphasis on the role of perforator flaps. 7. The relative advantages and disadvantages of muscle flaps versus perforator skin and fasciocutaneous flaps. Regional reconstructions of the axilla, posterolateral chest, and posterior trunk may prove difficult because of relative inaccessibility for pedicle flaps, exposure of prosthetic material, and loss of function. Review of past and current medical literature, together with personal experience, has enabled development of this article. A host of regional muscle and musculocutaneous pedicle flaps are available from both the upper and lower limb girdle. These muscle flaps, however, come at the price of compromising donor motor function. This donor morbidity can be reduced either by segmentally splitting muscle flaps or by recourse to perforator artery flaps. Some areas may be difficult to reach, especially the upper and lower back in the midline. Occasionally, microvascular reconstruction is required. Tissue expansion has a limited role in these reconstructions but most notably is an aid to separation of conjoined twins. A variety of regional fasciocutaneous and musculocutaneous flaps are available to cover congenital or acquired defects of the posterior trunk and axilla. Use of perforator flaps has recently been popularized. One must be cognizant of possible functional deficits that may result when using regional muscle flaps both on ambulation and potential to power a manual wheelchair or use crutches.


Immune cell populations within the duodenal mucosa of dogs with enteropathies.
The mucosal immune system may play a critical role in the pathogenesis of small intestinal enteropathies. The aim of the current study was to assess mucosal immune cell populations in dogs with inflammatory bowel disease (IBD), idiopathic antibiotic-responsive diarrhea (ARD), and adverse reactions to food (FR). Endoscopic biopsies were performed of the duodenum of dogs with these conditions and from a group of dogs without enteric disease. Additional control samples were collected after death from other dogs that did not have evidence of enteric disease. Immunohistochemistry and computer-aided morphometry were used to assess the distribution of immune cell subsets in both lamina propria and intestinal epithelium. Compared with controls, dogs with ARD had increased numbers of lamina propria immunoglobulin (Ig) A- plasma cells and CD4+ cells. More marked alterations were noted in dogs with IBD, with significant increases in lamina propria IgG+ plasma cells, T cells (CD3+), CD4+ cells, macrophages, and neutrophils, but with reduced mast cell numbers. Increased intraepithelial CD3+ T cells were also present in the dogs with IBD, compared with controls. However, lamina propria and epithelial populations were unaltered in dogs with FR when compared with controls. The altered mucosal immune cell populations observed in dogs with ARD or IBD may reflect an underlying immunologic pathogenesis in these disorders.


Characterization of infiltrating lymphocytes in human benign and malignant prostate tissue.
Immune checkpoint blockade has shown promising results in numerous cancer types. However, in prostate cancer (PC), absent or limited responses have been reported. To investigate further, we compared the phenotype of infiltrating T-cells isolated from prostate tissue from patients with PC (n = 5), benign prostatic hyperplasia (BPH) (n = 27), BPH with concurrent PC (n = 4) and controls (n = 7). The majority of T-cells were CD8+ and had a CCR7-CD45RO+ effector memory phenotype. However, the yield of T-cells isolated from PC lesions was on average 20-fold higher than that obtained from control prostates. Furthermore, there were differences between the prostate conditions regarding the percentage of T-cells expressing several activation markers and co-inhibitory receptors. In conclusion, many prostate-infiltrating T-cells express co-inhibitory receptors PD-1 and LAG-3, regardless of prostate condition. Despite the observed increase in counts and percentages of PD-1+ T-cells in PC, the concomitant demonstration of high percentage of PD-1+ T-cells in control prostates suggests that PD-1 may play a role in controlling the homeostasis of the prostate rather than in contributing to PC-associated immune-suppression. Thus, PD-1 may not be a good candidate for checkpoint blockade in PC and these data are relevant for evaluation of clinical trials and in designing future immunotherapeutic approaches of PC.


A simple simulation model of tuberculosis epidemiology for use without large-scale computers.
A large-scale computer service is not always available in many countries with tuberculosis problems needing epidemiological analysis. To facilitate work in such countries, a simple epidemiological model was made to calculate annual trends in the prevalence and incidence of tuberculosis and its infection, in tuberculosis mortality, and in BCG coverage, using average parameter values not specific for age groups or birth year cohorts. To test its approximation capabilities and limits, the model was applied to epidemiological data from Japan, where sufficient information was available from repeated nation-wide sample surveys and national statistics. The approximation was found to be satisfactory within certain limits. The model is best used with a desk-top computer, but the calculations can be performed with a small calculator or even by hand.


Futurism in nursing: Technology, robotics and the fundamentals of care.
To explore the concept of futurism and the emergence of robotics in relation to the fundamentals of care, highlighting how nurses need a more anticipatory and contemporary position towards technology to maintain relevance in the future. The future of nursing in Western countries will soon be linked with the emergence of robotics for efficient and cost-effective provision of fundamental care. Their emergence and roles with care of the body and more broadly assisting people with their daily living activities has enormous implications for the profession and health care. Despite this importance, how nursing understands and will respond to technological trends and developments is insufficiently reflected in the professions discourse. A discursive article. Literature from nursing fundamentals of care/fundamental care, information science, technology, humanities and philosophy informed the arguments in this article. This article examines the intersection of futurism and the fundamentals of care, and how adopting an anticipatory and posthuman perspective towards technological-care integration is necessary amidst a robot revolution in the techno-era. Nurses are currently challenged to understand, prioritise and deliver fundamental care. Health systems are challenged by a lack of care predicated by shortfalls in skilled staff and deficiencies in staff mobilisation. Both challenges can be compounded or alleviated by further integration of technology, but to maximise benefit requires forethought and understanding. This article can help open needed dialogue around planning for the future and is a call to action for the nursing profession to conceptualise its position on exponential technological growth and fundamental care provision.


Diagnosis and management of intestinal motility disorders.
Gastrointestinal motility disorders in their most severe forms may directly lead to intestinal failure. Abnormal motor function may also contribute to the overall gut dysfunction of children who have other underlying gastrointestinal diseases, such as Hirschsprung disease or gastroschisis. Understanding the extent and the severity of the dysmotile segments has direct therapeutic and prognostic implications. Our ability to study gastrointestinal motility has greatly improved in the past few years, with the development of less-invasive diagnostic tests. Optimal treatment of children with intestinal motility disorders relies on a multidisciplinary approach, which focuses on optimizing nutrition, improving gastrointestinal motility, and reducing psychosocial disability. Patient education is important to avoid aggravations of symptoms caused by dietary indiscretions.


Co-expression of multiple neurotransmitter enzyme genes in normal and immortalized sympathoadrenal progenitor cells.
We have examined the expression of mRNAs encoding five major neurotransmitter-synthesizing enzymes in MAH cells, a clonal cell line derived by retroviral immortalization of a rat embryonic sympathoadrenal progenitor cell. These mRNAs include tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), tryptophan hydroxylase (TpH), and glutamic acid decarboxylases (GADs) 1 and 2. We find that MAH cells express high levels of TH mRNA and low levels of ChAT and TpH mRNAs. Neither GAD1 nor GAD2 mRNAs are detectable using an RNase protection assay with a detection limit of less than one transcript per cell. A similar pattern of mRNA expression is observed in postnatal superior cervical ganglia, adrenal medulla, and in PC12 cells. Transmitter synthesis and accumulation assays indicate that MAH cells can synthesize both catecholamines and acetylcholine. Thus the TH and ChAT mRNAs detected in these cells are likely to be translated into active enzyme. To corroborate these data obtained using MAH cells, we performed similar transmitter synthesis and accumulation assays on sympathoadrenal progenitors directly isolated from E14.5 fetal adrenal glands by fluorescence-activated cell sorting. These progenitor cells also synthesize and accumulate both catecholamines and acetylcholine, albeit to different extents than MAH cells. Both MAH cells and their nonimmortal counterparts are able to increase slightly their cholinergic function upon short-term exposure to CDF/LIF, a factor known to induce acetylcholine synthesis in postmitotic sympathetic neurons. Taken together, these data suggest that progenitor cells in the sympathoadrenal lineage acquire the ability to simultaneously transcribe several different neurotransmitter enzyme genes early in development, prior to their choice of final cell fate. At the same time, the progenitors possess receptors which regulate expression of these genes in response to environmental factors. This ability may permit the cells to choose from several different transmitter phenotypes in response to different environments, as they migrate through the embryo. The persistent transcription of these genes in adult cells, moreover, may in part account for the phenotypic plasticity of cells in this lineage.


Engineered Nanoerythrocytes Alleviate Central Nervous System Inflammation by Regulating the Polarization of Inflammatory Microglia.
Microglial polarization is one of the most promising therapeutic strategies for multiple central nervous system (CNS) disorders. However, safe, effective, and controllable microglial regulation still faces formidable challenges. Although some anti-inflammatory factors promote microglia polarization, their short half-life, high cost, unpredictable in vivo behavior, and complex delivery operations, hamper their clinical application. Here, inspired by the natural microhemorrhage cleaning mechanism, an MG1 peptide and RVG29 peptide engineered nanoerythrocyte (NEMR) that can reprogram microglia are developed from classical M1 toward alternative M2 by inducing heme oxygenase-1 (HO-1), stimulating Notch1/Hes1/Stat3 signaling, and further inhibiting NF-κB p65 translocation. Moreover, anti-inflammatory carbon monoxide (CO) and bilirubin produced by endogenous metabolism of heme further reinforces the anti-inflammatory effect. In middle cerebral artery occlusion and experimental autoimmune encephalomyelitis models, a satisfactory prognosis is achieved, with precise regulation of inflammatory microglia in lesion sites, increased expression of anti-inflammatory factors, reduced blood-brain barrier permeability, as well as promotion of neurogenesis and functional recovery. Furthermore, NEMR can be integrated with clinical therapeutic agents, which facilitates precise drug delivery to enhance therapeutic effects. Hence, the natural nanoerythrocytes, as a feasible, efficient, safe, and practical tool, provides a new strategy for rebalancing of the immune environment in the CNS disorders.


Safety and efficacy of carotid arteriography in vascular surgery practice.
Carotid arteriography (CA) is an important method of assessing carotid artery occlusive disease and is the best method of planning for carotid angioplasty and stent placement (CAS). This study compared the results of CA performed by vascular surgeons in a contemporary series against widely recognized interdisciplinary quality standards for this procedure. Although many vascular surgeons perform CA, there is a paucity of data about its safety, efficacy, and compliance with quality standards in vascular practice. The importance of quality CA will likely increase as CAS emerges to assume a broader clinical role. Carotid arteriograms performed by seven vascular surgeons at three institutions from September 2000 to May 2004 were reviewed. These results were compared with quality standards for the performance of CA. Five hundred three carotid arteriograms were performed over 45 months. Indications for the procedure were extracranial cerebrovascular disease (86%), trauma (5%), and other conditions (9%). Indications for the procedure were appropriate in 100% of patients (as determined by guidelines document) and exceeded the recommended standard of appropriate indications in 99%. All procedures successfully provided the information required, exceeding the threshold of 98% for procedural success. Reversible neurologic deficits occurred in 0.6% (two transient ischemic attacks and one stroke) compared with the threshold of 2.5%. A permanent neurologic deficit occurred in 0.2% (1 patient) compared with the published guideline of 1% after carotid arteriography. Major non-neurologic complications occurred in 1.2% (6 patients), less than the standard of 2.0%. The safety and efficacy of a contemporary series of CA performed in vascular surgery practice compared favorably with recognized interdisciplinary quality standards for this procedure. Ensuring safe and effective CA is likely to support the successful growth of CAS as a treatment option.


Linear IgA disease presenting as desquamative gingivitis: a pattern poorly recognized in medicine.
Linear IgA disease is a subepidermal blistering disorder of unknown cause. Along with dermatologic blistering, other manifestations include oral ulceration and desquamative gingivitis. We present a case of linear IgA disease that manifested simply as oropharyngeal ulceration and desquamative gingivitis, resulting in considerable delay in diagnosis and treatment. This article (1) highlights the difficulties of diagnosing linear IgA disease when the predominant presenting features are mucosal and (2) reviews the current literature regarding linear IgA disease.


Visual SLAM for Handheld Monocular Endoscope.
Simultaneous localization and mapping (SLAM) methods provide real-time estimation of 3-D models from the sole input of a handheld camera, routinely in mobile robotics scenarios. Medical endoscopic sequences mimic a robotic scenario in which a handheld camera (monocular endoscope) moves along an unknown trajectory while observing an unknown cavity. However, the feasibility and accuracy of SLAM methods have not been extensively validated with human in vivo image sequences. In this work, we propose a monocular visual SLAM algorithm tailored to deal with medical image sequences in order to provide an up-to-scale 3-D map of the observed cavity and the endoscope trajectory at frame rate. The algorithm is validated over synthetic data and human in vivo sequences corresponding to 15 laparoscopic hernioplasties where accurate ground-truth distances are available. It can be concluded that the proposed procedure is: 1) noninvasive, because only a standard monocular endoscope and a surgical tool are used; 2) convenient, because only a hand-controlled exploratory motion is needed; 3) fast, because the algorithm provides the 3-D map and the trajectory in real time; 4) accurate, because it has been validated with respect to ground-truth; and 5) robust to inter-patient variability, because it has performed successfully over the validation sequences.


An experimental investigation of evolutionary dynamics in the Rock-Paper-Scissors game.
Game theory describes social behaviors in humans and other biological organisms. By far, the most powerful tool available to game theorists is the concept of a Nash Equilibrium (NE), which is motivated by perfect rationality. NE specifies a strategy for everyone, such that no one would benefit by deviating unilaterally from his/her strategy. Another powerful tool available to game theorists are evolutionary dynamics (ED). Motivated by evolutionary and learning processes, ED specify changes in strategies over time in a population, such that more successful strategies typically become more frequent. A simple game that illustrates interesting ED is the generalized Rock-Paper-Scissors (RPS) game. The RPS game extends the children's game to situations where winning or losing can matter more or less relative to tying. Here we investigate experimentally three RPS games, where the NE is always to randomize with equal probability, but the evolutionary stability of this strategy changes. Consistent with the prediction of ED we find that aggregate behavior is far away from NE when it is evolutionarily unstable. Our findings add to the growing literature that demonstrates the predictive validity of ED in large-scale incentivized laboratory experiments with human subjects.


Twenty years of workers' compensation costs due to falls from height among union carpenters, Washington state.
Falls from height (FFH) are a longstanding, serious problem in construction. We report workers' compensation (WC) payments associated with FFH among a cohort (n = 24,830; 1989-2008) of carpenters. Mean/median payments, cost rates, and adjusted rate ratios based on hours worked were calculated using negative-binomial regression. Over the 20-year period FFH accounted for $66.6 million in WC payments or $700 per year for each full-time equivalent (2,000 hr of work). FFH were responsible for 5.5% of injuries but 15.1% of costs. Cost declines were observed, but not monotonically. Reductions were more pronounced for indemnity than medical care. Mean costs were 2.3 times greater among carpenters over 50 than those under 30; cost rates were only modestly higher. Significant progress has been made in reducing WC payments associated with FFH in this cohort particularly through 1996; primary gains reflect reduction in frequency of falls. FFH that occur remain costly.


Synergistic and additive effects of microplastic, nickel and pyrene on survival, reproduction, and egestion of a tropical copepod.
Coastal tropical ecosystems provide livelihood for millions of people but are at the same time exposed to an increasing intensity of diverse anthropogenic stressors, including pollution. Nevertheless, the combined effects of pollutants on marine ecosystems are poorly understood, particularly regarding lower trophic levels (plankton) and tropical ocean. We exposed the tropical copepod Centropages velificatus to 4-5 concentrations of a heavy metal (nickel), an oil compound (pyrene) and microplastic (PET), either alone or in combination, and measured their egestion, reproduction, and mortality rates. Microplastic alone did not have any effect on pellet or egg production of copepods, whereas nickel reduced egg production rate at concentrations ≥1 µg L-1 and pyrene reduced both egg and pellet production rates at concentrations ≥1 nM. The addition of nickel and pyrene to PET - microplastic resulted in a reduction similar to one caused by nickel or pyrene alone, suggesting an additive effect. In contrast, a combination of nickel and pyrene had a synergistic effect, with a strong reduction in survival, egg and pellet production. Our results suggest that combinations of contaminants that are commonly found in tropical coastal waters have detrimental effects on copepods-the crucial link in the pelagic food web-at lower concentrations than suggested by single stressor studies. This can have an influence on the food web productivity - the basis of fisheries that local communities rely on.


Nanofibers based antibacterial drug design, delivery and applications.
Infections caused by microorganisms like bacteria, fungi, etc. are the main obstacle in healing processes. Conventional antibacterial administration routes can be listed as oral, intravenous/intramuscular, topical and inhalation. These kinds of drug administrations are faced with critical vital issues such as; more rapid delivery of the drug than intended which can result in bacterial resistance, dose related systemic toxicity, tissue irritation and finally delayed healing process that need to be tackled. Recently, studies have been focused on new drug delivery systems, overcoming resistance and toxicological problems and finally localizing the molecules at the site of action in a proper dose. In this regard, many nanotechnological approaches such as nanoparticulate therapeutic systems have been developed to address accompanying problems mentioned above. Among them, drug loaded electrospun nanofibers propose main advantages like controlled drug delivery, high drug loading capacity, high encapsulation efficiency, simultaneous delivery of multiple drugs, ease of production and cost effectiveness for pharmaceutical and biomedical applications. Therefore, some particular attention has been devoted to the design of electrospun nanofibers as promising antibacterial drug carrier systems. A variety of antibacterials e.g., biocides, antibiotics, quaternary ammonium salts, triclosan, metallic nanoparticles (silver, titanium dioxide, and zinc oxide) and antibacterial polymers (chitosan, polyethyleneimine, etc.) have been impregnated by various techniques into nanofibers that exhibit strong antibacterial activity in standard assays. This review highlights the design and delivery of antibacterial drug loaded nanofibers with particular focus on their function in the fields of drug delivery, wound healing, tissue engineering, cosmetics and other biomedical applications.


Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress.
Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.


Combined positron emission tomography/computed tomography imaging of orbital lymphoma.
To report a case of orbital lymphoma with systemic dissemination that was identified and localized by combined positron emission tomography (PET)/computed tomography. Case report. A 75-year-old woman presented with a 6-month history of painless, progressive fullness of her right upper eyelid. A PET/computed tomography was obtained to provide functional and anatomic assessment of the orbits. An orbitotomy was performed with sub-total excision of the lesion to obtain histologic diagnosis. The PET/computed tomography scan revealed intensive uptake of tracer in a right orbital mass measuring 2.3 x 1.8 x 2.6 cm. Foci of abnormal tracer uptake were also noted in the right neck, right hilar region, and central abdomen. Histopathologic findings were consistent with follicular cell lymphoma. The combination of PET/computed tomography provides accurate and precise information in an expedited manner not offered by alternative imaging modalities. PET/computed tomography imaging should be considered in the evaluation of orbital neoplasms, especially if lymphoma is suspected.


Treatment of facial lipoatrophy via autologous fat transfer.
The advent of highly active anti-retroviral therapy (HAART) has extended the lives of patients affected by human immunodeficiency virus (HIV) disease. A common cutaneous side effect of HAART is facial lipoatrophy. The hollowed out cheeks, temples and eye sockets often lead to a gaunt cachetic facies which can be a disconcerting stigmata of the disease and a psychological burden to the patient. Autologous fat transfer (ATF) is a minimally invasive surgical procedure that can temporarily improve the appearance in patients with facial lipoatrophy. Other corrective procedures (e.g., injectable fillers) are available, but, to date, the ideal procedure for permanent correction of facial lipoatrophy has not been found.


Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs.
To define the kinetics and safety of spinally infused recombinant-methionyl human brain-derived neurotrophic factor (r-metHuBDNF), beagle dogs were prepared with lumbar intrathecal catheters passed through the cisternal membrane to the L1-L4 lumbar level. For kinetic studies, r-metHuBDNF was delivered by bolus or infusion through one catheter and lumbar CSF was sampled periodically through a second. As a lumbar bolus, r-metHuBDNF displayed a biphasic clearance with t(1/2)a = 0.7 hr and t(1/2)b = 7. 9 hr. Lumbar to cisternal concentrations after bolus delivery were approximately 60:1. For safety studies, dogs received continuous intrathecal infusion (2.4 ml/day) for 28 days of saline (n = 6), r-metHuBDNF at 200 (n = 6), 800 (n = 6), or 2000 (n = 7) microg/day. Control dogs showed no changes. Intrathecally infused r-metHuBDNF produced a dose-dependent increase in muscle tone and decreased coordination. Low-dose r-metHuBDNF was associated with moderate increases in muscle tone after 22-28 days of infusion. No clinically important changes were noted in rectal temperature, arterial pressure, respiration and heart rate, body weight, food consumption, stool or urine output, or change in blood chemistries measured throughout the study. Cisternal CSF protein and glucose sampled at 28 days were not different between dose groups and all cultures were negative. Histopathological examination of the spinal cord typically revealed some degree of chronic inflammation around the catheter, including fibrotic adhesions and focal accumulations of lymphoid and plasma cells, but these effects were not dose dependent. In other dogs receiving r-metHuBDNF (2000 or 4000 microg/day), termination of infusion resulted in significant recovery.


Boosting Interleukin-12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR-Tagged Nanogold.
The clinical use of interleukin-12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor-homing peptide containing isoDGR, an αvβ3-integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head-to-tail cyclized-peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvβ3 and IL12-receptor recognition. Low-dose Iso1/Au/IL12, equivalent to 18-75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low-dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T-cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR-tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T-cell therapy.


How tumour necrosis factor blockers interfere with tuberculosis immunity.
Tumour necrosis factor (TNF) is a potent inflammatory cytokine that plays an important role in immunity to numerous bacterial infections, including Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans. Infliximab, adalimumab, certolizumab pegol and etanercept are anti-TNF agents used to treat a range of inflammatory/autoimmune diseases, such as rheumatoid arthritis. The use of some of these drugs has been linked to reactivation TB. In addition to blocking TNF-mediated immune responses, some anti-TNF drugs have been found to interfere with innate immune responses, such as phagolysosomal maturation and monocyte apoptosis, as well as cell-mediated responses, including interferon-gamma secretion by memory T cells, complement-mediated lysis of Mtb-reactive CD8+ T cells and increased regulatory T cell activity. This review summarizes some of the reported effects of TNF blockers on immune cell responses in the context of the observed clinical data on TB reactivation in patients on anti-TNF therapy.


Update on the use of preoperative pneumoperitoneum prior to the repair of large hernias of the abdominal wall.
A review of eight repairs of large hernias of the abdomen pretreated with progressive artificial pneumoperitoneum is presented. Although three recurrences were noted during the follow-up period, two of the recurrences were repaired easily without further herniation. The advantages and complications of this procedure are discussed. Although the use of pneumoperitoneum prior to herniorrhaphy has been well described in the past, current emphasis on prosthetic mesh repairs has overshadowed its advantages. Progressive preoperative pneumoperitoneum as an adjunct to the repair of large abdominal hernias and eventrations should be part of the armamentarium of surgeons who are confronted with these difficult operative problems.


Colour moult phenology and camouflage mismatch in polymorphic populations of Arctic foxes.
Species that seasonally moult from brown to white to match snowy backgrounds become conspicuous and experience increased predation risk as snow cover duration declines. Long-term adaptation to camouflage mismatch in a changing climate might occur through phenotypic plasticity in colour moult phenology and or evolutionary shifts in moult rate or timing. Also, adaptation may include evolutionary shifts towards winter brown phenotypes that forgo the winter white moult. Most studies of these processes have occurred in winter white populations, with little attention to polymorphic populations with sympatric winter brown and winter white morphs. Here, we used remote camera traps to record moult phenology and mismatch in two polymorphic populations of Arctic foxes in Sweden over 2 years. We found that the colder, more northern population moulted earlier in the autumn and later in the spring. Next, foxes moulted earlier in the autumn and later in the spring during colder and snowier years. Finally, white foxes experienced relatively low camouflage mismatch while blue foxes were mismatched against snowy backgrounds most of the autumn through the spring. Because the brown-on-white mismatch imposes no evident costs, we predict that as snow duration decreases, increasing blue morph frequencies might help facilitate species persistence.


Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal.
Enteric fever is a major global problem. Emergence of antibacterial resistance threatens to render current treatments ineffective. There is little research or public health effort directed toward Salmonella enterica serovar Paratyphi A, because it is assumed to cause less severe enteric fever than does S. enterica serovar Typhi. There are few data on which to base this assumption, little is known of the serovar's antibacterial susceptibilities, and there is no readily available tolerable vaccination. A prospective study was conducted of 609 consecutive cases of enteric fever (confirmed by blood culture) to compare the clinical phenotypes and antibacterial susceptibilities in S. Typhi and S. Paratyphi A infections. Variables independently associated with either infection were identified to develop a diagnostic rule to distinguish the infections. All isolates were tested for susceptibility to antibacterials. Six hundred nine patients (409 with S. Typhi infection and 200 with S. Paratyphi A infection) presented during the study period. The infections were clinically indistinguishable and had equal severity. Nalidixic acid resistance, which predicts a poor response to fluoroquinolone treatment, was extremely common (75.25% of S. Paratyphi A isolates and 50.5% of S. Typhi isolates; P < .001). S. Paratyphi A was more likely to be resistant to ofloxacin (3.6% vs. 0.5%; P = .007) or to have intermediate susceptibility to ofloxacin (28.7% vs. 1.8%; P < .001) or ciprofloxacin (39.4% vs. 8.2%; P < .001). MICs for S. Paratyphi A were higher than for S. Typhi (MIC of ciprofloxacin, 0.75 vs. 0.38 microg/mL [P < .001]; MIC of ofloxacin, 2.0 vs. 0.75 microg/mL [P < .001]). The importance of S. Paratyphi A has been underestimated. Infection is common, the agent causes disease as severe as that caused by S. Typhi and is highly likely to be drug resistant. Drug resistance and lack of effective vaccination suggest that S. Paratyphi A infection may become a major world health problem.


On Detection of Faint Edges in Noisy Images.
A fundamental question for edge detection in noisy images is how faint can an edge be and still be detected. In this paper we offer a formalism to study this question and subsequently introduce computationally efficient multiscale edge detection algorithms designed to detect faint edges in noisy images. In our formalism we view edge detection as a search in a discrete, though potentially large, set of feasible curves. First, we derive approximate expressions for the detection threshold as a function of curve length and the complexity of the search space. We then present two edge detection algorithms, one for straight edges, and the second for curved ones. Both algorithms efficiently search for edges in a large set of candidates by hierarchically constructing difference filters that match the curves traced by the sought edges. We demonstrate the utility of our algorithms in both simulations and applications involving challenging real images. Finally, based on these principles, we develop an algorithm for fiber detection and enhancement. We exemplify its utility to reveal and enhance nerve axons in light microscopy images.


Early alterations of renal function in insulin-dependent diabetic pregnancies and their importance in predicting pre-eclamptic toxaemia.
Renal function, blood pressure and glycaemic control were assessed during gestation in 23 non-azotaemic insulin-dependent diabetic women. Pre-eclamptic toxaemia (PET) developed in nine cases, and was predicted by higher levels of albuminuria excretion, mean blood pressure and serum urate early in pregnancy, as well as by the primigravid state. Mean blood pressure, serum creatinine and urate remained stable in the first trimester and rose thereafter in women who developed PET. Levels of mean blood pressure were significantly higher in the second (p less than 0.005) and third (p less than 0.0001) trimesters, serum urate was higher in the first, second (p less than 0.04) and third (p less than 0.0001) trimesters, as was AER (p range less than 0.02-0.0001), and serum creatinine levels were higher in the third trimester (p less than 0.02) in comparison to those women who did not develop PET. Glycaemic control was similar in both groups. In addition, physiological alterations in creatinine clearance, and in serum levels of creatinine and urate were attenuated in cases uncomplicated by PET. Insulin-dependent diabetic pregnancies are characterized by disturbances of renal function early in pregnancy which may be predictive of PET, particularly in primigravidae and/or when accompanied by increases in mean blood pressure.


Increased calcium influx in dystrophic muscle.
We examined pathways which might result in the elevated resting free calcium [( Ca2+]i) levels observed in dystrophic mouse (mdx) skeletal muscle fibers and myotubes and human Duchenne muscular dystrophy myotubes. We found that mdx fibers, loaded with the calcium indicator fura-2, were less able to regulate [Ca2+]i levels in the region near the sarcolemma. Increased calcium influx or decreased efflux could lead to elevated [Ca2+]i levels. Calcium transient decay times were identical in normal and mdx fibers if resting [Ca2+]i levels were similar, suggesting that calcium-sequestering mechanisms are not altered in dystrophic muscle, but are slowed by the higher resting [Ca2+]i. The defect appears to be specific for calcium since resting free sodium levels and sodium influx rates in the absence of Na+/K(+)-ATPase activity were identical in normal and dystrophic cells when measured with sodium-binding benzofuran isophthalate. Calcium leak channels, whose opening probabilities (Po) were voltage independent, could be the major calcium influx pathway at rest. We have shown previously that calcium leak channel Po is significantly higher in dystrophic myotubes. These leak channels were selective for calcium over sodium under physiological conditions. Agents that increased leak channel activity also increased [Ca2+]i in fibers and myotubes. These results suggest that increased calcium influx, as a result of increased leak channel activity, could result in the elevated [Ca2+]i in dystrophic muscle.


International connectedness and local disconnectedness: MNE strategy, city-regions and disruption.
Much of the rising international connectedness of city-regions has developed from MNEs replacing local connections with (superior) international ones. This often creates local disconnectedness that energizes the current populist backlash against MNE activities. We develop approaches to new IB theory, addressing the interdependencies of MNEs and city-regions that we propose as a crucial avenue for future research. We contrast two generic MNE strategies. The first is the traditional one: the 'global orchestration' of resources and markets. We argue that it exacerbates local disconnectedness. The second, that we call 'local spawning,' involves engaging with the local entrepreneurial eco-system to create and renew local connectedness, diffusing populist responses. Some MNEs are better able to implement a local spawning strategy, due to industry factors like innovation clock-speed, and firm characteristics like organizational path dependency. Finally, we distinguish between disconnection, which is an outcome of MNE strategy, and global disruptions, like the coronavirus (COVID-19) pandemic, which are primarily stochastic events. Addressing disconnections requires MNEs to re-orient their strategies while dealing with disruptions requires undertaking risk mitigation. We present empirical evidence from city-regions around the world to illustrate our theory.


Chiral recognition mechanism studies of Tyr-Arg-Phe-Lys-NH2 tetrapeptide on crown ether-based chiral stationary phase.
Even though chiral recognition for crown-ether CSPs is generally understood, on a molecular level, exact mechanisms for the resolution are still unclear. Furthermore, short peptide analytes often contain multiple amino moieties capable of binding to the crown ether selector. In order to extend the understanding in chiral recognition mechanisms, polar organic mode separation of Tyr-Arg-Phe-Lys-NH2 tetrapeptide llll/dddd enantiomers on S- and R-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 stationary phases was studied with 50-mM perchloric acid in methanol as mobile phase. Deviation from the generally acceptable 1:1 stoichiometry was supported by mass spectroscopy analysis of the formed complexes between tetrapeptide enantiomer and crown ether selectors, which revealed adducts possessing 1:1, 1:2, and 1:3 stoichiometry. Further investigation of complexation induced shifts by NMR indicated on different binding mechanisms between llll/dddd enantiomers of Tyr-Arg-Phe-Lys-NH2 and crown ether selectors. Enantioselective proton shifts were observed in studied tetrapeptide tyrosine and phenylalanine residues exclusively for llll enantiomer upon binding with S-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 selector (and dddd enantiomer with R-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 selector), indicating that these two amino acid residues contribute to chiral recognition. The obtained results were in agreement with the LC data.


The BUILT study: a single-center 5-year experience of Lung Cancer screening in Taiwan.
Background: There are no uniform guidelines on low-dose computed tomography (LDCT) follow-up in lung cancer screening. Few studies have analyzed the incidental abnormalities and role of tumor markers in lung cancer screening. The purpose of this study was to investigate the diagnostic performance of LDCT, optimal follow-up duration, incidental findings, and role of tumor markers in diagnosing lung cancer. Methods: We retrospectively analyzed subjects who underwent their first LDCT in Taipei Tzu Chi Hospital between September 1, 2015, and August 31, 2016. All chest CT scans until August 31, 2020, were recorded. A non-calcified nodule with a diameter ≥2 mm on LDCT was defined as a positive result. We extracted the data, including possible risk factors of lung cancer and follow-up outcomes. Results: A total of 1502 subjects were recruited. Of the 38 subjects who underwent biopsy, 31 had confirmed lung cancer. Lung cancer in all patients was diagnosed within 4 years. Univariate logistic regression analysis revealed that a family history of lung cancer in first-degree relatives and abnormal serum carcinoembryonic antigen (CEA) levels were the significant risk factors for lung cancer. A cumulative lung cancer incidence of 54.7 patients per 1000 person-years was determined solely via radiological follow-up. In total, 271 (18%) subjects exhibited incidental findings on baseline LDCT. Conclusion: The overall lung cancer detection rate in this study was 2.1% in the 5-year study period. A family history of lung cancer and abnormal serum CEA levels are important risk factors for lung cancer. A minimum of 4-year follow-up is required to track suspicious nodules. A purely radiological follow-up detects a high incidence of lung cancer.


Association between isotretinoin use and central retinal vein occlusion in an adolescent with minor predisposition for thrombotic incidents: a case report.
We report an adolescent boy with minimal pre-existing risk for thromboses who suffered central retinal vein occlusion associated with isotretinoin use for acne. To the best of our knowledge, this is the first well documented case of this association. An otherwise healthy 17-year-old white man who was treated with systemic isotretinoin for recalcitrant acne was referred with central retinal vein occlusion in one eye. Although a detailed investigation was negative, DNA testing revealed that the patient was a heterozygous carrier of the G20210A mutation of the prothrombin gene. Despite the fact that this particular mutation is thought to represent only a minor risk factor for thromboses, it is probable that isotretinoin treatment greatly increased the risk of a vaso-occlusive incident in this patient. Isotretinoin use may be associated with sight- and life-threatening thrombotic adverse effects even in young patients with otherwise minimal thrombophilic risk. Physicians should be aware of such potential dangers.


[Changes in body composition in relation to the stage of dementia in a group of institutionalized elderly].
To assess the nutritional status of a group of institutionalized elderly with dementia by analysing the changes in the body composition according to their evolutionary state. A cross-sectional study was carried out assessing the nutritional status and the body composition (anthropometry, MNA and bioimpedance) in 63 institutionalized elderly with a diagnosis of dementia in evolutionary stages 5, 6 and 7 of the GDS (Global Deterioration Scale) scales and the FAST (Functional Assessment Stating) scale. The fat mass index (FMI) and the fat-free mass index (FFMI) were calculated. The results were analysed by one-factor ANOVA and Kruskal-Wallis factorial ANOVA and Scheffé's a posteriori contrasts. The significance level was set at p < 0.05. Mean age was 80.6 years (95%CI: 78.3-83.0; Range: 51-95). According to MNA, 38.1% of the sample had hyponutrition, 60.3% was at risk for malnourishment; and 1.6% had normal nutrition. The average body mass index was 23.06 (22.01-24.10) kg/m2, without any significant difference by the degree of evolutionary state, except for those on palliative care (mean: 19.85; 95%CI: 78.3-83.0 kg/m2). The patients in the non-palliative stages GDS/FAST 5, 6 and 7 presented a Z-Score of FMI close to a 0 SD, and a Z-Score for the FFMI of approximately -1 DS. These results are compatible with a sarcopenia situation. In patients on palliative care (GDS/FAST =?7c) both indexes were significantly lower. The analysis of body composition should always be included in the assessment of the nutritional status. If not, it would not be possible to detect situations of sarcopenic obesity, which is rather prevalent in elderly people with these characteristics.


Assortative mating by colored ornaments in blue tits: space and time matter.
Assortative mating is a potential outcome of sexual selection, and estimating its level is important to better understand local adaptation and underlying trait evolution. However, assortative mating studies frequently base their conclusions on small numbers of individuals sampled over short periods of time and limited spatial scales even though spatiotemporal variation is common. Here, we characterized assortative mating patterns over 10 years in four populations of the blue tit (Cyanistes caeruleus), a passerine bird. We focused on two plumage ornaments-the blue crown and the yellow breast patch. Based on data for 1,657 pairs of birds, we found large interannual variation: assortative mating varied from positive to negative. To determine whether there was nonetheless a general trend in the data, we ran a within-study meta-analysis. It revealed that assortative mating was moderately positive for both ornaments. It also showed that mating patterns differed among populations and especially between two neighboring populations that displayed phenotypic divergence. Our results therefore underscore that long-term studies are needed to draw broad conclusions about mating patterns in natural populations. They also call for studying the potential role of assortative mating in local adaptation and evolution of ornaments in both sexes.


Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction.
Disruption of retinoic acid (RA) signaling during early development results in severe respiratory tract abnormalities, including lung agenesis. Previous studies suggest that this might result from failure to selectively induce fibroblast growth factor 10 (Fgf10) in the prospective lung region of the foregut. Little is known about the RA-dependent pathways present in the foregut that may be crucial for lung formation. By performing global gene expression analysis of RA-deficient foreguts from a genetic [retinaldehyde dehydrogenase 2 (Raldh2)-null] and a pharmacological (BMS493-treated) mouse model, we found upregulation of a large number of Tgfbeta targets. Increased Smad2 phosphorylation further suggested that Tgfbeta signaling was hyperactive in these foreguts when lung agenesis was observed. RA rescue of the lung phenotype was associated with low levels of Smad2 phosphorylation and downregulation of Tgfbeta targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgfbeta signaling with exogenous TGF beta 1. Preventing activation of endogenous Tgfbeta signaling with a pan-specific TGFbeta-blocking antibody allowed bud formation and gene expression in the lung field of both Raldh2-null and BMS493-treated foreguts. Our data support a novel mechanism of RA-Tgfbeta-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgfbeta activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.


Illuminating solvent-free synthesis of zeolites.
With the merits of the accelerated crystallization process, high volume yields, and reduced waste production, solvent-free syntheses give new opportunities for the fabrication of zeolites. In this Frontier, a background overview is provided, consisting of a brief introduction of challenges in traditional zeolite syntheses and how solvent-free syntheses provide the right combination of properties for achieving a more sustainable route. Next, recent advancements in zeolites synthesized under solvent-free conditions are exemplified along with discussions about the strategies and principles involved. Finally, the remaining challenges and opportunities for this synthetic route are outlined.


Evaluation of tolerance limits for humans under heat stress and the problems involved.
Investigators are divided about the limits of tolerable ambient temperatures and air humidities, even under equal boundary conditions. In 266 climatic chamber experiments, mostly lasting 4 h, 13 young healthy men were exposed to combinations of ambient temperature (20 to 55 degrees C) and relative humidity (5 to 97%) at an air velocity of 0.3 m.s-1. They were lightly clad and performed equal treadmill work (metabolic rate about 850 kJ.h-1). Mean rectal isotherms and their standard deviations were calculated from the final rectal temperatures of the 13 men and plotted on a psychrometric chart. The slopes of the isotherms were compared with those of various "indices of heat stress." The probability of reaching the potentially critical rectal temperature of 39 degrees C was calculated according to data of Wyndham & Heyns. It increased from about 1:500,000 to 1:150 in climates corresponding to mean isotherms of 37.6 and 38.2 degrees C, respectively. Most of the limits thus far proposed are situated between these two isotherms, and they differ merely in regard to health risk. It is useless to discuss "correct" or "incorrect" limits until society has decided what risk is to be accepted. An upper tolerable limit per se does not and cannot exist. For several reasons the 37.6 degrees C isotherm might be taken into consideration as a limit.


The microbiology of moxifloxacin.
Moxifloxacin is a new group IV 8-methoxyquinolone. It is slightly less active than ciprofloxacin against enterobacteria and much less effective against P. aeruginosa. However, moxifloxacin is clearly better than ciprofloxacin in treating atypical microorganisms and especially anaerobic bacteria and aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. In recent years there has been an increase in the resistance of some respiratory pathogens to beta-lactam and macrolide antibiotics. Bearing in mind that moxifloxacin is well tolerated, its microbiological properties and pharmacokinetic characteristics mean that it will undoubtedly be useful in treating certain infections, particularly community-acquired respiratory infections, hospital-acquired respiratory infections caused by aerobic Gram-positive cocci, infections caused by anaerobic bacteria and skin infections. Studies have shown that moxifloxacin is effective and well tolerated in all of these conditions.


The road to forgiveness: a meta-analytic synthesis of its situational and dispositional correlates.
Forgiveness has received widespread attention among psychologists from social, personality, clinical, developmental, and organizational perspectives alike. Despite great progress, the forgiveness literature has witnessed few attempts at empirical integration. Toward this end, we meta-analyze results from 175 studies and 26,006 participants to examine the correlates of interpersonal forgiveness (i.e., forgiveness of a single offender by a single victim). A tripartite forgiveness typology is proposed, encompassing victims' (a) cognitions, (b) affect, and (c) constraints following offense, with each consisting of situational and dispositional components. We tested hypotheses with respect to 22 distinct constructs, as correlates of forgiveness, that have been measured across different fields within psychology. We also evaluated key sample and study characteristics, including gender, age, time, and methodology as main effects and moderators. Results highlight the multifaceted nature of forgiveness. Variables with particularly notable effects include intent (r = -.49), state empathy (r = .51), apology (r = .42), and state anger (r = -.41). Consistent with previous theory, situational constructs are shown to account for greater variance in forgiveness than victim dispositions, although within-category differences are considerable. Sample and study characteristics yielded negligible effects on forgiveness, despite previous theorizing to the contrary: The effect of gender was nonsignificant (r = .01), and the effect of age was negligible (r = .06). Preliminary evidence suggests that methodology may exhibit some moderating effects. Scenario methodologies led to enhanced effects for cognitions; recall methodologies led to enhanced effects for affect.


Antibiotic Charge Profile Determines the Extent of L3 Dynamics in OmpF: An Expedited Passage for Molecules with a Positive Charge.
Efficient permeation into Gram-negative bacterial cells is a much-desired property in the design of antibacterial agents. The goal is to arrive at one or more chemical modifications of molecules that improve their uptake into the cell while maintaining a good binding affinity to the intracellular target. Previously, we proposed a mechanistic rationale for the fast permeation of bulky antibiotics that involves induced conformational dynamics in the constriction loop L3 of the OmpF channel. This flexibility is caused by the perturbation of a hydrogen bond network stabilizing the L3 loop due to the strong interactions of the positively charged moiety on the antibiotic with the residues of the L3 loop. In the present work, we examine how differences in the charge profile of antibiotic molecules can affect the permeation process, in particular, the L3 dynamics. To this end, we have performed all-atom molecular dynamics simulations to study the permeation process of molecules with differences in the net charge through the Escherichia coli OmpF channel. The results from these simulations suggest that a positively charged moiety on the antibiotic is responsible for strong interactions with the negatively charged residues of the L3 loop, promoting conformational dynamics in the L3 loop. In contrast, antibiotics without a positively charged moiety are unable to initiate such a dynamic response in the L3 loop. This distinct behavior of the L3 loop in the presence of molecules with different charge characteristics provides a plausible mechanism whereby large molecules with an appropriate charge distribution can leverage an L3 dynamic-dependent pathway to permeate efficiently. The results are relevant to the structure-based design of molecules with improved uptake properties achieved through systematic chemical modifications that effectively engage the L3 loop.


New insights into the evolution and functional divergence of the SWEET family in Saccharum based on comparative genomics.
The SWEET (Sugars Will Eventually be Exported Transporters) gene family is a recently identified group of sugar transporters that play an indispensable role in sugar efflux, phloem loading, plant-pathogen interaction, nectar secretion, and reproductive tissue development. However, little information on Saccharum SWEET is available for this crop with a complex genetic background. In this study, 22 SWEET genes were identified from Saccharum spontaneum Bacterial Artificial Chromosome libraries sequences. Phylogenetic analyses of SWEETs from 11 representative plant species showed that gene expansions of the SWEET family were mainly caused by the recent gene duplication in dicot plants, while these gene expansions were attributed to the ancient whole genome duplication (WGD) in monocot plant species. Gene expression profiles were obtained from RNA-seq analysis. SWEET1a and SWEET2s had higher expression levels in the transitional zone and maturing zone than in the other analyzed zones. SWEET1b was mainly expressed in the leaf tissues and the mature zone of the leaf of both S. spontaneum and S. officinarum, and displayed a peak in the morning and was undetectable in both sclerenchyma and parenchyma cells from the mature stalks of S. officinarum. SsSWEET4a\4b had higher expression levels than SWEET4c and were mainly expressed in the stems of seedlings and mature plants. SWEET13s are recently duplicated genes, and the expression of SWEET13s dramatically increased from the maturing to mature zones. SWEET16b's expression was not detected in S. officinarum, but displayed a rhythmic diurnal expression pattern. Our study revealed the gene evolutionary history of SWEETs in Saccharum and SWEET1b was found to be a sucrose starvation-induced gene involved in the sugar transportation in the high photosynthetic zones. SWEET13c was identified as the key player in the efflux of sugar transportation in mature photosynthetic tissues. SWEET4a\4b were found to be mainly involved in sugar transportation in the stalk. SWEET1a\2a\4a\4b\13a\16b were suggested to be the genes contributing to the differences in sugar contents between S. spontaneum and S. officinarum. Our results are valuable for further functional analysis of SWEET genes and utilization of the SWEET genes for genetic improvement of Saccharum for biofuel production.


OPGs: promising anode materials with high specific capacity and rate capability for Li/Na ion batteries.
Two-dimensional (2D) nanostructures with high specific capacity and high rate capability have attracted extensive attention due to their promising applications as anode materials for rechargeable ion batteries. In this study, we have employed density functional theory calculations to explore the electrochemical properties of Li and Na atoms, adsorption and diffusion on 2D carbon nanosheets named Octagon-Pentagon-Graphenes (OPGs). Two types of OPGs are considered, i.e. OPG_L and OPG_Z, and were found to be stable with much lower binding energies than that of graphdiyne. Both the nanosheets can combine Li/Na atoms strongly and easily. In the OPG_L, low energy barriers of 0.292 and 0.265 eV are obtained for the diffusion of Li and Na atoms, while in the OPG_Z, these barriers are much smaller. At room temperature, the diffusion rate of a Li atom on the OPGs is estimated to be at least 10 times faster than that on graphene. An ultrahigh Li/Na storage capacity of 2230 mA h g-1 can be achieved in both the OPG_L and OPG_Z, which is about 6 times larger than the 372 mAh g-1 of graphene. During the whole processes of Li/Na ion insertion, the OPGs exhibit a low average operating voltage and good metallic properties. Our results suggest that high specific capacity and rate capability could be expected in OPG-based Li/Na ion batteries.


Pesticide Residue Trends in Fruits and Vegetables from Farm to Fork in Kampala Metropolitan Area, Uganda-A Mixed Methods Study.
This mixed methods study used laboratory measurements of pesticide residues in produce, semi-structured questionnaires, and in-depth interview data to describe trends in pesticide residue in produce and handling and processing practices for fruits (watermelon and passion fruit) and vegetables (tomato, cabbage, and eggplant) along the farm to fork chain. Of the 50 farmers visited, 34 (68.0%) sold their fruits and vegetables to transporters, 11 (22.0%) to market vendors, and 4 (8.0%) directly to homes and restaurants. The majority 42 (93.3%) of the consumers (home/restaurant) purchased their fruits and vegetables from market vendors and transporters. Washing with water or vinegar, wiping with a cloth, peeling the outer layer, and blending and cooking were the most common post-harvesting processing methods used by stakeholders along the supply chain. Some farmers and market vendors reported spraying fruits and vegetables with pesticides either prior- or post-harvest to increase shelf life. Statistically significant decreasing pesticide residue trends along the farm to fork chain were observed for dioxacarb, likely due to degradation or washing, peeling, cooking, blending, or wiping by consumers. Increasing trends were observed for methidathion and quinalphos possibly due to pesticide applications. There is a need in Uganda to promote practices that minimize pesticide use and exposure through diet, while maintaining food integrity.


Newborn cord care practices in Haiti.
Newborn cord infections commonly lead to neonatal sepsis and death, particularly in low-resource countries where newborns may receive unhygienic cord care. Topical application of chlorhexidine to the newborn's cord has been shown to prevent infection. Such benefits may be particularly important in Haiti. We explored current cord care practices by conducting a qualitative study using five focus groups among key community stakeholders (mothers of newborns/children under age two years, pregnant women, traditional birth attendants, community health workers, traditional healers) in Petit-Goâve, Haiti. Data collection was guided by the Health Belief Model. Results suggest community stakeholders recognise that infants are susceptible to cord infection and that cord infection is a serious threat to newborns. Long-held traditional cord care practices are potential barriers to adopting a new cord care intervention. However, all groups acknowledged that traditional practices could be harmful to the newborn while expressing a willingness to adopt practices that would protect the newborn. Results demonstrate potential acceptability for altering traditional cord care practices among neonatal caretakers in Haiti. An informational campaign designed to educate local health workers and new mothers to eliminate unhygienic cord applications while promoting chlorhexidine application may be a strong approach for preventing neonatal cord infections.


Incidence and histologic features of mixed renal tumors.
Guidelines for management of renal cell carcinoma (RCC) incompletely address the implications of mixed renal tumor histology. We investigate the incidence of mixed renal tumors identified at renal surgery and determine the association with pathologic features. Institutional kidney tumor database was reviewed to identify 536 patients who underwent partial or radical nephrectomy. Clinical, demographic, and pathologic data were collected. A linear fixed effects model and logistic regression determined the association of mixed tumor histology with tumor size, stage, grade, and nephrometry score. Three hundred and eighteen men and 218 women with a median BMI of 31 and median tumor size of 3.5 cm were included. 469 (87.5%) patients had pathologic kidney cancer with the most common histologies being clear cell carcinoma in 343 (73.1%) patients, papillary in 81 (17.3%) patients, and chromophobe in 25 (5.3%) patients. Twenty (4.3%) patients had mixed tumors on final pathology. Clear cell RCC was the most common primary pathology in patients with mixed tumor histology (n = 14, 75%) with additional primary tumor histologies included papillary and chromophobe. When considering secondary histologies, 85% were coexistent primary renal cancers while 15% (n = 3) were benign renal tumors. No association of mixed tumor histology and adverse pathologic features was noted. Mixed tumor histology is an uncommon entity that is not associated with adverse features in a solitary renal mass. These results are especially relevant in discussing the role of renal mass biopsy, and provide further evidence that renal sampling is a valuable tool in the appropriate clinical context.


A hydrophilic lamin-binding domain from the Drosophila YA protein can target proteins to the nuclear envelope.
The nuclear lamina provides an architectural framework for the nuclear envelope and an attachment site for interphase chromatin. In Drosophila eggs and early embryos its major constituent, lamin Dm0, interacts with a lamina protein called YA. When the lamin-interaction region of YA is deleted, YA still enters nuclei but fails to localize to nuclear envelopes, suggesting that lamin interaction targets YA to the nuclear envelope. Here, we show that C-terminal lamin-interacting region of YA is sufficient to target the heterologous soluble protein GFP-NLS to the nuclear periphery in Drosophila tissue culture cells. Yeast two-hybrid analysis and transient transfection assays further defined this domain: residues 556-696 of YA are sufficient for both lamin Dm0 interaction and the targeting of GFP-NLS to the nuclear periphery. This region of YA is hydrophilic and lacks any transmembrane domain or known membrane-targeting motifs. We propose that the localization of YA to the nuclear lamina involves interaction with polymerized lamin Dm0 mediated by the lamin-targeting domain of YA. This hydrophilic YA domain might provide a useful molecular tool for targeting heterologous non-membrane-associated proteins to the nuclear envelope.


[Ventilator-associated pneumonia and multiresistant bacteria].
Ventilator-associated pneumonia remains the most serious nosocomial infection in critically ill patients. Providing appropriate antibiotic therapy promptly is crucial for successful treatment; whereas the diagnostic approach seems to play a minor role. The empirical antibiotic therapy should be guided by the risk for infections due to multiresistant bacteria. For patients at risk a combination therapy, considering local resistance data and formerly applied antibiotic substances, is recommended. Reevaluation and deescalation of antibiotic therapy based on microbiological culture results and discontinuation of antimicrobial treatment after one week is essential for the control of broadspectrum antibiotic use and antibiotic resistance.


[Changes in the activity of superoxide dismutase, glutathione peroxidase, microsomal lipid peroxidation, and content of trace elements in organs and tissues following copper introduction].
Chronic application of various copper concentrations on the skin decreases endogenous levels of iron, zinc, and copper in the serum. Single introduction of disperse copper positively correlates with the level of the oxidation products and Fe/Zn ratio in the liver. Single introduction of ionic and electron-neutral copper induces phased changes in superoxide dismutase and glutathione peroxidase activities. Positive correlation between activities of these enzymes points to efficient control of O2-radicals, dismutation products, and hydroperoxides level by the antioxidant enzymes in animal tissues treated with copper.


Eukaryotic translation initiation factor 5 is critical for integrity of the scanning preinitiation complex and accurate control of GCN4 translation.
The integrity of eukaryotic translation initiation factor (eIF) interactions in ribosomal pre-initiation complexes is critical for the proper regulation of GCN4 mRNA translation in response to amino acid availability. Increased phosphorylation of eIF2 under amino acid starvation conditions leads to a corresponding increase in GCN4 mRNA translation. The carboxyl-terminal domain (CTD) of eIF5 (eIF5-CTD) has been identified as a potential nucleation site for pre-initiation complex assembly. To further characterize eIF5 and delineate its role in GCN4 translational control, we isolated mutations leading to temperature sensitivity (Ts- phenotype) targeted at TIF5, the structural gene encoding eIF5 in yeast (Saccharomyces cerevisiae). Nine single point mutations were isolated, in addition to an allele in which the last 15 amino acids were deleted. The nine point mutations clustered in the eIF5-CTD, which contains two conserved aromatic/acidic boxes. Six of the point mutations derepressed GCN4 translation independent of eIF2 phosphorylation (Gcd- phenotype) at a permissive temperature, directly implicating eIF5-CTD in the eIF2/GTP/Met-tRNA(i)Met ternary complex binding process required for GCN4 translational control. In addition, stronger restriction of eIF5-CTD function at an elevated temperature led to failure to derepress GCN4 translation (Gcn- phenotype) in all of the mutants, most likely due to leaky scanning of the first upstream open reading frame of GCN4 mRNA. This latter result directly implicates eIF5-CTD in the process of accurate scanning for, or recognition of, AUG codons. Taken together, our results indicate that eIF5-CTD plays a critical role in both the assembly of the 43S complex and the post-assembly process in the 48S complex, likely during the scanning process.


Fiber glass-bioactive glass composite for bone replacing and bone anchoring implants.
Although metal implants have successfully been used for decades, devices made out of metals do not meet all clinical requirements, for example, metal objects may interfere with some new medical imaging systems, while their stiffness also differs from natural bone and may cause stress-shielding and over-loading of bone. Peer-review articles and other scientific literature were reviewed for providing up-dated information how fiber-reinforced composites and bioactive glass can be utilized in implantology. There has been a lot of development in the field of composite material research, which has focused to a large extent on biodegradable composites. However, it has become evident that biostable composites may also have several clinical benefits. Fiber reinforced composites containing bioactive glasses are relatively new types of biomaterials in the field of implantology. Biostable glass fibers are responsible for the load-bearing capacity of the implant, while the dissolution of the bioactive glass particles supports bone bonding and provides antimicrobial properties for the implant. These kinds of combination materials have been used clinically in cranioplasty implants and they have been investigated also as oral and orthopedic implants. The present knowledge suggests that by combining glass fiber-reinforced composite with particles of bioactive glass can be used in cranial implants and that the combination of materials may have potential use also as other types of bone replacing and repairing implants.


Optimization of the Recovery of Secondary Metabolites from Defatted Brassica carinata Meal and Its Effects on the Extractability and Functional Properties of Proteins.
The sustainable extraction of secondary metabolites from Brassica agro-industrial by-products often involves the use of high concentrations of ethanol, and/or high temperatures, which tends to decrease the efficiency of protein extraction (yield, profile, etc.). To understand the limits of the combination of these two extraction processes, aqueous ethanol extraction of secondary metabolites (e.g., phenolic compounds and glucosinolates) from Brassica carinata defatted meal was optimized using Response Surface Methodology. The validated models predicted that aqueous ethanol extraction of defatted Carinata meal, with a low aqueous EtOH concentration (22% EtOH) at moderate Te (50 °C), enables the efficient recovery of secondary metabolites (sinapine = 9.12 ± 0.05 mg/gDM, sinigrin = 86.54 ± 3.18 µmol/gDM) while maintaining good protein extractability (59.8 ± 2.1%) from successive alkaline extractions. The evaluation of functional properties of the resulting protein isolates revealed that aqueous extraction, under optimized conditions, improves foaming activity while preserving emulsion ability.


The role of threat level and intolerance of uncertainty in extinction.
Recent evidence suggests that individual differences in intolerance of uncertainty (IUS) are associated with disrupted threat extinction. However, it is unknown what maintains the learned threat association in high IUS individuals: is it the experienced uncertainty during extinction or the combination of experienced uncertainty with potential threat during extinction? Here we addressed this question by running two independent experiments with uncertain auditory stimuli that varied in threat level (Experiment 1, aversive human scream (n = 30); Experiment 2, neutral tone (n = 47) and mildly aversive tone (n = 49)). During the experiments, we recorded skin conductance responses and subjective ratings to the learned cues during acquisition and extinction. In experiment 1, high IUS was associated with heightened skin conductance responding to the learned threat vs. safe cue during extinction. In experiment 2, high IUS was associated only with larger skin conductance responding to the learned cues with more threatening properties during extinction i.e. mildly aversive tone. These findings suggest that uncertainty in combination with threat, even when mild, disrupts extinction in high IUS individuals. Such findings help us understand the link between IUS and threat extinction, and its relevance to anxiety disorder pathology.


Fatal Pulmonary Hemorrhagic Infarction Caused by Pulmonary Vein Thrombotic Occlusion During Venoarterial Extracorporeal Membrane Oxygenation.
A 20-year-old man with arrhythmogenic right ventricular cardiomyopathy (ARVC) was resuscitated from ventricular fibrillation. He was transferred to our hospital because of progressive multiorgan dysfunction despite mechanical circulatory support with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pump (IABP). At admission to our hospital, chest X-ray showed bilateral complete lung opacification, and echocardiography revealed a massive thrombus occupying the left atrium (LA) and left ventricle (LV). Conversion to central ECMO with transapical LV venting and thrombectomy were performed. The huge LA thrombus occluded all pulmonary veins (PVs). Despite the surgery and intensive care, complete lung opacity remained, and he died of multiorgan failure associated with sepsis. Autopsy demonstrated bilateral pulmonary multiple red infarctions, and histopathology showed alveolar wall necrosis with extensive hemorrhage, confirming a diagnosis of pulmonary hemorrhagic infarction. Extensive pulmonary infarction was attributable to PV occlusion due to massive LA thrombus. PV thrombosis should be considered when refractory lung opacities are encountered during VA-ECMO and necessitates early intervention.


Impact of Using Blood Warmer During Continuous Kidney Replacement Therapy in Patients With Acute Kidney Injury.
We investigated the impact of blood warmer use on hypotensive episodes in patients with acute kidney injury (AKI) receiving continuous kidney replacement therapy (CKRT). We included patients with AKI undergoing CKRT between January 1, 2012, and January 1, 2021, at a tertiary academic hospital. Hypotensive episodes were defined as mean arterial pressure (MAP) <60 mm Hg or a decrease in MAP by ≥10 mm Hg, systolic blood pressure (SBP) < 90 mm Hg or a decrease in SBP by ≥20 mm Hg, or increased vasopressor requirement. These were analyzed by Poisson regression with repeated-measures analysis of variance using generalized estimation equation. There were 669 patients with AKI that required CKRT. Use of blood warmer on first day of CKRT was in 324 (48%) patients. Incidence rate ratio of hypotensive episodes during the first 24-h of CKRT in patients where a blood warmer was used was 1.06 (95% confidence interval [CI]: 0.98-1.13) compared to those where blood warmer was not used. This did not change in adjusted model. Overall, the within-subject effect of temperature on hypotensive episodes showed that higher temperature was associated with fewer episodes (0.94, 95% CI: 0.9-0.99 per 10 degrees increase, P = .007). Blood rewarming was not associated with hypotensive episodes during CKRT.


Clinical recognition of early schizophrenic decompensation.
The early signs and symptoms of schizophrenic decompensation are subtle and variegated. Today's community patient often presents with vague complaints of brief duration making it imperative that today's diagnostician be able to recognize and appropriately treat early psychopathology. This paper collates a number of observations of developing psychotic phenomena -- self reports, clinical studies and controlled experiments -- and provides a useful format for organizing these complex and changing behaviors. Data are presented and discussed using our clinical schema for detailing the natural progression of developing psychotic phenomena into four distinct stages. Efficacy of early recognition and treatment in aborting or diminishing a major psychotic episode is discussed. The advantages of recognizing the early signs of psychotic decompensation are apparent. First, with adequate intervention and treatment, the overt psychotic state may be attenuated. Although the feasibility of reducing the incidence of schizophrenia through intervention in "high risk" groups, or those experiencing insidious symptoms remain speculative (further investigation in this area is urgently needed), nonetheless, early diagnosis and comprehensive rehabilitative care significantly improves social and occupational adjustment. A second advantage accrues from early diagnosis. It enables patient and family to better cope with the illness. We have previously outlined a schema detailing the natural progression of developing psychotic phenomena into four distinct stages. The phenomena, when identified, can be seen as a continuum. However, many clinicians fail to recognize the earlier phases and typically the diagnosis of psychosis is made relatively late at what we call stage three of the four stages we described.


Effects of neurobehavioral assessment on feeding and weight gain in preterm neonates.
Neonatal intensive care unit personnel and parents often are concerned that developmental assessment will tire preterm neonates and impair their feeding ability and subsequent weight gain. Therefore, the amount of fluid consumed by 108 preterm neonates (<or=36.5 wk gestational age) was compared before and after administration of the Neurobehavioral Assessment of the Preterm Infant (NAPI). In addition, the weight gain of 35 preterm neonates who were administered the NAPI was compared with that of a matched control group of 35 preterm neonates who were not administered the NAPI. There were no differences in the amount of fluid consumed before and after NAPI administration, and there were no differences in weight gain between neonates who were and were not administered the NAPI. The effects of NAPI administration did not differ as a function of gestational age group. Therefore, the NAPI can be administered safely to preterm neonates without affecting feeding performance or weight gain.


Investigating age-related differences in responses to screening items for internalising disorders in three national surveys.
Epidemiological studies typically report lower prevalence of mental disorders among older adults relative to middle-aged and young adults. A possible explanation is that age-related bias in the screening items of diagnostic instruments leads to older adults being differentially screened out of the full assessment. This study investigated potential age-related bias in screening items for internalising disorders in three epidemiological surveys. Measurement invariance was estimated for the internalising disorder screening items in the 2007 and 1997 Australian National Survey of Mental Health and Wellbeing, and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions. These surveys assessed mental disorders using the Composite International Diagnostic Interview (CIDI) and the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version (AUDADIS-IV). A series of multi-group confirmatory factor analyses (CFA) were performed for each survey across older (65-85 years), middle (35-64 years) and young (16-34 years) adults. Differences between successive CFA models for each survey were negligible, indicating measurement invariance across age groups for the CIDI and AUDADIS-IV screening items. The number of items and symptoms representing internalising pathology differed between surveys. The samples excluded people in aged-care institutions. While findings do not rule out that other measurement errors may be present (e.g., age-related bias in the remaining items), these results support the validity of the screening items in the CIDI and AUDADIS-IV. Low prevalence estimates of internalising disorders in older adults are unlikely attributable to differences in response patterns to screening items.


Detection of quantitative trait loci for teat number and female reproductive traits in Meishan × Large White F2 pigs.
A quantitative trait locus (QTL) analysis of female reproductive data from a three-generation experimental cross between Meishan (MS) and Large White (LW) pig breeds is presented. Six F1 boars and 23 F1 sows, progeny of six LW boars and six MS sows, produced 573 F2 females and 530 F2 males. Six traits, i.e. teat number (TN), age at puberty (AP), ovulation rate (OR), weight at mating (WTM), number of viable embryos (NVE) and embryo survival (ES) at 30 days of gestation were analysed. Animals were genotyped for a total of 137 markers covering the entire porcine genome. Analyses were carried out based on interval mapping methods, using a line-cross (LC) regression and a half-full sib (HFS) maximum likelihood test. Genome-wide (GW) highly significant (P < 0.001) QTL were detected for WTM on SSC 7 and for AP on SSC 13. They explained, respectively, 14.5% and 8.9% of the trait phenotypic variance. Other GW significant (P < 0.05) QTL were detected for TN on SSC 3, 7, 8, 16 and 17, for OR on SSC 4 and 5, and for ES on SSC 9. Two additional chromosome-wide significant (P < 0.05) QTL were detected for TN, three for WTM, four for AP, three for OR, three for NVE and two for ES. With the exception of the two above-mentioned loci, the QTL explained from 1.2% to 4.6% of trait phenotypic variance. QTL alleles were in most cases not fixed in the grand-parental populations and Meishan alleles were not systematically associated with higher reproductive performance.


Disruption of Macrodomain Protein SCO6735 Increases Antibiotic Production in Streptomyces coelicolor.
ADP-ribosylation is a post-translational modification that can alter the physical and chemical properties of target proteins and that controls many important cellular processes. Macrodomains are evolutionarily conserved structural domains that bind ADP-ribose derivatives and are found in proteins with diverse cellular functions. Some proteins from the macrodomain family can hydrolyze ADP-ribosylated substrates and therefore reverse this post-translational modification. Bacteria and Streptomyces, in particular, are known to utilize protein ADP-ribosylation, yet very little is known about their enzymes that synthesize and remove this modification. We have determined the crystal structure and characterized, both biochemically and functionally, the macrodomain protein SCO6735 from Streptomyces coelicolor This protein is a member of an uncharacterized subfamily of macrodomain proteins. Its crystal structure revealed a highly conserved macrodomain fold. We showed that SCO6735 possesses the ability to hydrolyze PARP-dependent protein ADP-ribosylation. Furthermore, we showed that expression of this protein is induced upon DNA damage and that deletion of this protein in S. coelicolor increases antibiotic production. Our results provide the first insights into the molecular basis of its action and impact on Streptomyces metabolism.